quinoxalinone–benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties

Accepted Manuscript Friedländer reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties Vakhid A. Mamedov , Saniya F. Kadyrova , Nataliya A. Zhukova , Venera R. Galimullina , Fedor M. Polyancev , Shamil K. Latypov PII:

S0040-4020(14)00853-9

DOI:

10.1016/j.tet.2014.06.007

Reference:

TET 25672

To appear in:

Tetrahedron

Received Date: 18 April 2014 Revised Date:

19 May 2014

Accepted Date: 2 June 2014

Please cite this article as: Mamedov VA, Kadyrova SF, Zhukova NA, Galimullina VR, Polyancev FM, Latypov SK, Friedländer reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties, Tetrahedron (2014), doi: 10.1016/ j.tet.2014.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Dedicated to the 60th anniversary of Professor Igor Sergeyevich Antipin

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Friedländer reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties Vakhid A. Mamedov,* Saniya F. Kadyrova, Nataliya A. Zhukova, Venera R. Galimullina, Fedor M. Polyancev, Shamil K. Latypov

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A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center of Russian Academy of Sciences, Arbuzov str. 8, 420088 Kazan, Russian Federation [email protected]

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ABSTRACT: A protocol has been developed for the efficient synthesis of structurally diverse 4(benzimidazol-2-yl)quinolines via reactions of 3-(2-aminophenyl)quinoxalin-2(1Н)-ones and ketones, including acetone, acetophenones, 1,3-pentanedione and ethyl acetoacetate. The selective formation of the very different quinoline derivatives depends on the structure of ketones. The key steps are proposed to involve the new acid-catalyzed rearrangement of the spiro-quinoxalinone derivatives formed in situ from the reaction of 3-(2-aminophenyl)quinoxalin-2(1Н)-ones and ketones under the modified Friedländer reaction. This transformation would facilitate the synthesis by short reaction times, large-scale synthesis, simple and prompt isolation of the products, which are the main advantages of this procedure. Keywords: Synthetic methods; Tandem reactions; 3-(2-Aminophenyl)quinoxalin-2(1Н)-one; Quinoxalinone-benzimidazole rearrangement; 4-(Benzimidazol-2-yl)quinolines

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1. Introduction

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Quinolines and their derivatives are very important compounds1 that exhibit a broad range of biological activities such as anti-malarial,2 anti-inflammatory,3 anti-bacterial,4 anti-asthmatic,5 and anti-hypertensive.6 In addition to medicinal applications, quinolines have been employed in the study of bioorganic and bioorganometallic processes.7 Quinolines are also known for their formation of conjugated molecules and polymers that combine enhanced electronic, optoelectronic, or nonlinear optical properties with excellent mechanical properties.8 Accordingly, numerous methods for the assembly of the quinoline ring system have been developed, the most recognized being the Skraup,9 Doebner-von Miller,9,10 Friedländer,8a,11 Pfitzinger,1 Conrad-Limpach-Knorr12 and Combes13 protocols, all of which are likely to involve an initial and intermolecular reaction of an aniline with a carbonyl-containing compound or a precursor thereof. However, the principal shortcomings of these conventionally named routes involve the impossibility to use them for synthesizing the quinoline derivatives with various types of the heterocyclic ring system directly bonded to a quinoline core in their structure. The Friedländer annulation8a,11 appears to be still the best of the simplest method for preparing quinolines and polypyridyl bridging ligands.14 In its original form, the Friedländer reaction is the

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reaction between an aromatic o-aminoaldehyde and an aldehyde or ketone bearing α-methylene functionality. Since its initial discovery, the Friedländer reaction has been extended to a wide range of substrates, including aromatic o-aminoketones and hetero-analogues of o-aminoaromatic aldehydes such as 2-aminonicotinaldehyde.11e We have previously shown15a-n that due to the imine function between the C3 and N4 atoms of the pyrazine ring the derivatives of quinoxalin-2(1H)-one Q (X = CH, R2 = H, Me, Cl and etc.) and their aza-analogues (X = N, R2 = H),15f depend on the nature of substituents R1 at the position 3. They behave like iminoanalogues of α-chloroketones (in the case of R1 = CH(Cl)Ph),15a αaminoketones (in the case of R1 = CH(NH2)Ph),15b α-azidoketones (in the case of R1 = CH(N3)(СH2)nPh),15c α-diketones (in the case of R1 = C(O)Ar, C(O)Alk),15d-i usual ketones (in the case of R1 = Me)15jl and β-diketones (in the case of R1 = CH2(CO)Ar),15k,l and are subjected to the novel acid-catalyzed rearrangement in the reactions with various N-nucleophiles. In this case they result in 2-heteroarylsubstituted benzimidazole derivatives (Chart 1).

Chart 1. Common presentation of the rearrangement for the synthesis of 2-heteroarylbenzimidazoles.

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The process proceeds through the heteroarylspiroquinoxalin-3′(4′Н)-ones sQ, the formation of which occurs as one of the classic reactions of the synthesis of heterocycles. In the cases of the syntheses of spiro[quinoxalin-2,2′-quinoxalin]-3′(4′Н)-ones sQI, spiro[pyrazin-2,2′-quinoxalin]3′(4′Н)-ones sQII and spiro[imidazolin-5,2′-quinoxalin]-3′(4′Н)-ones sQIII the derivatives of quinoxalin-2(1Н)-one with the R1 = C(O)Ar and C(O)Alk were the heteroanalogues of α-diketones in the Hinsberg-Körner16 and Debus-Radziszewski-Japp17 reactions. In the cases of the syntheses of spiro[indolizin-2,2′-quinoxalin]-3′(4′Н)-ones sQIV the derivatives of quinoxalin-2(1Н)-one with R1 = CH(Cl)Ar) acted as the heteroanalogues of α-chloroketones in the Chichibabin18 reaction. In the cases of the syntheses of spiro[pyrazolin-5,2′-quinoxalin]-3′(4′Н)-ones sQV and spiro[pirrollin-3,2′quinoxalin]-3′(4′Н)-ones sQVI the derivatives of quinoxalin-2(1Н)-one with R1 = CH2C(O)Ar and R1 = CH(NH2)Ar served as heteroanalogues of β-diketones and α-aminoketones in the Knorr19 reactions. The second stage of the process involves a fundamentally new acid-catalyzed rearrangement15n,o of heteroarylspiroquinoxalin-3′(4′Н)-ones sQ(I-VI) in the benzimidazole derivatives BI(I-VI) (Chart 1). We have also shown that 3-(β-2-nitrostyryl)quinoxalin-2-(1Н)-ones 3, are easily prepared from 3-methylquinoxalin-2(1Н)-one 1 and o-nitrobenzaldehyde 2, and when exposed to sodium dithionite are converted into 2-(benzimidazol-2-yl)quinolines 5. The process occurs under reduction conditions in a cascade of the modified Friedländer reaction and the new acid-catalyzed rearrangement through the intermediately formed products – 3-(β-2-aminostyryl)quinoxalin-2(1H)-ones 415j (Scheme 1).

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Py +

R1

N R2 1

O

4

N

3 2

H O

R1, R2 = H, Alk

R1

NO2 2

Ac2O, R1 reflux

R3 = H, Cl

NO2 N1 O R2 3 1. Na2S2O4 2. EtOH, H2O, reflux 3. HCl, H2O, reflux 4. Na2CO3

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R1

R3

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R

N

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2' 2

N 1' R2

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5

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N R2 4

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Scheme 1. The cascade of the modified Friedländer reaction and the new acid-catalyzed rearrangement for the synthesis of 2-(benzimidazol-2-yl)quinolines 5.

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2. Results and discussion

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As can be seen from the structure of the compound 5 (Scheme 1), the o-aminostyryle substituent and the C2, C3 atoms of the amide and imine fragments of the pyrazine ring of quinoxalin-2(1Н)one 4 are involved in the construction of two new heterocyclic systems. In this case the formation of the pyridine ring of the quinoline system occurs as the result of the proceeding new rearrangement.15n,o As can be seen from the scheme 1, the atoms C2 and C3 of the quinoxalin-2(1Н)one system become the atoms C2′ and C2 of the benzimidazole and quinoline systems of the compounds 5 respectively.

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Synthesis of 4-(benzimidazol-2-yl)quinolines. Following the logics described in our previous papers15a-l and specifically in the paper15j on the new rearrangement of the quinoxalin-2(1H)-one derivatives, we assumed that in the latter reaction 3-(2-aminophenyl)quinoxaline-2(1H)-one derivatives 6 can be used instead of 3-methylquinoxalin-2(1Н)-one 1 and o-nitrobenzaldehyde 2 derivatives as the heteroanalogues of o-aminoaromatic aldehydes and ketones bearing an active αmethylene functionality. The ketones can be condensed with compounds 6 capable of providing a two-carbon fragment in the construction of the quinoline system, which makes it possible to synthesize the 4-(benzimidazol-2-yl)quinolines 8,10,12 isomeric to the 2-(benzimidazol-2 yl)quinolines 5. Herein we report the results of the above assumption proposed. To optimize the process, we initially carried out the reaction of 3-(2-aminophenyl)quinoxalin2(1Н)-one 6а with acetone in acetic acid with various ratios of reagents and different reaction times. Regardless of the molar ratio of the reagents (1:32, 1:16, 1:8, 1:4; 1a:acetone) and the reaction time (6, 4 or 2 hours) the reaction proceeded in the same way with the formation of the ~85% yield of the crude product, which contains ~90% of the quinoline 8a and ~10% of the qunoxaline 7a derivatives on the basis of the 1H NMR spectrum (Scheme 2).

ACCEPTED MANUSCRIPT 4 R1 Acetone, AcOH, 55 oC, 2 h

N N O H 6 a,b

NH2

-2H2O

R1 = H (a), F (b)

R1

N

NH

R1

N N H 7a (5%)a 7b (1%)a

+

N

N 8a (75%)a 8b (62%)a yields

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a Isolated

Scheme 2. The reaction of 3-(2-aminophenyl)quinoxaline-2(1H)-ones derivatives 6а,b with acetone.

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The first product is formed as a result of the rearrangement, whereas the second product is the result of the intramolecular cyclocondensation of the quinoxaline derivative 6а. The optimal temperature conditions for this reaction approximately correspond to the boiling temperature of acetone (55 oC). This temperature condition appears to be optimal for the reaction of 3-(2aminophenyl)quinoxalin-2(1Н)-one 6а with acetophenone 9а and 4-bromoacetophenone 9b. As can be seen from the table 1 the optimal ratio in these cases is 1:2 (6a:9а and 6a:9b) when the reactions are carried out for 5 h (entries 4, 9), because when the ratio of the reagents was 1:1 there occurred the increase in the yield of compound 7a and the decrease in the overall yield of the mixture of compounds 7a and 10a,b (entries 1, 6, 7). When the ratio of the starting compounds was 1:10 or 1:5 (Table 1, entries 5, 10) whereas in spite of the satisfactory yield of the desired product, there appeared some difficulties in the purification of the final products.

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Table 1 Optimization of the reaction conditions

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Entry Substrate Ratio of Temperature Time Ratio of o (h) productsa reagents ( C) 9 6a:9 1 1:1 55 2 7a + 10a (20:80) 9a 2 1:2 reflux 2 7a + 10a (15:85) 9a 3 1:2 55 2 7a + 10a (12:88) 9a 4 1:2 55 5 7a + 10a (15:85) 9a 5 1:10 55 5 7a + 10a (15:85) 9a 6 1:1 55 2 7a + 10b (8:92) 9b 7 1:1 55 6 7a + 10b (8:92) 9b 8 1:2 55 2 7a + 10b (5:95) 9b 9 1:2 55 5 7a + 10b (4:96) 9b 10 1:5 55 5 7a + 10b (4:96) 9b a Estimated on the basis of 1H NMR spectra of the reaction mixture. b Yields based on isolated mixture of products.

Total yield (%)b 7a + 10 54 52 75 95 80 40 46 79 86 72

To explore the scope and limitations of the reaction, the procedure was extended to 3-(2amino-5-fluorophenyl)quinoxaline-2(1H)-one 6b and various acetophenones 9a-f. As indicated in

ACCEPTED MANUSCRIPT 5 Table 2, the reactions proceeded very efficiently, and led to the formation of the corresponding 4(benzimidazol-2-yl)quinolines 10a-l as major and 6H-indolo[2,3-b]quinoxaline 7a,b as minor products.

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Table 2 Reaction of 3-(2-aminophenyl)-quinoxalin-2(1Н)-ones 6а,b with acetophenones 9a-f

R1

R2

Products

1 6a 9a 2 6a 9b 3 6a 9c 4 6a 9d 5 6a 9e 6 6a 9f 7 6b 9a 8 6b 9b 9 6b 9c 10 6b 9d 11 6b 9e 12 6b 9f a Isolated yields.

H H H H H H F F F F F F

H 4-Br 3-Br 2-Br 4-Cl 2-Cl H 4-Br 3-Br 2-Br 4-Cl 2-Cl

7а + 10a 7а + 10b 7а + 10c 7а + 10d 7а + 10e 7а + 10f 7b + 10g 7b + 10h 7b + 10i 7b + 10j 7b + 10k 7b + 10l

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Yield (%)a 7 10 6 80 4 76 4 78 4 73 4 77 4 71 1 68 1 66 1 64 1 61 2 65 1 62

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Entry Substrate

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The structure of compounds 7 and 8 can be almost “directly” established by various 1D/2D NMR correlation methods.20 For instance, at first the NH proton (Fig. 1a) of the indole fragment was unequivocally assigned for the 9-fluoro-6H-indolo[2,3-b]quinoxaline 7b from the 1H-15N HSQC spectra (see SI). Then, the NOE between the NH and H7 proton allows to assign the end nuclei of one spin-system. The next excitation of the H7 (or 8, 10) makes it possible to reveal all the protons belonging to the system in the 1D TOCSY spectra. The 1H spectra with the decoupling from the 19F (see SI) and 2D 19F-1H HETCOR spectra additionally support this assignment. After that, from the 1 H-13C HSQC and 1H-15N/13C HMBC correlations (e.g. in Fig. 1 these are shown colored respectively) the structure of indolo[2,3-b]quinoxaline 7b up to N5 and C10b can be revealed (see SI for details). In its turn, the 1D TOCSY experiments allow discriminating all the protons of the quinoxaline fragment. Then all the nuclei up to N5 and N11 can be established from the 1H-13C and 1 H-15N HSQC/HMBC connectivity. Thus, the whole structure of 7b is unequivocally established. Finally, the good correlations of the calculated21 versus experimental 13C CSs additionally support this structural hypothesis (see SI). Theoretical 15N CSs for the compound 7b is also in good agreement with experimental data (see SI).

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Fig. 1. 1H NMR spectra (DMSO-d6, 303 K) of 9-fluoro-6H-indolo[2,3-b]quinoxaline 7b with structure and principal NMR correlations.

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Based on the known chemistry of amines,22 enolizable ketones,23 enamines,24 quinoxalinones,25 and the previous reports15a-n a plausible mechanism for the reaction of the formation of 4(benzimidazol-2-yl)quinolines 10 has been proposed (Scheme 3). The reaction starts with the condensation of ketones with 3-(2-aminophenyl)quinoxalin-2(1Н)-one 6a to form imine A, which transforms to intermediate B by tautomerization. Subsequently intermediate B is easily cyclized through the intramolecular nucleophilic addition to give the spiro-quinoxaline derivative C. The rearrangement of the spiro-quinoxalinone C is then assumed to occur according to Scheme 3, which proceeds by cascade reactions involving: a) the ring-opening with the cleavage of the C3-N4 bond in the spiro-compound D with the intermediate formation of the quinoline derivative E, b) the intramolecular nucleophilic attack by the amino group on the carbonyl group with the intermediate formation of the hydroxy-derivative F, and с) the elimination of water leading to the formation of the final product 10. All the stages of the reaction include acid-catalyzed processes.

Scheme 3. A plausible mechanism for the formation of 4-(benzimidazol-2-yl)quinolines 10. An additional synthesis with deuterium-labeled reagents was also carried out to obtain independent support to the proposed reaction mechanism. Thus, in the same conditions the reaction of 6a with a readily available deuteriated acetone instead of a normal one leads to the target product 8a′′ in which the C2-C3 part of the quinoline skeleton is supplied by this isotopically labeled reagent. The graphic evidence of the above can be obtained from the comparison of the 13C and 1H NMR

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spectra of 8a versus 8a′′ (Fig. 2). As can be observed the C2(CH3) and C3 carbon signals in the 13C spectra are modified both due to the spin-spin couplings with quadrupole deuterium (in different isotopomers differently) and due to the deuterium-induced isotope effects. The indications of this effect are also observed on the 1H spectra: the C3(H)-C2(CH3) signals are spectacularly changed.

Fig. 2. 1H (a, b) and 13C (c, d) NMR spectra of 2-methyl-4-(benzimidazol-2-yl)quinoline 8a (a, c) and its deuterated analogue 8a′′ (b, d) in DMSO-d6 at 303 K.

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With this result in hand, we went on to study the scope of the methodology, first with respect to the 1,3-diacetylbenzene 11 (Scheme 4). As can be seen, this chemistry is not limited to mono- and disubstituted systems, and a compound with two acetyl fragments is an acceptable substrate as well.

Scheme 4. Reaction of 3-(2-aminophenyl)quinoxalin-2(1Н)-ones 6а,b with 1,3-diacetylbenzene 11. Synthesis of benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolines. The scope of this chemistry was also investigated with respect to the compounds with two same and different carbonyl groups in their compositions. The 3-(2-aminophenyl)quinoxalin-2(1Н)-ones 6а,b were allowed to react with 1,3-pentanedione 13 and ethyl acetoacetate 14, in AcOH (Scheme 5). Again, the isolated yields of the products are all high, but there occurs the formation of benzimidazolo[2,1-a]pyrrolo[3,4-

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c]quinoline derivatives 17а,b and 18а,b instead of the expected 4-(benzimidazol-2-yl)quinolines 15а,b and 16а,b correspondingly, with acetyl and ester groups at position 3 of the quinoline system. The formation of pentacyclic condensed systems 17а,b and 18а,b can be due to the intramolecular nucleophilic addition of the N atom of the benzimidazole system to the carbonyl group of the substituents at position 3 of the quinoline system of compounds 15а,b and 16а,b. In this case compounds 15а,b with the acetyl group provided the formation of alcohols 17а,b, while compounds 16а,b with the ester group provided the formation of ketones 18а,b.

Scheme 5. Reaction of 3-(2-aminophenyl)quinoxalin-2(1Н)-ones 6а,b with acetylacetone 13 and ethyl acetoacetate 14.

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The structures of the compounds 17 and 18 were unequivocally established by various correlation NMR experiments (e.g. Fig. 3 for 17b). Firstly, the 1H-13C HMBC connectivity from the OH allow to exactly establish the C7(CH3) and C8(CH3) signals. After that, starting from H5 the C7(CH3)/H5 NOE and COSY correlations make it possible for us to reveal the spin system of the benzimidazole moiety. In a similar way the quinoxaline fragment was established from the 19F-1H HETCOR and 1H-1H-COSY connectivity. Finally, the net of 1H-13C HSQC and 1H-13C/15N HMBC correlations allows to link both fragments into one whole. The good agreement (R2 = 0.998) between the experimental and calculated 13C chemical shifts additionally supports this structural hypothesis (see SI).

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Fig. 3. 1H (a) and 1H{19F} (b) NMR spectra (CDCl3, 303 K) of 12-fluoro-7,8-dimethyl-7Hbenzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-ole 17b with the structure and the principal NMR correlations. 3. Conclusion

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To summarize, we have developed an important reaction of 3-(2-aminophenyl)-quinoxalin2(1Н)-ones and various ketones and dicarbonyl compounds, providing different types of products depending on the nature of the carbonyl component. Mechanisms for the formation of the resulting 4-(benzimidazol-2-yl)quinoline and benzimidazolo[2,1-a]pyrrolo[3,4-c]quinoline derivatives have been proposed to involve the new acid-catalyzed rearrangement of the spiro-quinoxalinones formed in situ from the reaction of 3-(2-aminophenyl)quinoxalin-2(1Н)-ones and ketones under the modified Friedländer reaction. The mild reaction conditions offer the potential for the employing of this method in the synthesis of complex molecules. It is anticipated that this methodology will have versatile applications in the practical syntheses of biologically important pharmaceutical molecules with benzimidazole and quinoline moieties. Further extension of the reaction scope and the synthetic applications of this methodology are in progress at our laboratory. 4. Experimental section 4.1. General methods Melting points were determined on a Boetius hot-stage apparatus. Infrared (IR) spectra were recorded on a Bruker Vector-22 FT-IR spectrometer. ESI MS experiments were performed on an

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4.2. Synthesis of starting materials

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AmaZon X (Bruker Daltonics) ion-trap mass spectrometer. The spectra reported here were obtained by infusing the solutions with a syringe pump at a flow rate of 0.2 mL/min. For the infusion experiment, the optimized ion source values were as follows: spray voltage, 4.5 kV; nebulizer, 8 psi; nitrogen dry gas, 5L/min; heated capillary, 220 °C. The navigator software (DataAnalysis 4.0 for Bruker Daltonics) was used to acquire data in this study. MALDI-TOF MS measurements were performed with an Ultraflex III TOF/TOF (Bruker Daltonics) mass spectrometer equipped with a Nd:YAG laser. The high resolution mass spectra were measured in the positive mode. The instrument was calibrated prior to each measurement with an external standard PEG – 400 (polyethylene glycol 400) and PEG - 1000 in the required measurement range. MS data were processed using the software FlexAnalysis 3.0 and an isotope pattern calculator from Bruker Daltonics. Column chromatography was performed on silica gel (Kieselgel, 0.060-0.200 mm, 40 Å) with CHCl3, i-PrOH and a mixture of hexane/i-PrOH as eluents. The determination of the volume of Rf was performed on silica gel plates (Sorbfil, Imid LTD) with an UV lamp and CHCl3/nC6H14/MeOH (6:3:1) as an eluent. All NMR experiments were performed with a Bruker AVANCE600 (400 and 600 MHz for 1H NMR, 150 and 100 MHz for 13C NMR, 60 MHz for 15N NMR) and AVANCE-400 (376 MHz for 19F NMR) spectrometers equipped with a 5 mm diameter gradient inverse broad band probehead and a pulsed gradient unit capable of producing magnetic field pulse gradients in the z-direction of 53.5 G·cm-1. NMR experiments were carried out using standard Bruker pulse programs. DPFGNOE,26 DPFGROE and TOCSY spectra were obtained using a Hermite-shaped pulse for selective excitation. The quantum chemical calculations were performed using a Gaussian 98w software package.27 Full geometry optimizations have been carried out within the framework of DFT (B3LYP) method using 6-31G(d) basis sets. Chemical shifts (CSs) were calculated by the GIAO method at the same level of theory. All data were referred to as TMS (1H and 13C) and NH3 (15N) chemical shifts, which were calculated under the same conditions.

4.2.1. 3-(2-Aminophenyl)quinoxalin-2(1Н)-one 6а was prepared according to the procedure described in literature in a 80% yield.28

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4.2.2. 3-(2-Amino-5-fluorophenyl)quinoxaline-2(1H)-one (6b). 5 4a 6 7 8 8a

F 5 6

4

N

3

N H1

1 2

O

4

Ar

3 2

NH2

6b

5-Fluoroisatin (5.0 g, 30 mmol) was dissolved in an aqueous solution of potassium hydroxide (aq., 8% 50 mL), the o-phenylenediamine (3.27 g, 30 mmol) was added and the mixture was heated at 60 o C for 3 h (or until a clear solution was obtained). The pH was then adjusted to ca. 5.5 by adding acetic acid. After 2 days the resulting precipitate was filtered off and dried on air at ambient temperature to yield 6.71 g (88%) of compound 6b. The recrystallization from i-PrOH was accomplished to afford 6.02 g (79%) of analytically pure 6b as yellow crystals, m.p. 264-265 оС (lit.29 262-263 oC); [Found: C, 65.73; H, 3.87; N, 16.26. C14H10FN3O requires C, 65.88; H, 3.95; N, 16.46%]; νmax(KBr) 3380, 2852, 1659, 1574, 1258, 1484, 1432, 1169, 894, 757, 597 cm-1; δH (400 MHz, DMSO-d6) 6.48 (2 H, br s, NH2), 6.81 (1 H, dd, 3JHH 9.0 Hz, 4JHF 5.3 Hz, H3 Ar), 7.04 (1 H, ddd, 3JHH 9.0 Hz, 3JHF 7.9 Hz, 4JHH 3.1 Hz, H4 Ar), 7.31 (1 H, ddd, 3JHH 8.7, 7.5 Hz, 4JHH 1.4 Hz, H6), 7.32 (1 H, d, 3JHH 7.5 Hz, H8), 7.52 (1 H, ddd, 3JHH 7.9, 7.5 Hz, 4JHH 1.4 Hz, H7), 7.81 (1 H, dd, 3 JHH 8.7 Hz, 4JHH 1.4 Hz, H5), 8.05 (1 H, dd, 3JHF 11.5 Hz, 4JHH 3.1 Hz H6 Ar), 12.53 (1 H, s, NH);

ACCEPTED MANUSCRIPT 11 δC (100 MHz, DMSO-d6) 115.0 (C8), 116.6 (d, 2JCF 24.5 Hz, C6 Ar), 117.0 (d, 3JCF 7.7 Hz, C1 Ar), 117.2 (d, 3JCF 7.7 Hz, C3 Ar), 118.1 (d, 2JCF 24.5 Hz, C4 Ar), 123.4 (C6), 128.1 (C5), 130.0 (C7), 131.1 (C4a), 131.5 (C8a), 145.6 (C2 Ar), 148.5 (d, 1JCF 228.6 Hz, C5 Ar), 154.4 (d, 3JHH 2.3 Hz, C3), 154.5 (C2); δN (60 MHz, DMSO-d6) 63.9 (NH2), 81.4 (N), 153.2 (NH); δF (376 MHz, DMSOd6) –130.1 (F).

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4.3. Reaction of 3-(2-aminophenyl)quinoxalin-2(1H)-ones 6a,b with acetone

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4.3.1.1. 2-Methyl-4-(benzimidazol-2-yl)quinoline (8a).

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4.3.1. 2-Methyl-4-(benzimidazol-2-yl)quinoline (8a) and 6H-indolo[2,3-b]quinoxaline (7a). AcOH (5 mL) was added to a suspension of 3-(2-aminophenyl)quinoxalin-2(1H)-one 6a (200 mg, 0.84 mmol) in acetone (2 mL) and the reaction mixture was stirred for 2 h at 55 оС. The solvent was evaporated and ether (5 mL) was added to the residue. The resulting precipitate was filtered off and dried on air to yield a 14.4 mg (8%) compound 7a. Purification by column chromatography with hexane/i-PrOH (98:2) as eluent to afford analytically pure 9.20 mg (5%) 7a. The ether filtrate was concentrated and the residue was purified by column chromatography (i-PrOH) to give analytically pure 163 mg (75%) 8a.

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Pink crystals, m.p. 225-227 oC; [Found: C, 78.87; H, 4.94; N, 16.01. C17H13N3 requires C, 78.74; H, 5.05; N, 16.20%]; Rf 0.16; νmax(KBr) 3253, 3067, 2915, 2785, 2752, 1606, 1434, 1393, 1276, 768, 738 cm-1; δH (400 MHz, DMSO-d6) 2.77 (3 H, s, Me), 7.24-7.36 (2 H, m, H5 + H6 BI), 7.60-7.66 (1 H, m, H4 BI), 7.66 (1 H, ddd, 3JHH 8.3, 6.9 Hz, 4JHH 1.2 Hz, H6 Q), 7.80 (1 H, ddd, 3JHH 8.3, 6.9 Hz, 4 JHH 1.5 Hz, H7 Q), 7.78-7.84 (1 H, m, H7 BI), 7.92 (1 H, s, H3 Q), 8.02 (1 H, br d, 3JHH 8.2 Hz, H8 Q), 9.23 (1 H, br d, 3JHH 8.5 Hz, H5 Q), 13.28 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 24.8 (Me), 111.7 (C7 BI), 119.5 (C4 BI), 121.6 (C3 Q), 122.0 (C5 BI), 123.1 (C4a Q), 123.5 (C6 BI), 126.4 (C6 Q), 126.5 (C5 Q), 128.7 (C8 Q), 129.6 (C7 Q), 134.3 (C7a BI), 134.7 (C4 Q), 143.8 (C3a BI), 148.3 (C8a Q), 149.1 (C2 BI), 158.2 (C2 Q); δN (60 MHz, DMSO-d6) 311.6 (N1 Q); MS (ESI): m/z 260 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 260.1166. C17H14N3 requires 260.1182. 4.3.1.2. 6H-Indolo[2,3-b]quinoxaline (7a).

White crystals, m.p. 299-300 oC (lit.30 294-295 oC); [Found: C, 76.81; H, 4.05; N, 19. C14H9N3 requires C, 76.70; H, 4.14; N, 19.17%]; Rf 0.58; δH (600 MHz, DMSO-d6) 7.35 (1 H, ddd, 3JHH 7.5, 7.5 Hz, 4JHH 0.9 Hz, H9), 7.58 (1 H, d, 3JHH 8.1 Hz, H7), 7.70 (1 H, ddd, 3JHH 7.7, 7.6 Hz, 4JHH 1.3 Hz, H8), 7.72 (1 H, ddd, 3JHH 7.7, 7.5 Hz, 4JHH 1.5 Hz, H2), 7.79 (1 H, ddd, 3JHH 8.6 Hz, 3JHH 7.7 Hz, 4 JHH 1.5 Hz, H3), 8.06 (1 H, dd, 3JHH 8.6 Hz, 4JHH 1.5 Hz, H4), 8.24 (1 H, dd, 3JHH 8.6 Hz, 4JHH 1.3 Hz, H1), 8.34 (1 H, d, 3JHH 7.5 Hz, H10), 12.00 (1 H, s, H6); δC (100 MHz, DMSO-d6) 111.9 (C7), 118.9 (C10a), 120.6 (C9), 122.2 (C10), 125.9 (C2), 127.4 (C4), 128.7 (C3), 130.0 (C1), 131.2 (C8),

ACCEPTED MANUSCRIPT 12 138.5 (C11a), 139.7 (C10b), 140.1 (C4a), 143.9 (C6a), 145.8 (C5a); δN (60 MHz, DMSO-d6) 116.2 (N6), 260.0 (N5), 306.9 (N11); HRMS (MALDI): m/z [M + H]+, found 220.0863. C14H10N3 requires 220.0869,

N

NH

F N

8b

SC

4.3.2.1. 2-Methyl-4-(benzimidazol-2-yl)-6-fluoroquinoline (8b).

RI PT

4.3.2. 2-Methyl-4-(benzimidazol-2-yl)-6-fluoroquinoline (8b) and 9-fluoro-6H-indolo[2,3b]quinoxaline (7b). Сompounds 7b, 8b were synthesized from 3-(2-amino-5fluorophenyl)quinoxalin-2(1H)-one 6b (200 mg, 0.78 mmol) and acetone (2 mL) according to the procedure described above, with the only difference that with the purification of quinoline 8b by column chromatography on silica gel the mixture of hexane/i-PrOH (90:10) as eluent was used.

TE D

M AN U

Yield: 134 mg (62%), pink crystals, m.p. 218-220 oC; [Found: C, 73.82; H, 4.47; N, 14.98. C17H12FN3 requires C, 73.63; H, 4.36; N, 15.15%]; Rf 0.55; νmax(KBr) 2923, 1624, 1604, 1505, 1446, 1419, 1364, 1221, 747 cm-1; δH (400 MHz, DMSO-d6) 2.76 (3 H, s, Me), 7.26-7.38 (2 H, m, H5 + H6 BI), 7.60-7.66 (1 H, m, H4 BI), 7.71 (1 H, ddd, 3JHH 9.3 Hz, 3JHF 8.6 Hz, 4JHH 3.0 Hz, H7 Q), 7.82-7.88 (1 H, m, H7 BI), 8.02 (1 H, s, H3 Q), 8.08 (1 H, dd, 3JHH 8.7 Hz, 3JHF 5.8 Hz, H8 Q), 9.22 (1 H, dd, 3JHF 11.3 Hz, 4JHH 2.9 Hz, H5 Q), 13.28 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 24.7 (Me), 110.3 (d, 2JCF 24.5 Hz, C5 Q), 111.7 (C7 BI), 119.5 (d, 2JCF 27.4 Hz, C7 Q), 119.6 (C4 BI), 122.0 (C3 Q), 122.2 (C5 BI), 123.6 (C4a Q), 123.7 (C6 BI), 131.5 (d, 3JCF 8.7 Hz, C8 Q), 133.8 (d, 4JCF 6.0 Hz, C4 Q), 134.2 (C7a BI), 143.8 (C3a BI), 145.7 (C8a Q), 148.8 (C2 BI), 157.8 (C2 Q), 160.0 (d, 1JCF 244.0 Hz, C6 Q); δN (60 MHz, DMSO-d6) 149.8 (N1 Q); MS (ESI): m/z 278 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 278.1098. C17H13FN3 requires 278.1088.

EP

4.3.2.2. 9-Fluoro-6H-indolo[2,3-b]quinoxaline (7b).

AC C

Yield: 1.85 mg (1%), light-yellow powder, m.p. 270-271 oC (lit.31 265 oC); [Found: C, 70.57; H, 3.54; N, 17. C14H8FN3 requires C, 70.88; H, 3.40; N, 17.71.%]; Rf 0.49; νmax(KBr) 1636, 1600, 1491, 1465, 1163, 1124, 756 cm-1; δH (600 MHz, DMSO-d6) 7.55 (1 H, ddd, 3JHH 8.8, 3JHF 8.7 Hz, 4 JHH 2.3 Hz, H8), 7.59 (1 H, dd, 3JHH 8.8 Hz, 4JHF 4.5 Hz, H7), 7.72 (1 H, dd, 3JHH 8.1, 7.1 Hz, H2), 7.81 (1 H, dd, 3JHH 8.1, 7.1 Hz, H3), 8.06 (1 H, d, 3JHH 8.6 Hz, H4), 8.12 (1 H, dd, 3JHF 8.4 Hz, 4JHH 2.2 Hz, H10), 8.23 (1 H, d, 3JHH 8.6 Hz, H1), 12.06 (1 H, s, H6); δC (150 MHz, DMSO-d6) 107.9 (d, 2 JCF 24.2 Hz, C10), 113.3 (d, 3JCF 8.4 Hz, C7), 118.9 (d, 2JCF 25.3 Hz, C8), 119.5 (d, 3JCF 9.1 Hz, C10a), 126.2 (C2), 127.5 (C4), 129.1 (C1), 129.2 (C3), 138.5 (C11a), 139.3 (d, 4JCF 3.3 Hz, C10b), 140.3 (C6a), 140.4 (C4a), 146.5 (C5a), 157.2 (d, 1JCF 236.8 Hz, C9); δF (376 MHz, DMSO-d6) – 122.0 (F9); δN (DMSO-d6, 60 MHz) 114.9 (N6), 261.6 (N5), 308.7 (N11); HRMS (MALDI): m/z [M + H]+, found 238.0776. C14H9FN3 requires 238.0775. 4.4. Reaction of 3-(2-aminophenyl)quinoxalin-2(1H)-ones 6a,b with acetophenones 9a-f

ACCEPTED MANUSCRIPT 13

M AN U

4.4.1.1. 2-Phenyl-4-(benzimidazol-2-yl)quinoline (10а).

SC

RI PT

4.4.1. Typical procedure for the synthesis of 2-aryl-4-(benzimidazol-2-yl)quinolines 10a-f. 3-(2Aminophenyl)quinoxalin-2(1H)-one 6a (200 mg, 0.84 mmol) and acetophenones 9а-f (2.36 mmol) in glacial AcOH (6 mL) were heated for 5 h at 55 оС. The solvent was evaporated and the residue was triturated with ether (5 mL). The resulting precipitate was filtered off and dried on air to yield 9.20-14.4 mg (5-8%) compound 7a. Purification by column chromatography with hexane/i-PrOH (98:2) as eluent to afford analytically pure 7.36, 10.9 mg (4.0, 6.0%) 7a. The characteristics of this compound are identical to those described above. The ether filtrates were concentrated and the residues were purified by column chromatography to give analytically pure compounds 10а,c,d,e. In the cases of acetophenones 9b and 9f the precipitation of crystals from the reaction mixture occurred. They were filtered off and washed with ether (3 × 5 mL), then dried on air to afford analytically pure quinolines 10b and 10f. The additional amount of quinolines 10b and 10f were obtained from the evaporated ether mother solution with the triturated with i-PrOH (in the case of 10b) and ether (in the case of 10f).

AC C

EP

TE D

Yield: 216 mg (80%), cream crystals, m.p. 230-232 оС; i-PrOH; [Found: C, 82.39; H, 4.57; N, 12.91. C22H15N3 requires C, 82.22; H, 4.70; N, 13.08.%]; Rf 0.51; νmax(KBr) 3385, 3063, 2883, 1601, 1549, 1448, 1433, 1374, 1337, 1275, 1229, 1033, 771, 745, 699, 640 cm-1; δH (600 MHz, DMSO-d6) 7.30-7.38 (2 H, m, H5 + H6 BI), 7.56 (1 H, dd, 3JHH 7.3, 6.6 Hz, H4 Ar), 7.61 (2 H, dd, 3 JHH 7.3, 7.3 Hz, H3 + H5 Ar), 7.72 (1 H, dd, 3JHH 8.1, 7.3 Hz, H6 Q), 7.77 (2 H, br s, H4 + H7 BI), 7.86 (1 H, dd, 3JHH 8.1, 7.3 Hz, H7 Q), 8.18 (1 H, d, 3JHH 8.1 Hz, H8 Q), 8.38 (2 H, d, 3JHH 8.1 Hz, H2 + H6 Ar), 8.61 (1 H, s, H3 Q), 9.39 (1 H, d, 3JHH 8.1 Hz, H5 Q); δC (DMSO-d6, 100 MHz) 111.9 (C7 BI), 118.3 (C3 Q), 119.6 (C4 BI), 122.8 (C5 + C6 BI), 123.8 (C4a Q), 126.8 (C5 Q), 127.2 (C2 + C6 Ar), 127.3 (C6 Q), 128.8 (C3 + C5 Ar), 129.6 (C8 Q), 129.8 (C4 Ar), 130.1 (C7 Q), 134.0 (C7a BI), 135.4 (C4 Q), 138.3 (C1 Ar), 144.0 (C3a BI), 148.6 (C8a Q), 149.2 (C2 BI), 155.7 (C2 Q); 15N NMR (60 MHz, DMSO-d6) 305.8 (N1 Q); MS (ESI): m/z 322 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 322.1332. C22H16N3 requires 322.1339. 4.4.1.2. 2-(4-Bromophenyl)-4-(benzimidazol-2-yl)quinoline (10b).

Yield: 256 mg (76%), beige crystals, m.p. 228-231 оС; [Found: C, 65.94; H, 3.61; N, 10.67. C22H14BrN3 requires C, 66.01; H, 3.53; N, 10.50%]; νmax(Nujol) 3386, 1589, 1544, 1451, 1377, 1232, 1075, 1010, 827, 765, 746 cm-1; δH (400 MHz, DMSO-d6) 7.29-7.38 (2 H, m, H6 + H5 BI), 7.68 (1 H, br d, 3JHH 7.6 Hz, H4 BI), 7.74 (1 H, ddd, 3JHH 7.7, 7.5 Hz, 4JHH 1.3 Hz, H6 Q), 7.82 (2 H, d, 3JHH 8.5 Hz, H3 + H5 Ar), 7.85-7.90 (2 H, m, H7 Q + H7 BI), 8.17 (1 H, d, 3JHH 8.4 Hz, H8 Q),

ACCEPTED MANUSCRIPT 14

RI PT

8.35 (2 H, d, 3JHH 8.5 Hz, H2 + H6 Ar), 8.63 (1 H, s, H3 Q), 9.45 (1 H, d, 3JHH 8.3 Hz, H5 Q), 13.36 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 111.7 (C7 BI), 118.0 (C3 Q), 119.6 (C4 BI), 122.2 (C5 BI), 123.6 (C4 Ar), 123.7 (C6 BI), 123.9 (C4a Q), 126.8 (C5 Q), 127.5 (C6 Q), 129.2 (C2 + C6 Ar), 129.6 (C8 Q), 130.2 (C7 Q), 131.8 (C3 + C5 Ar), 134.3 (C7a BI), 135.5 (C4 Q), 137.4 (C1 Ar), 143.9 (C3a BI), 148.6 (C8a Q), 149.1 (C2 BI), 154.5 (C2 Q); δN (60 MHz, DMSO-d6) 150.3 (N1 BI, N3 BI), 305.8 (N1 Q); MS (ESI): m/z 400, 402 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 400.0432. C22H1579BrN3 requires 400.0444. 4.4.1.3. 2-(3-Bromophenyl)-4-(benzimidazol-2-yl)quinoline (10c). NH

N

10c

Br

SC

N

TE D

M AN U

Yield: 262 mg (78%), beige crystals, m.p. 223-225 оС; hexane/i-PrOH, 90:10; [Found: C, 65.90; H, 3.44; N, 10.35. C22H14BrN3 requires C, 66.01; H, 3.53; N, 10.50%]; Rf 0.62; νmax(KBr) 3456, 3099, 1591, 1544, 1503, 1449, 1433, 1402, 1354, 1327, 1278, 1231, 766, 745 cm-1; δH (400 MHz, DMSOd6) 7.31-7.38 (2 H, m, H5 + H6 BI), 7.58 (1 H, dd, 3JHH 8.1, 7.7 Hz, H5 Ar), 7.66-7.72 (1 H, m, H4 BI), 7.72-7.80 (2 H, m, H6 Q + H4 Ar), 7.85-7.91 (2 H, m, H7 Q + H7 BI), 8.20 (1 H, br d, 3JHH 8.3 Hz, H8 Q), 8.41 (1 H, ddd, 3JHH 8.1, 7.8 Hz, 4JHH 1.5 Hz, H6 Ar), 8.58 (dd, 1H, 4JHH 1.8, 1.5 Hz, H2 Ar), 8.65 (1 H, s, H3 Q), 9.50 (1 H, d, 3JHH 8.4 Hz, H5 Q), 13.35 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 111.7 (C7 BI), 118.2 (C3 Q), 119.6 (C4 BI), 122.2 (C5 BI), 122.4 (C3 Ar), 123.7 (C6 BI), 124.0 (C4a Q), 126.2 (C6 Ar), 126.9 (C5 Q), 127.7 (C6 Q), 129.7 (C2 Ar), 129.7 (C8 Q), 130.2 (C7 Q), 131.0 (C5 Ar), 132.5 (C4 Ar), 134.3 (C7a BI), 135.6 (C4 Q), 140.6 (C1 Ar), 143.9 (C3a BI), 148.6 (C8a Q), 149.1 (C2 BI), 154.0 (C2 Q); MS (ESI): m/z 400, 402 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 400.0409. C22H1579BrN3 requires 400.0444.

AC C

EP

4.4.1.4. 2-(2-Bromophenyl)-4-(benzimidazol-2-yl)quinoline (10d).

Yield: 245 mg (73%), reddish-brown crystals, m.p. 248-250 оС; hexane/i-PrOH, 95:5; [Found: C, 66.07; H, 3.46; N, 10.62. C22H14BrN3 requires C, 66.01; H, 3.53; N, 10.50%]; Rf 0.58; νmax(Nujol) 3449, 3060, 1594, 1550, 1502, 1425, 1397, 1334, 1277, 1025, 764, 747 cm-1; δH (400 MHz, DMSOd6) 7.26-7.38 (2 H, m, H5 + H6 BI), 7.48 (1 H, ddd, 3JHH 7.3, 7.3 Hz, 4JHH 1.5 Hz, H4 Ar), 7.60 (1 H, ddd, 3JHH 7.7, 7.6 Hz, 4JHH 1.1 Hz, H5 Ar), 7.60-7.66 (1 H, m, H4 BI), 7.74 (1 H, dd, 3JHH 7.5 Hz, 4 JHH 1.6 Hz, H6 Ar), 7.80 (1 H, ddd, 3JHH 7.7, 7.0 Hz, 4JHH 1.5 Hz, H6 Q), 7.82-7.87 (1 H, m, H7 BI), 7.84 (1 H, dd, 3JHH 7.7 Hz, 4JHH 1.1 Hz, H3 Ar), 7.90 (1 H, ddd, 3JHH 7.3, 7.0 Hz, 4JHH 1.5 Hz, H7 Q), 8.17 (1 H, d, 3JHH 8.4 Hz, H8 Q), 8.26 (1 H, s, H3 Q), 9.51 (1 H, d, 3JHH 8.4 Hz, H5 Q), 13.25 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 111.7 (C7 BI), 119.6 (C4 BI), 121.2 (C2 Ar), 121.7 (C3 Q), 122.2 (C5 BI), 123.6 (C4a Q), 123.7 (C6 BI), 126.8 (C5 Q), 127.8 (C6 Q), 127.9 (C5 Ar), 129.6 (C8 Q), 130.1 (C7 Q), 130.6 (C4 Ar), 131.5 (C6 Ar), 133.0 (C3 Ar), 134.3 (7a BI), 134.4 (C4

ACCEPTED MANUSCRIPT 15

RI PT

Q), 140.8 (C1 Ar), 143.9 (C3a BI), 148.3 (C8a Q), 148.8 (C2 BI), 157.9 (C2 Q); MS (ESI): m/z 400, 402 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 400.0414. C22H1579BrN3 requires 400.0444. 4.4.1.5. 2-(4-Chlorophenyl)-4-(benzimidazol-2-yl)quinoline (10e).

M AN U

SC

Yield: 230 mg (77%), lilac crystals, m.p. 239-241 оС; i-PrOH; [Found: C, 74.47; H, 3.89; N, 11.65. C22H14ClN3 requires C, 74.26; H, 3.97; N, 11.81%]; Rf 0.60; νmax(Nujol) 3362, 3152, 3052, 1595, 1546, 1436, 1339, 1273, 1094, 837, 770, 745 cm-1; δH (400 MHz, DMSO-d6) 7.29-7.37 (2 H, m, H5 + H6 BI), 7.60 (2 H, d, 3JHH 8.6 Hz, H3 + H5 Ar), 7.68 (1 H, ddd, 3JHH 7.7, 7.7 Hz, 4JHH 1.4 Hz, H6 Q), 7.70-7.78 (2 H, m, H4 + H7 BI), 7.84 (1 H, ddd, 3JHH 7.6, 7.6 Hz, 4JHH 1.6 Hz, H7 Q), 8.14 (1 H, d, 3JHH 7.7 Hz, H8 Q), 8.30 (2 H, d, 3JHH 8.6 Hz, H2 + H6 Ar), 8.46 (1 H, s, H3 Q), 9.14 (1 H, dd, 3 JHH 7.7 Hz, 4JHH 1.3 Hz, H5 Q), 13.36 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 112.5 (C7 BI), 118.9 (C3 Q), 120.0 (C4 BI), 123.4 (C5 BI), 124.1 (C6 BI), 124.3 (C4a Q), 126.9 (C5 Q), 128.2 (C6 Q), 129.50 (C3 + C5 Ar), 129.53 (C2 + C6 Ar), 130.1 (C8 Q), 131.0 (C7 Q), 134.9 (C7a BI), 135.4 (C4 Ar), 136.4 (C4 Q), 137.5 (C1 Ar), 144.2 (C3a BI), 148.9 (C8a Q), 149.5 (C2 BI), 155.2 (C2 Q); MS (ESI): m/z 356 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 356.0918. C22H1535ClN3 requires 356.0949.

TE D

4.4.1.6. 2-(2-Chlorophenyl)-4-(benzimidazol-2-yl)quinoline (10f).

AC C

EP

Yield: 212 mg (71%), reddish-brown crystals, m.p. 245-246 оС; [Found: C, 74.41; H, 4.06; N, 11.96. C22H14ClN3 requires C, 74.26; H, 3.97; N, 11.81%]; νmax(KBr) 3063, 1596, 1549, 1445, 1421, 1398, 1336, 1278, 765, 746 cm-1; δH (400 MHz, DMSO-d6) 7.28-7.36 (2 H, m, H5 + H6 BI), 7.527.60 (2 H, m, H4 + H5 Ar), 7.60-7.66 (1 H, m, H4 BI), 7.66-7.70 (1 H, m, H3 Ar), 7.76-7.84 (2 H, m, H6 Ar + H6 Q), 7.85-7.89 (1 H, m, H7 BI), 7.90 (1 H, ddd, 3JHH 7.7, 7.2 Hz, 4JHH 1.3 Hz, H7 Q), 8.17 (1 H, d, 3JHH 8.4 Hz, H8 Q), 8.29 (1 H, s, H3 Q), 9.48 (1 H, d, 3JHH 8.4 Hz, H5 Q), 13.26 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 111.7 (C7 BI), 119.6 (C4 BI), 121.8 (C3 Q), 122.2 (C5 BI), 123.6 (C4a Q), 123.7 (C6 BI), 126.8 (C5 Q), 127.4 (C5 Ar), 127.8 (C6 Q), 129.6 (C8 Q), 129.9 (C3 Ar), 130.1 (C7 Q), 130.6 (C4 Ar), 131.4 (C2 Ar), 131.7 (C6 Ar), 134.3 (C7a BI), 134.6 (C4 Q), 138.8 (C1 Ar), 143.9 (C3a BI), 148.4 (C8a Q), 148.8 (C2 BI), 156.5 (C2 Q); MS (ESI): m/z 356 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 356.0976. C22H1535ClN3 requires 356.0949. 4.4.2. Typical procedure for the synthesis of 2-aryl-4-(benzimidazol-2-yl)quinolines 10g-l. 3-(2Amino-5-fluorophenyl)quinoxalin-2(1H)-one 6b (300 mg, 1.18 mmol) and acetophenones 9а-f (2.36 mmol) in glacial AcOH (6 mL) were heated for 5 h at 55 оС. The acetic filtrate was evaporated and the residue was triturated with ether (5 mL). The resulting precipitate was filtered off and dried on air to yield 5.60-11.2 mg (2-4%) compound 7b. Purification was carried out according to the procedure described above to provide 2.80, 5.60 mg (1, 2%) analytically pure compound 7b. The

ACCEPTED MANUSCRIPT 16

SC

4.4.2.1. 4-(Benzimidazol-2-yl)-2-phenyl-6-fluoroquinoline (10g).

RI PT

characteristics of this compound are identical to those described above. The ether filtrates were concentrated and the residues were purified by column chromatography on silica gel to give analytically pure compounds 10g,j,l. In the cases of acetophenones 9b,9c and 9e there occurred the precipitation of crystals from the reaction mixture, which were then filtered off and dried on air to afford analytically pure quinolines 10h,10i and 10k. The additional amounts of quinolines 10h,10i and 10k were obtained by column chromatography of the ether filtrate.

TE D

M AN U

Yield: 272 mg (68%), lilac crystals, m.p. 223-225 оС; hexane/i-PrOH, 98:2; [Found: C, 77.62; H, 4.27; N, 12.23. C22H14FN3: C, 77.86; H, 4.16; N, 12.38%]; Rf 0.51; νmax(Nujol) 3414, 3055, 1623, 1597, 1550, 1232, 1151, 1117, 1074, 1031, 826, 771, 746, 689 cm-1; δH (400 MHz, DMSO-d6) 7.327.38 (2 H, m, H5 + H6 BI), 7.52-7.58 (1 H, m, H4 Ar), 7.60-7.66 (2 H, m, H3 + H5 Ar), 7.68-7.74 (1 H, m, H4 BI), 7.78 (1 H, ddd, 3JHH 9.1 Hz, 3JHF 8.6 Hz, 4JHH 2.9 Hz, H7 Q), 7.84-7.92 (1 H, m, H7 BI), 8.23 (1 H, dd, 3JHH 9.1 Hz, 4JHF 5.9 Hz, H8 Q), 8.38 (2 H, br d, 3JHH 7.2 Hz, H2 + H6 Ar), 8.72 (1 H, s, H3 Q), 9.41 (1 H, dd, 3JHF 11.3 Hz, 4JHH 2.9 Hz, H5 Q), 13.42 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 110.5 (d, 2JCF 25.2 Hz, C5 Q), 111.7 (C7 BI), 118.6 (C3 Q), 119.7 (C4 BI), 120.1 (d, 2JCF 25.9 Hz, C7 Q), 122.3 (C5 BI), 123.9 (C6 BI), 124.4 (d, 3JCF 10.9 Hz, C4a Q), 127.2 (С2 + C6 Ar), 128.8 (С3 + C5 Ar), 129.9 (C4 Ar), 132.5 (d, 3JCF 9.4 Hz, C8 Q), 134.1 (C3a BI), 134.5 (d, 4JCF 5.4 Hz, C4 Q), 138.0 (C1 Ar), 143.8 (C7a BI), 146.0 (C8a Q), 148.9 (C2 BI), 155.4 (d, 6JCF 2.2 Hz, C2 Q), 160.4 (d, 1JCF 245.3 Hz, C6 Q); δF (376 MHz, DMSO-d6) –111.7 (F6 Q); δN (60 MHz, DMSOd6) 149.6 (N1 BI), 305.0 (N1 Q); MS (ESI): m/z 340 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 340.1208. C22H15FN3 requires 340.1245.

AC C

EP

4.4.2.2. 4-(Benzimidazol-2-yl)-2-(4-bromophenyl)-6-fluoroquinoline (10h).

Yield: 325 mg (66%), beige crystals, m.p. 235-237 оС; hexane/i-PrOH, 90:10; [Found: C, 63.25; H, 3.06; N, 9.94. C22H13BrFN3: C, 63.17; H, 3.13; N, 10.05%]; Rf 0.65; νmax(Nujol) 3239, 1623, 1597, 1548, 1488, 1411, 1277, 1234, 835, 746 cm-1; δH (400 MHz, DMSO-d6) 7.30-7.38 (m, 2H, H5 + H6 BI), 7.65-7.71 (m, 1H, H4 BI), 7.73 (ddd, 1H, 3JHH 9.1 Hz, 3JHF 8.7 Hz, 4JHH 2.9 Hz, H7 Q), 7.79 (d, 2H, 3JHH 8.3 Hz, H3 + H5 Ar), 7.85-7.91 (d, 1H, 3JHH 7.2 Hz, H7 BI), 8.19 (dd, 1H, 3JHH 9.1 Hz, 4 JHF 5.7 Hz, H8 Q), 8.30 (d, 2H, 3JHH 8.3 Hz, H2 + H6 Ar), 8.68 (s, 1H, H3 Q), 9.39 (dd, 1H, 3JHF 11.3 Hz, 4JHH 2.9 Hz, H5 Q), 13.39 (s, 1H, H1 BI); δC (100 MHz, DMSO-d6) 110.6 (d, 2JCF 25.2 Hz, C5 Q), 111.7 (C7 BI), 118.3 (C3 Q), 119.7 (C4 BI), 120.2 (d, 2JCF 26.0 Hz, C7 Q), 122.3 (C5 BI), 123.7 (C4 Ar), 123.9 (C6 BI), 124.5 (d, 3JCF 11.2 Hz, C4a Q), 129.1 (C2 + C6 Ar), 131.8 (C3 + C5 Ar), 132.4 (d, 3JCF 9.5 Hz, C8 Q), 134.1 (C7a BI), 134.6 (d, 4JCF 5.4 Hz, C4 Q), 137.2 (C1 Ar), 143.8 (C3a BI), 145.9 (C8a Q), 148.8 (C2 BI), 154.1 (C2 Q), 160.5 (d, 1JCF 245.6 Hz, C6 Q); δF (376

ACCEPTED MANUSCRIPT 17 MHz, DMSO-d6) –111.2 (F6 Q); MS (ESI): m/z 418, 420 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 418.0305. C22H1479BrFN3 418.0350.

RI PT

4.4.2.3. 4-(Benzimidazol-2-yl)-2-(3-bromophenyl)-6-fluoroquinoline (10i).

TE D

M AN U

SC

Yield: 316 mg (64%), cream powder, m.p. 233-235 оС; hexane/i-PrOH, 99:1; [Found: C, 63.31; H, 3.21; N, 10.18. C22H13BrFN3 requires C, 63.17; H, 3.13; N, 10.05%]; Rf 0.58; νmax(Nujol) 3060, 1626, 1597, 1550, 1507, 1420, 1238, 1152, 1120, 1078, 830, 746 cm-1; δH (400 MHz, DMSO-d6) 7.31 (1 H, br dd, 3JHH 8.1, 6.7 Hz, H5 BI), 7.38 (1 H, br dd, 3JHH 7.8, 7.1 Hz, H6 BI), 7.58 (1 H, dd, 3 JHH 8.1, 7.8 Hz, H5 Ar), 7.69 (1 H, br d, 3JHH 7.6 Hz, H4 BI), 7.75 (1 H, dd, 3JHH 7.6 Hz, 4JHH 1.0 Hz, H4 Ar), 7.79 (1 H, ddd, 3JHH 9.2 Hz, 3JHF 7.7 Hz, 4JHH 3.0 Hz, H7 Q), 7.88 (1 H, br d, 3JHH 7.6 Hz, H7 BI), 8.25 (1 H, dd, 3JHH 9.2 Hz, 4JHF 5.8 Hz, H8 Q), 8.38 (1 H, dd, 3JHH 7.6 Hz, 4JHH 1.0 Hz, H6 Ar), 8.56 (1 H, br s, H2 Ar), 8.72 (1 H, s, H3 Q), 9.43 (1 H, dd, 4JHF 9.2 Hz, 3JHH 3.0 Hz, H5 Q), 13.40 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 110.6 (d, 2JCF 26.2 Hz, C5 Q), 111.7 (C7 BI), 118.5 (C3 Q), 119.7 (C4 BI), 120.3 (d, 2JCF 26.3 Hz, C7 Q), 122.3 (C5 BI), 122.4 (C3 Ar), 123.9 (C6 BI), 124.7 (d, 3JCF 11.2 Hz, C4a Q), 126.2 (C6 Ar), 129.6 (C2 Ar), 131.0 (C5 Ar), 132.5 (C4 Ar), 132.6 (d, 3JCF 8.9 Hz, C8 Q), 134.1 (C7a BI), 134.6 (d, 4JCF 5.5 Hz, C4 Q), 140.3 (C1 Ar), 143.8 (C3a BI), 145.9 (C8a Q), 148.8 (C2 BI), 153.7 (d, 6JCF 2.5 Hz, C2 Q), 160.6 (d, 1JCF 245.3 Hz, C6 Q); δF (376 MHz, DMSO-d6) –111.0 (F6 Q); δN (60 MHz, DMSO-d6)150.0 (N1 BI), 306.0 (N1 Q); MS (ESI): m/z 418, 420 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 418.0352. C22H1479BrFN3 418.0350. 4.4.2.4. 4-(Benzimidazol-2-yl)-2-(2-bromophenyl)-6-fluoroquinoline (10j). N

NH

EP

F

Br N

10j

AC C

Yield: 301 mg (61%), pink powder, m.p. 242-244 оС; hexane/i-PrOH, 98:2; [Found: C, 63.03; H, 3.04; N, 9.90. C22H13BrFN3 requires C, 63.17; H, 3.13; N, 10.05%]; Rf 0.53; νmax(KBr) 3436, 3169, 3141, 3088, 3059, 3026, 1625, 1599, 1552, 1505, 1483, 1414, 1365, 1342, 1279, 1232, 1209, 1024, 928, 890, 844, 822, 758, 741, 728 cm-1; δH (600 MHz, DMSO-d6) 7.30-7.36 (2 H, m, H5 + H6 BI), 7.48 (1 H, br dd, 3JHH 7.4, 7.1 Hz, H4 Ar), 7.60 (1 H, br dd, 3JHH 7.4, 7.4 Hz, H5 Ar), 7.62-7.67 (1 H, m, H4 BI), 7.73 (1 H, br d, 3JHH 7.5 Hz, H6 Ar), 7.80-7.89 (3 H, m, H7 Q + H7 BI + H3 Ar), 8.23 (1 H, dd, 3JHH 9.2 Hz, 4JHF 5.8 Hz, H8 Q), 8.35 (1 H, s, H3 Q), 9.44 (1 H, dd, 3JHF 11.6 Hz, 4JHH 3.1 Hz, H5 Q); δC (DMSO-d6, 150 MHz) 110.7 (d, 2JCF 25.2 Hz, C5 Q), 111.9 (C7 BI), 119.8 (C4 BI), 120.3 (d, 2JCF 26.1 Hz, C7 Q), 121.3 (C2 Ar), 122.2 (C3 Q), 122.5 (C5 BI), 124.0 (C6 BI), 124.4 (d, 3JCF 11.1 Hz, C4a Q), 128.0 (C5 Ar), 130.9 (C4 Ar), 131.6 (C6 Ar), 132.7 (d, 3JCF 9.3 Hz, C8 Q), 133.1 (C3 Ar), 133.7 (d, 4JCF 5.5 Hz, C4 Q), 134.6 (C7a Q), 140.6 (C1 Ar), 143.9 (C3a BI), 145.7 (C8a Q), 148.6 (C2 BI), 157.6 (d, 6JCF 2.2 Hz, C2 Q), 160.8 (d, 1JCF 245.3 Hz, C6 Q); δF (376 MHz, DMSOd6) –110.7 (F6 Q); δN (60 MHz, DMSO-d6) 314.6 (N1 Q); MS (ESI): m/z 418, 420 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 418.0329. C22H1479BrFN3 requires 418.0350.

ACCEPTED MANUSCRIPT 18

RI PT

4.4.2.5. 4-(Benzimidazol-2-yl)-2-(4-chlorophenyl)-6-fluoroquinoline (10k).

M AN U

SC

Yield: 287 mg (65%), beige powder, m.p. 226-228 оС; hexane/i-PrOH, 98:2; [Found: C, 70.88; H, 3.61; N, 11.39. C22H13ClFN3 requires C, 70.69; H, 3.51; N, 11.24%]; Rf 0.51; νmax(Nujol) 3234, 1621, 1594, 1547, 1411, 1332, 1276, 1235, 1087, 1011, 840, 745 cm-1; δH (400 MHz, DMSO-d6) 7.31-7.36 (2 H, m, H5 + H6 BI), 7.67 (2 H, d, 3JHH 8.5 Hz, H3 + H5 Ar), 7.74-7.83 (3 H, m, H7 Q + H4 BI + H7 BI), 8.22 (1 H, dd, 3JHH 9.0 Hz, 4JHF 5.7 Hz, H8 Q), 8.40 (2 H, d, 3JHH 8.5 Hz, H2 + H6 Ar), 8.72 (1 H, s, H3 Q), 9.41 (1 H, dd, 3JHF 11.4 Hz, 4JHH 3.0 Hz, H5 Q); δC (100 MHz, DMSO-d6) 110.6 (d, 2JCF 25.4 Hz, C5 Q), 115.0 (C7 BI), 118.4 (C3 Q), 120.0 (C4 BI), 120.2 (d, 2JCF 26.9 Hz, C7 Q), 123.0 (C5 + C6 BI), 124.5 (d, 3JCF 11.3 Hz, C4a Q), 128.8 (C2 + C6 Ar), 128.9 (C3 + C5 Ar), 132.5 (d, 3JCF 9.6 Hz, C8 Q), 134.6 (d, 4JCF 5.7 Hz, C4 Q), 134.9 (C4 Ar), 136.8 (C1 Ar), 145.9 (C8a Q), 148.8 (C2 BI), 154.1 (d, 6JCF 5.7 Hz, C2 Q), 160.5 (d, 1JCF 244.8 Hz, C6 Q); δF (DMSO-d6, 376 MHz) –111.3 (F6 Q); MS (ESI): m/z 374 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 374.0882. C22H1435ClFN3 374.0855.

TE D

4.4.2.6. 4-(Benzimidazol-2-yl)-2-(2-chlorophenyl)-6-fluoroquinoline (10l).

AC C

EP

Yield: 273 mg (62%), reddish-brown crystals, m.p. 236-237 оС; hexane/i-PrOH, 90:10; [Found: C, 70.91; H, 3.42; N, 11.12. C22H13ClFN3: C, 70.69; H, 3.51; N, 11.24%]; Rf 0.58; νmax(Nujol) 3086, 3060, 1624, 1598, 1552, 1503, 1415, 1342, 1278, 1232, 1208, 760, 743 cm-1; δH (400 MHz, DMSOd6) 7.30-7.36 (2 H, m, H5 + H6 BI), 7.54-7.59 (2 H, m, H3 + H5 Ar), 7.60-7.66 (1 H, m, H4 BI), 7.67-7.70 (1 H, m, H4 Ar), 7.76-7.79 (1 H, m, H6 Ar), 7.83 (1 H, ddd, 3JHH 9.0 Hz, 3JHF 8.5 Hz, 4JHH 3.0 Hz, H7 Q), 7.85-7.91 (1 H, m, H7 BI), 8.23 (1 H, dd, 3JHH 9.2 Hz, 4JHF 5.9 Hz, H8 Q), 8.37 (1 H, s, H3 Q), 9.43 (1 H, dd, 3JHF 11.5 Hz, 4JHH 3.1 Hz, H5 Q), 13.31 (1 H, s, H1 BI); δC (100 MHz, DMSO-d6) 110.6 (d, 2JCF 25.0 Hz, C5 Q), 111.8 (C7 BI), 119.7 (C4 BI), 120.3 (d, 2JCF 26.0 Hz, C7 Q), 122.1 (C3 Q), 122.4 (C5 BI), 124.0 (C6 BI), 124.4 (d, 3JCF 11.2 Hz, C4a Q), 127.5 (C5 Ar), 129.9 (C4 Ar), 130.7 (C3 Ar), 131.4 (C2 Ar), 131.7 (C6 Ar), 132.6 (d, 3JCF 9.5 Hz, C8 Q), 133.8 (d, 4 JCF 5.6 Hz, C4 Q), 134.2 (BI7a), 138.6 (C1 Ar), 143.8 (C3a BI), 145.8 (C8a Q), 148.6 (C2 BI), 156.1 (d, 6JCF 2.6 Hz, C2 Q), 160.8 (d, 1JCF 245.7 Hz, C6 Q); δF (376 MHz, DMSO-d6) –110.8 (F6 Q); δN (60 MHz, DMSO-d6) 150.4 (N1 BI), 315.2 (N1 Q); MS (ESI): m/z 374 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 374.0898. C22H1435ClFN3 requires 374.0855. 4.5. Synthesis of 1,3-bis[4-(benzimidazol-2-yl)quinolin-2-yl]benzenes 12a,b from 3-(2aminophenyl)quinoxalin-2(1H)-ones 6a,b and 1,3-diacetylbenzene 11 4.5.1. 1,3-Bis[4-(benzimidazol-2-yl)quinolin-2-yl]benzene (12a).

ACCEPTED MANUSCRIPT 19

M AN U

SC

RI PT

3-(2-Aminophenyl)quinoxalin-2(1H)-one 6a (300 mg, 1.26 mmol) and 1,3-diacetylbenzene 11 (82.0 mg, 0.51 mmol) in AcOH (6 mL) were heated for 5 h at 55 оС. After completion of the reaction the solvent was evaporated and ether (5 mL) was added to the residue. The resulting precipitate was filtered off and dried on air to yield 251 mg (87%) compound 12a. Purification by column chromatography with hexane/i-PrOH (50:50) as an eluent was carried out to afford analytically pure 227 mg (79%) 12a as a white powder, m.p. 286-287 оС; [Found: C, 80.59; H, 4.19; N, 15.05. C38H24N6 requires C, 80.83; H, 4.28; N, 14.88%]; Rf 0.64; νmax(KBr) 3423, 3061, 1596, 1505, 1446, 1419, 764, 743 cm-1; δH (400 MHz, DMSO-d6) 7.29-7.41 (4 H, m, 2 × H5 + 2 × H6 BI), 7.66-7.72 (2 H, m, 2 × H4 BI), 7.77 (2 H, ddd, 3JHH 7.7, 7.6 Hz, 4JHH 1.2 Hz, H6 Q), 7.84-7.92 (5 H, m, 2 × H7 BI + H5 Ar + 2 × H7 Q), 8.29 (2 H, d, 3JHH 8.1 Hz, 2 × H8 Q), 8.56 (2 H, dd, 3JHH 8.1 Hz, 4JHH 1.7 Hz, H4 + H6 Ar), 8.78 (2 H, s, 2 × H3 Q), 9.31 (1 H, br s, H2 Ar), 9.44 (2 H, d, 3JHH 8.1 Hz, 2 × H5 Q), 13.42 (2 H, br s, 2 × H1 BI); δC (100 MHz, DMSO-d6) 111.7 (2 × C7 BI), 118.7 (2 × C3 Q), 119.7 (2 × C4 BI), 122.2 (2 × C5 BI), 123.6 (2 × C6 BI), 124.0 (2 × C4a Q), 126.1 (C2 Ar), 126.8 (2 × C5 Q), 127.5 (2 × C6 Q), 128.8 (C4 + C6 Ar), 129.5 (C5 Ar), 129.7 (2 × C8 Q), 130.2 (C7 Q), 134.4 (2 × C7a BI), 135.7 (2 × C4 Q), 139.2 (C1 + C3 Ar), 143.9 (2 × C3a BI), 148.7 (2 × C8a Q), 149.2 (2 × C2 BI), 155.7 (2 × C2 Q); δN (60 MHz, DMSO-d6) 150.6 (N1 BI), 306.3 (N1 Q); MS (ESI): m/z 565 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 565.2117. C38H25N6 requires 565.2135.

TE D

4.5.2. 1,3-Bis[4-(benzimidazol-2-yl)-6-fluoroquinolin-2-yl]benzene (12b).

AC C

EP

3-(2-Amino-5-fluorophenyl)quinoxalin-2(1H)-one 6b (300 mg, 1.18 mmol) and 1,3-diacetylbenzene 11 (76.6 mg, 0.47 mmol) in AcOH (6 mL) were heated for 5 h at 55 оС. After completion of the reaction the solvent was evaporated and ether (5 mL) was added to the residue. The resulting precipitate was filtered off and dried on air to yield 243 mg (86%) compound 12b. The recrystallization from i-PrOH was accomplished to afford 189 mg (67%) analytically pure 12b as a white powder, m.p. 284-285 оС; [Found: C, 76.25; H, 3.80; N, 14.19. C38H22F2N6 requires C, 75.99; H, 3.69; N, 13.99%]; νmax(KBr) 3317, 3194, 1594, 1500, 1446, 1412, 1338, 1278, 1258, 1219, 1147, 740 cm-1; δH (400 MHz, DMSO-d6) 7.28-7.42 (4 H, m, 2 × H5 + 2 × H6 BI), 7.66-7.72 (2 H, m, 2 × H4 BI), 7.80-7.94 (5 H, m, 2 × H7 Q + H5 Ar + 2 × H7 BI), 8.35 (2 H, dd, 3JHH 9.4 Hz, 4JHF 5.7 Hz, 2 × H8 Q), 8.54 (2 H, dd, 3JHH 7.7 Hz, 4JHH 1.7 Hz, H4 + H6 Ar), 8.86 (2 H, s, 2 × H3 Q), 9.29 (1 H, dd, 4JHH 2.0, 1.7 Hz, H2 Ar), 9.39 (2 H, dd, 3JHF 11.2 Hz, 4JHH 3.0 Hz, 2 × H5 Q); δC (100 MHz, DMSO-d6) 109.2 (2 × C7 BI), 110.7 (d, 3JCF 25.1 Hz, 2 × C5 Q), 119.1 (2 × C3 Q), 119.9 (2 × C4 BI), 120.4 (d, 3JCF 25.8 Hz, 2 × C7 Q), 122.3 (2 × C5 BI), 124.1 (2 × C6 BI), 124.7 (d, 3JCF 11.0 Hz, 2 × C4a Q), 126.1 (C2 Ar), 128.9 (C4 + C6 Ar), 129.7 (C5 Ar), 132.7 (d, 3JCF 9.3 Hz, 2 × C8 Q), 134.4 (2 × C7a BI), 134.9 (d, 4JCF 5.5 Hz, 2 × C4 Q), 139.1 (C1 + C3 Ar), 143.9 (2 × C3a BI), 146.1 (2 × C8a Q), 148.9 (2 × C2 BI), 155.4 (d, 6JCF 2.6 Hz, 2 × C2 Q), 160.6 (d, 1JCF 246.0 Hz, 2 × C6 Q); δF (376 MHz, DMSO-d6) –111.3 (F6); MS (ESI): m/z 601 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 601.1986. C38H23F2N6 requires 601.1947.

ACCEPTED MANUSCRIPT 20 4.6. Synthesis of 7,8-dimethyl-7H-benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-oles 17a,b from 3-(2-aminophenyl)quinoxalin-2(1H)-ones 6a,b and acetylacetone 13

RI PT

4.6.1. 7,8-Dimethyl-7H-benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-ole (17a).

TE D

M AN U

SC

3-(2-Aminophenyl)quinoxalin-2(1H)-one 6a (300 mg, 1.26 mmol) and acetylacetone 13 (378 mg, 3.78 mmol) in AcOH (6 mL) were heated for 6 h at 55 оС. Then the reaction mixture was heated further for 3 h at reflux. After the completion of the reaction the solvent was evaporated and the residue was purified through a short pad of silica gel eluted with i-PrOH to afford 300 mg (79%) analytically pure 17a as a light-brown powder, m.p. 223-225 оС; [Found: C, 75.52; H, 4.91; N, 13.79. C19H15N3O requires C, 75.73; H, 5.02; N, 13.94%]; Rf 0.55; νmax(KBr) 3383, 1622, 1591, 1507, 1433, 1370, 1332, 1203, 1123, 765, 742 cm-1; δH (400 MHz, DMSO-d6) 2.09 (3 H, s, Me7), 2.91 (3 H, s, Me8), 7.33 (1 H, ddd, 3JHH 7.6, 7.3 Hz, 4JHH 1.2 Hz, H3), 7.39 (1 H, ddd, 3JHH 7.6, 7.2 Hz, 4JHH 1.2 Hz, H4), 7.47 (1 H, s, OH), 7.79 (1 H, br dd, 3JHH 7.8, 7.2 Hz, H12), 7.81 (1 H, br d, 3 JHH 7.4 Hz, H5), 7.86 (1 H, br d, 3JHH 7.2 Hz, H2), 7.87 (1 H, ddd, 3JHH 7.4, 7.2 Hz, 4JHH 1.6 Hz, H11), 8.08 (1 H, d, 3JHH 7.4 Hz, H10), 8.85 (1 H, ddd, 3JHH 7.4 Hz, 4JHH 1.6 Hz, 5JHH 1.2 Hz, H13); δC (100 MHz, DMSO-d6) 21.6 (Me8), 23.9 (Me7), 88.8 (C7), 110.8 (C5), 120.3 (C13a), 120.5 (C2), 122.3 (C3), 123.8 (C4), 124.6 (C13), 127.4 (C12), 128.5 (C10), 130.6 (C11), 130.7 (C5a), 131.8 (C13b), 141.9 (C7a), 147.9 (C9a), 148.9 (C1a), 153.0 (C13c), 154.2 (C8); δN (60 MHz, DMSO-d6) 187.0 (N6), 315.3 (N9); MS (ESI): m/z 302 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 302.1302. C19H16N3O requires 302.1288.

EP

4.6.2. 12-Fluoro-7,8-dimethyl-7H-benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-ole (17b).

AC C

3-(2-Amino-5-fluorophenyl)quinoxalin-2(1H)-one 6b (300 mg, 1.18 mmol) and acetylacetone 13 (354 mg, 3.54 mmol) in AcOH (6 mL) were heated for 6 h at 55 оС. Then the reaction mixture was heated further for 3 h at reflux. After the completion of the reaction the solvent was evaporated and the residue was purified through a short pad of silica gel eluted with CHCl3 to afford 230 mg (61% yield) analytically pure 17b as a beige powder, m.p. 307-309 оС; [Found: C, 71.68; H, 4.31; N, 12.99. C19H14FN3O requires C, 71.46; H, 4.42; N, 13.16%]; Rf 0.51; νmax(KBr) 3425, 1623, 1600, 1508, 1375, 1229, 1176, 1146, 746 cm-1; δH (400 MHz, DMSO-d6) 2.08 (3 H, s, Me7), 2.89 (3 H, s, Me8), 7.32 (1 H, ddd, 3JHH 7.6, 7.2 Hz, 4JHH 1.1 Hz, H3), 7.39 (1 H, ddd, 3JHH 7.6, 7.2 Hz, 4JHH 1.2 Hz, H4), 7.51 (1 H, br s, OH), 7.81 (1 H, ddd, 3JHH 9.3 Hz, 3JHF 9.0 Hz, 4JHH 3.0 Hz, H11), 7.82 (1 H, d, 3JHH 7.6 Hz, H5), 7.86 (1 H, br d, 3JHH 7.6 Hz, H2), 8.16 (1 H, dd, 3JHH 9.3 Hz, 4JHF 5.3 Hz, H10), 8.42 (1 H, dd, 3JHF 8.8 Hz, 4JHH 3.0 Hz, H13); δC (100 MHz, DMSO-d6) 21.4 (Me8), 23.7 (Me7), 89.0 (C7), 107.7 (d, 2JCF 22.9 Hz, C13), 110.9 (C5), 120.6 (C2), 120.7 (d, 3JCF 11.5 Hz, C13a), 120.8 (d, 2JCF 25.8 Hz, C11), 122.4 (C3), 123.9 (C4), 130.7 (C5a), 131.60 (C13b), 131.65 (d, 3JCF 9.6 Hz,

ACCEPTED MANUSCRIPT 21 C10), 142.6 (C7a), 145.2 (C9a), 148.9 (C1a), 152.5 (C13c), 153.8 (d, 6JCF 2.5 Hz, C8), 160.2 (d, 1JCF 247.6 Hz, C12); δF (376 MHz, DMSO-d6) –111.7 (F12); δN (60 MHz, DMSO-d6) 186.8 (N6), 315.0 (N9); MS (ESI): m/z 320 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 320.1201. C19H15FN3O requires 320.1194.

RI PT

4.7. Synthesis of 8-methyl-7H-benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-ones 18a,b from 3(2-aminophenyl)quinoxalin-2(1H)-ones 6a,b and ethyl acetoacetate 14

SC

4.7.1. 8-Methyl-7H-benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-one (18а).

EP

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3-(2-Aminophenyl)quinoxalin-2(1H)-one 6a (200 mg, 0.84 mmol) and ethyl acetoacetate 14 (328 mg, 2.53 mmol) in AcOH (6 mL) were heated for 6 h at 55 оС. Then the reaction mixture was heated further for 3 h at reflux. After the completion of the reaction the solvent was evaporated and the residue was purified through a short pad of silica gel eluted with hexane/i-PrOH (96:4) to afford 180 mg (75%) analytically pure 18a as an orange powder, m.p. 216-218 oC; [Found: C, 75.53; H, 3.77; N, 14.55. C18H11N3O requires C, 75.78; H, 3.89; N, 14.73%]; Rf 0.55; νmax(KBr) 3422, 1753, 1618, 1561, 1483, 1429, 1365, 1290, 1129, 771, 748 cm-1; δH (400 MHz, DMSO-d6) 2.94 (3 H, s, Me), 7.24 (1 H, ddd, 3JHH 7.7, 7.4 Hz, 4JHH 1.1 Hz, H3), 7.33 (1 H, ddd, 3JHH 7.8, 7.6 Hz, 4JHH 1.1 Hz, H4), 7.60 (1 H, br dd, 3JHH 8.5, 7.8 Hz, H12), 7.69 (1 H, br d, 3JHH 7.7 Hz, H2), 7.70 (1 H, br d, 3JHH 7.7 Hz, H5), 7.79 (1 H, ddd, 3JHH 8.5, 7.8 Hz, 4JHH 1.2 Hz, H11), 7.97 (1 H, d, 3JHH 8.5 Hz, H10), 8.60 (1 H, d, 3JHH 8.5 Hz, H13); δC (100 MHz, DMSO-d6) 21.2 (Me), 112.1 (C5), 119.8 (C13a), 121.4 (C2), 123.8 (C7a), 124.8 (C3), 125.2 (C13), 127.2 (C4), 128.0 (C12), 128.7 (C10), 129.1 (C5a), 133.1 (C11), 138.9 (C13b), 149.2 (C1a), 150.8 (C9a), 154.6 (C13c), 155.8 (C8), 160.5 (C7); δN (60 MHz, DMSO-d6) 316.1 (N9); MS (ESI): m/z 286 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 286.0961. C18H12N3O requires 286.0975.

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4.7.2. 12-Fluoro-8-methyl-7H-benzimidazolo[2,1-a]pyrrolo[3,4-c]quinolin-7-one (18b).

3-(2-Amino-5-fluorophenyl)quinoxalin-2(1H)-one 6b (400 mg, 1.57 mmol) and ethyl acetoacetate 14 (612 mg, 4.70 mmol) in AcOH (20 mL) were stirred for 6 h at 55 оС. Then the reaction mixture was heated further for 3 h at reflux. Upon cooling the precipitate was filtered and dried on air to afford an 167 mg (35%) analytically pure compound 18b as bright-yellow powder, m.p. 276-278 oC. An additional amount of compound 18b (138 mg, 29%) was obtained from the filtrate. [Found: C, 71.12; H, 3.23; N, 14.02. C18H10FN3O requires C, 71.28; H, 3.32; N, 13.85%]; νmax(KBr) 3423, 1754, 1620, 1598, 1515, 1478, 1369, 1330, 1223, 1134, 829, 750 cm-1; δH (400 MHz, CDCl3) 3.04 (3 H, s, Me), 7.35 (1 H, ddd, 3JHH 7.7, 7.6 Hz, 4JHH 1.1 Hz, H3), 7.43 (1 H, ddd, 3JHH 7.7, 7.6 Hz, 4 JHH 1.1 Hz, H4), 7.65 (1 H, ddd, 3JHH 9.4 Hz, 3JHF 8.7 Hz, 4JHH 2.8 Hz, H11), 7.80 (1 H, d, 3JHH 7.7

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Hz, H2), 7.81 (1 H, d, 3JHH 7.7 Hz, H5), 8.15 (1 H, dd, 3JHH 9.4 Hz, 4JHF 5.0 Hz, H10), 8.34 (1 H, dd, 3 JHF 8.1 Hz, 4JHH 2.8 Hz, H13); δC (100 MHz, CDCl3) 20.5 (Me), 108.7 (d, 2JCF 23.4 Hz, C13), 112.3 (C5), 120.5 (d, 3JCF 11.4 Hz, C13a), 121.7 (C2), 124.0 (d, 2JCF 26.5 Hz, C11), 124.5 (C7a), 125.0 (C3), 127.5 (C4), 129.1 (C5a), 130.7 (d, 3JCF 10.4 Hz, C10), 139.1 (d, 4JCF 25.1 Hz, C13b), 147.1 (C9a), 149.3 (C1a), 153.9 (C13c), 159.5 (d, 6JCF 2.8 Hz, C8), 159.9 (C7), 161.3 (d, 1JCF 254.3 Hz, C12); δF (376 MHz, CDCl3) –108. 5 (F12); MS (ESI): m/z 304 [M + H]+; HRMS (MALDI): m/z [M + H]+, found 304.0893. C18H11FN3O requires 304.0881. Acknowledgments

This work was supported by the Russian Foundation for Basic Research (grants №13-03-00123a, 14-03-31194-mol_a).

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Supplementary data

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1D and 2D NMR spectra for all compounds. Supplementary data related to this article can be found at References and notes

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1. Kouznetsov, V. V.; Vargas Méndez, L. Y.; Meléndez Gómez, C. M. Curr. Org. Chem. 2005, 9, 141 and references cited therein. 2. Chauhan, P. M. S.; Srivastava, S. K. Curr. Med. Chem. 2001, 8, 1535. 3. (a) Roma, G.; Di Braccio, M.; Grossi, G.; Mattioli, F.; Ghia M. Eur. J. Med. Chem. 2000, 35, 1021; (b) Kalluraya, B.; Sreenivasa, S. Farmaco 1998, 53, 399. 4. Chen, Y.-L.; Fang, K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem. 2001, 44, 2374. 5. Dubé, D.; Blouin, M.; Brideau, C.; Chan, C.-C.; Desmarais, S.; Ethier, D.; Falgueyret, J.-P.; Friesen, R. W.; Girard, M.; Girard, Y.; Guay, J.; Riendeau, D.; Tagari, P.; Young, R. N. Bioorg. Med. Chem. Lett. 1998, 8, 1255. 6. Ferrarini, P. L.; Mori, C.; Badawneh, M.; Calderone, V.; Greco, R.; Manera, C.; Martinelli, A.; Nieri, P.; Saccomanni, G. Eur. J. Med. Chem. 2000, 35, 815. 7. Nakatani, K.; Sando, S.; Saito, I. Bioorg. Med. Chem. 2001, 9, 2381. 8. (a) Palimkar, S. S.; Siddiqui, S. A.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. J. Org. Chem. 2003, 68, 9371. (b) Jenekhe, S. A.; Lu, L.; Alam, M. M. Macromolecules 2001, 34, 7315. 9. Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocyclic Compds. 2006, 42, 701. 10. Kürti, L.; Czakó, B. Strategic Applications of Named Reactions in Organic Synthesis; Elsevier Academic Press: Burlington, MA, 2005; pp 414–416 and references cited therein. 11. (a) Hsiao, Y.; Rivera, N. R.; Yasuda, N.; Hughes, D. L.; Reider, P. J. Org. Lett. 2001, 3, 1101; (b) Cho, C. S.; Kim, B. T.; Kim, T.-J.; Shim, S. C. Chem. Commun. 2001, 2576; (c) Arcadi, A.; Chiarini, M.; Di Giuseppe, S.; Marinelli, F. Synlett 2003, 203; (d) McNaughton, B. R.; Miller, B. L. Org. Lett. 2003, 5, 4257; (e) Dormer, P. G.; Eng, K. K.; Farr, R. N.; Humphrey, G. R.; McWilliams, J. C.; Reider, P. J.; Sager, J. W.; Volante, R. P. J. Org. Chem. 2003, 68, 467. For a review of the Friedländer synthesis of quinolines see: (f) Cheng, C.-C.; Yan, S.-J. Org. React. 1982, 28, 37; (g) Marco-Contelles, J.; Pérez-Mayoral, E.; Samadi, A.; do Carmo Carreiras, M.; Soriano, E. Chem. Rev. 2009, 109, 2652 and references cited therein. 12. (a) Heindel, N. D.; Bechara, I. S.; Lemke, T. F.; Fish, V. B. J. Org. Chem. 1967, 32, 4155; (b) Walz, A. J.; Sundberg, R. J. J. Org. Chem. 2000, 65, 8001. 13. West, A. P.; Van Engen, D., Paskal, Jr. R. A. J. Org. Chem. 1992, 57, 784. 14. Zong, R.; Wang, D.; Hammitt, R.; Thummel, R. P. J. Org. Chem. 2006, 71, 167.

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15. (a) Mamedov, V. A.; Saifina, D. F.; Gubaidullin, A. T.; Saifina, A. F.; Rizvanov, I. Kh. Tetrahedron Lett. 2008, 49, 6231; (b) Mamedov, V. A.; Khafizova, E. A.; Gubaidullin, A. T.; Murtazina, A. M. Adgamova, D. I.; Samigullina, A. I.; Litvinov, I. A. Russ. Chem. Bull., Int. Ed. 2011, 60, 368; (c) Mamedov, V. A.; Zhukova, N. A.; Sykaev, V. V.; Gubaidullin, A. T.; Beschastnova, T. N.; Adgamova, D. I.; Samigullina, A. I.; Latypov, Sh. K. Tetrahedron 2013, 69, 1403; (d) Kalinin, A. A.; Isaikina, O. G.; Mamedov, V. A. Chem. Heterocycl. Compd. 2007, 43, 1307; (e) Mamedov, V. A.; Saifina, D. F.; Rizvanov, I. Kh.; Gubaidullin, A. T. Tetrahedron Lett. 2008, 49, 4644; (f) Mamedov, V. A.; Zhukova, N. A.; Beschastnova, T. N.; Gubaidullin, A. T.; Balandina, A. A.; Latypov, Sh. K. Tetrahedron 2010, 66, 9745; (g) Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Gorbunova, E. A.; Litvinov, I. A. Russ. J. Org. Chem. 2006, 42, 1532; (h) Mamedov, V. A.; Zhukova, N. A.; Beschastnova, T. N.; Zakirova, E. I.; Kadyrova, S. F.; Mironova, E. V.; Nikonova, A. G.; Latypov, Sh. K.; Litvinov, I. A. Tetrahedron Lett. 2012, 53, 292; (i) Mamedov, V. A., Zhukova, N. A., Beschastnova, T. N., Gubaidullin, A. T., Rakov, D. V., Rizvanov, I. Kh. Tetrahedron Lett. 2011, 52, 4280; (j) Mamedov, V. A.; Saifina, D. F.; Gubaidullin, A. T.; Ganieva, V. R.; Kadyrova, S. F.; Rakov, D. V.; Rizvanov, I. Kh.; Sinyashin, O. G. Tetrahedron Lett. 2010, 51, 6503; (k) Mamedov, V. A.; Murtazina, A. M.; Gubaidullin, A. T.; Hafizova, E. A.; Rizvanov, I. Kh. Tetrahedron Lett. 2009, 50, 5186; (l) Mamedov, V. A.; Murtazina, A. M.; Gubaidullin, A. T.; Khafizova, E. A.; Rizvanov, I. Kh.; Litvinov, I. A. Russ. Chem. Bull., Int. Ed. 2010, 59, 1645; (m) Mamedov, V. A.; Murtazina, A. M. Russ. Chem. Rev. 2011, 80, 397-420; (n) Mamedov, V. A.; Zhukova, N. A. In Progress in Heterocyclic Chemistry; Gribble, G. W.; Joule, J. A., Eds.; Elsevier: Amsterdam, 2013; Vol. 25, Ch. 1, pp 1-45; (o) Hassner, A.; Namboothiri, I. Organic Syntheses Based on Name Reactions, 3th ed.; Elsevier: Amsterdam, 2012; pp 299-300. 16. (a) Hinsberg, O. Ber. Dtsch. Chem. Ges. 1884, 17, 318; (b) Körner, G. Ber. Dtsch. Chem. Ges. 1884, 17, 572. 17. (a) Debus, H. Ann. 1858, 107, 204; (b) Radziszewski, B. Chem. Ber. 1882, 15, 1493; (c) Japp, F. R.; Robinson, H. H. Chem. Ber. 1882, 15, 1268. 18. Tschitschibabin, A. E. Chem. Ber. 1927, 60, 1607. 19. (a) Knorr, L. Chem. Ber. 1884, 17, 1635; (b) Knorr, L. Ann. 1886, 236, 290. 20 (a) Derome, A. E. Modern NMR Techniques for Chemistry Research; Pergamon: Cambridge, 1988; (b) Atta-ur-Rahman One and Two Dimensional NMR Spectroscopy; Elsevier: Amsterdam, 1989. 21. (a) Bifulco, G.; Dambruoso, P.; Gomez-Paloma, L.; Riccio, R. Chem. Rev. 2007, 107, 3744; (b) Balandina, A. A.; Kalinin, A. A.; Mamedov, V. A.; Figadere, B.; Latypov, Sh. K. Magn. Res. Chem. 2005, 43, 816. 22. Smith, M. B.; March, J. In March’s Advanced Organic Chemistry, 5th ed.; Wiley: New York, 2001; pp 1185-1187. 23. Wang, Z. Comprehensive Organic Name Reactions and Reagents; Wiley: Hoboken, New Jersey, 2009; Vol. 1, pp 1137-1142. 24. Rappoport, Z. The chemistry of enamines; Wiley: Chichester, 1994. 25. Cheeseman, G. W. H.; Cookson, R. F. In Condensed Pyrazines; Wiley-Interscience Publication: New York, 1979. 26. (a) Stott, K.; Stonehouse, J.; Keeler, J.; Hwang, T. L.; Shaka, A. J. J. Am. Chem. Soc. 1995, 117, 4199; (b) Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn. Reson. 1997, 125, 302. 27. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;

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Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople J. A. Gaussian 98, Revision A.3; Gaussian, Inc.: Pittsburgh, PA, 1998. 28. Bergman J.; Engqvist, R.; Stålhandske, Wallberg, H. Tetrahedron 2003, 59, 1033. 29. Dowlatabadi, R.; Khalaj, A.; Rahimian, S.; Montazeri, M.; Amini, M.; Shahverdi, A.; Mahjub, E. Synth. Comm., 2011, 41, 1650. 30 (а) Sarkis, G. Y.; Al-Badri, H. T. J. Heterocycl. Chem. 1980, 17, 813; (b) Shibinskaya, M. O.; Kutuzova, N. A.; Mazepa, A. V.; Lyakhov, S. A.; Andronati, S. A. Zubritsky, M. Ju.; Galat, V. F.; Lipkowski, J.; Kravtsove V. Ch. J. Heterocycl. Chem. 2012, 49, 678. 31. Joshi, K. C.; Chand, P.; Dandia, A. Ind. J. Chem. 1984, 23B, 743.

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Graphical abstract

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Friedländer reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties

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Vakhid A. Mamedov,* Saniya F. Kadyrova, Nataliya A. Zhukova, Venera R. Galimullina, Fedor M. Polyancev, Shamil K. Latypov

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SUPPORTING INFORMATION FOR:

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Friedländer reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties

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Vakhid A. Mamedov,* Saniya F. Kadyrova, Nataliya A. Zhukova, Venera R. Galimullina, Fedor M. Polyancev, Shamil K. Latypov

A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of Russian Academy of Sciences, Arbuzov str. 8, 420088 Kazan, Russian Federation

Table of Contents

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[email protected]

Figure S1. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10h in DMSO at T = 303 K. 1

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Figure S3. 2D 1H-13C HSQC NMR spectra of 10h in DMSO at T = 303 K.

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Figure S4. 2D 1H-13C HMBC NMR spectra of 10h in DMSO at T = 303 K.

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Figure S5. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10i in DMSO at T = 303 K.

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Figure S6. 2D 1H-1H COSY NMR spectra of 10i in DMSO at T = 303 K.

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Figure S7. 2D 1H-13C HSQC NMR spectra of 10i in DMSO at T = 303 K.

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Figure S2. 2D H- H COSY NMR spectra of 10h in DMSO at T = 303 K.

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Figure S8. 2D H- C HMBC NMR spectra of 10i in DMSO at T = 303 K.

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Figure S9. 1D 1H DPFGNOE NMR spectra of 10i in DMSO at T = 303 K.

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Figure S10. 2D 1H-15N HSQC NMR spectra of 10i in DMSO at T = 303 K.

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Figure S12. 2D 19F-1H HETCOR NMR spectra of 10i in DMSO at T = 303 K.

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Figure S13. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10j in DMSO at T = 303 K.

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Figure S14. 2D 1H-1H COSY NMR spectra of 10j in DMSO at T = 303 K.

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Figure S15. 2D 1H-13C HSQC NMR spectra of 10j in DMSO at T = 303 K. 1

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Figure S16. 2D H- C HMBC NMR spectra of 10j in DMSO at T = 303 K. Figure S17. 2D 19F-1H HETCOR NMR spectra of 10j in DMSO at T = 303 K.

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Figure S11. 2D 1H-15N HMBC NMR spectra of 10i in DMSO at T = 303 K.

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Figure S19. 2D 1H-1H COSY NMR spectra of 10k in DMSO at T = 303 K.

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Figure S18. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10k in DMSO at T = 303 K. Figure S20. 2D 1H-13C HSQC NMR spectra of 10k in DMSO at T = 303 K.

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Figure S21. 2D 1H-13C HMBC NMR spectra of 10k in DMSO at T = 303 K.

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Figure S23. 2D 1H-1H COSY NMR spectra of 10l in DMSO at T = 303 K.

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Figure S24. 2D 1H-13C HSQC NMR spectra of 10l in DMSO at T = 303 K.

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Figure S25. 2D 1H-13C HMBC NMR spectra of 10l in DMSO at T = 303 K.

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Figure S26. 1D 1H (a), 1H DPFGNOE (b), and 1H TOCSY (c, d) NMR spectra of 10l in DMSO at T = 303 K.

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Figure S27. 2D 1H-15N HSQC NMR spectra of 10l in DMSO at T = 303 K.

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Figure S22. 1D H (a), H{ F} (b), F{ H} (c), C DEPT (d) and C{ H} (e) NMR spectra of 10l in DMSO at T = 303 K.

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Figure S28. 2D H- N HMBC NMR spectra of 10l in DMSO at T = 303 K.

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Figure S29. 2D 19F-1H HETCOR NMR spectra of 10l in DMSO at T = 303 K.

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Figure S30. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 12a in DMSO at T = 303 K.

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Figure S31. 2D 1H-1H COSY NMR spectra of 12a in DMSO at T = 303 K.

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Figure S32. 2D 1H-13C HSQC NMR spectra of 12a in DMSO at T = 303 K.

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Figure S33. 2D H- C HMBC NMR spectra of 12a in DMSO at T = 303 K. 1

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Figure S34. 1D H (a), H DPFGROE (b, c), and H TOCSY (d, e and f) NMR spectra of 12a in DMSO at T = 303 K. S2

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Figure S36. 2D 1H-15N HMBC NMR spectra of 12a in DMSO at T = 303 K.

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Figure S37. 1D 1H (a), 1H{19F} (b), 19F{1H} (c) and 13C{1H} (d) NMR spectra of 12b in DMSO at T = 303 K.

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Figure S38. 2D 1H-1H COSY NMR spectra of 12b in DMSO at T = 303 K.

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Figure S39. 2D 1H-13C HSQC NMR spectra of 12b in DMSO at T = 303 K. 1

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Figure S40. 2D H- C HMBC NMR spectra of 12b in DMSO at T = 303 K.

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Figure S35. 2D 1H-15N HSQC NMR spectra of 12a in DMSO at T = 303 K.

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Figure S42. 2D 19F-1H HETCOR NMR spectra of 12b in DMSO at T = 303 K.

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Figure S41. 1D 1H (a), 1H DPFGROE (b, c, d), and 1H TOCSY (e, f and g) NMR spectra of 12b in DMSO at T = 303 K.

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Figure S43. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 17a in DMSO at T = 303 K.

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Figure S44. 2D 1H-1H COSY NMR spectra of 17a in DMSO at T = 303 K.

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Figure S45. 2D 1H-13C HSQC NMR spectra of 17a in DMSO at T = 303 K.

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Figure S47. 1D 1H TOCSY NMR spectra of 17a in DMSO at T = 303 K.

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Figure S48. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 17b in DMSO at T = 303 K.

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Figure S49. 2D 1H-1H COSY NMR spectra of 17b in DMSO at T = 303 K.

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Figure S50. 2D 1H-13C HSQC NMR spectra of 17b in DMSO at T = 303 K.

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Figure S51. 2D 1H-13C HMBC NMR spectra of 17b in DMSO at T = 303 K.

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Figure S46. 2D H- C HMBC NMR spectra of 17a in DMSO at T = 303 K.

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Figure S52. 1D H DPFGNOE NMR spectra of 17b in DMSO at T = 303 K.

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Figure S53. 2D 1H-15N HMBC NMR spectra of 17b in DMSO at T = 303 K.

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Figure S54. 2D 19F-1H HETCOR NMR spectra of 17b in DMSO at T = 303 K.

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Figure S55. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 18a in DMSO at T = 303 K.

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Figure S56. 2D 1H-1H COSY NMR spectra of 18a in DMSO at T = 303 K.

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Figure S57. 2D H- C HSQC NMR spectra of 18a in DMSO at T = 303 K. Figure S58. 2D H- C HMBC NMR spectra of 18a in DMSO at T = 303 K. S3

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Figure S60. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 18b in CDCl3 at T = 303 K.

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Figure S61. 2D 1H-1H COSY NMR spectra of 18b in CDCl3 at T = 303 K.

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Figure S62. 2D 1H-13C HSQC NMR spectra of 18b in CDCl3 at T = 303 K.

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Figure S63. 2D 1H-13C HMBC NMR spectra of 18b in CDCl3 at T = 303 K. 1

Figure S64. 1D H TOCSY NMR spectra of 18b in CDCl3 at T = 303 K.

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Figure S65. 2D 19F-1H HETCOR NMR spectra of 18b in CDCl3 at T = 303 K. Calculation

Figure S68. Calculated vs. experimental 13C chemical shifts for 7b. 15

Figure S69. Calculated vs. experimental N chemical shifts for 7b. Figure S70. Calculated vs. experimental 13C chemical shifts for 8a.

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Figure S66. Calculated vs. experimental 13C chemical shifts for 7a. Figure S67. Calculated vs. experimental 15N chemical shifts for 7a.

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Figure S59. 1D 1H TOCSY NMR spectra of 18a in DMSO at T = 303 K.

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Figure S72. Calculated vs. experimental 13C chemical shifts for 10g.

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Figure S73. Calculated vs. experimental 13C chemical shifts for 10h.

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Figure S74. Calculated vs. experimental 13C chemical shifts for 10l

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Figure S71. Calculated vs. experimental 13C chemical shifts for 8b.

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Figure S75. Calculated vs. experimental C chemical shifts for 12a. Figure S76. Calculated vs. experimental 13C chemical shifts for 12b.

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Figure S77. Calculated vs. experimental 13C chemical shifts for 17a.

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Figure S78. Calculated vs. experimental 13C chemical shifts for 17b.

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Figure S79. Calculated vs. experimental 13C chemical shifts for 18a.

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Figure S80. Calculated vs. experimental C chemical shifts for 18b.

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Figure S1. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10h in DMSO at T = 303 K. S5

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Figure S2. 2D 1H-1H COSY NMR spectra of 10h in DMSO at T = 303 K. S6

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Figure S3. 2D 1H-13C HSQC NMR spectra of 10h in DMSO at T = 303 K. S7

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Figure S4. 2D 1H-13C HMBC NMR spectra of 10h in DMSO at T = 303 K. S8

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Figure S5. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10i in DMSO at T = 303 K. S9

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Figure S6. 2D 1H-1H COSY NMR spectra of 10i in DMSO at T = 303 K. S10

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Figure S7. 2D 1H-13C HSQC NMR spectra of 10i in DMSO at T = 303 K. S11

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Figure S8. 2D 1H-13C HMBC NMR spectra of 10i in DMSO at T = 303 K. S12

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Figure S9. 1D 1H DPGNOE NMR spectra of 10i in DMSO at T = 303 K. S13

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Figure S10. 2D 1H-15N HSQC NMR spectra of 10i in DMSO at T = 303 K. S14

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Figure S11. 2D 1H-15N HMBC NMR spectra of 10i in DMSO at T = 303 K. S15

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Figure S12. 2D 19F-1H HETCOR NMR spectra of 10i in DMSO at T = 303 K. S16

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Figure S13. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10j in DMSO at T = 303 K.

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Figure S14. 2D 1H-1H COSY NMR spectra of 10j in DMSO at T = 303 K. S18

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Figure S15. 2D 1H-13C HSQC NMR spectra of 10j in DMSO at T = 303 K. S19

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Figure S16. 2D 1H-13C HMBC NMR spectra of 10j in DMSO at T = 303 K. S20

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Figure S17. 2D 19F-1H HETCOR NMR spectra of 10j in DMSO at T = 303 K. S21

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Figure S18. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10k in DMSO at T = 303 K.

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Figure S19. 2D 1H-1H COSY NMR spectra of 10k in DMSO at T = 303 K. S23

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Figure S20. 2D 1H-13C HSQC NMR spectra of 10k in DMSO at T = 303 K. S24

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Figure S21. 2D 1H-13C HMBC NMR spectra of 10k in DMSO at T = 303 K. S25

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Figure S22. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10l in DMSO at T = 303 K. S26

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Figure S23. 2D 1H-1H COSY NMR spectra of 10l in DMSO at T = 303 K. S27

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Figure S24. 2D 1H-13C HSQC NMR spectra of 10l in DMSO at T = 303 K. S28

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Figure S25. 2D 1H-13C HMBC NMR spectra of 10l in DMSO at T = 303 K. S29

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Figure S26. 1D 1H (a), 1H DPFGNOE (b), and 1H TOCSY (c, d) NMR spectra of 10l in DMSO at T = 303 K.

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Figure S27. 2D 1H-15N HSQC NMR spectra of 10l in DMSO at T = 303 K. S31

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Figure S28. 2D 1H-15N HMBC NMR spectra of 10l in DMSO at T = 303 K. S32

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Figure S29. 2D 19F-1H HETCOR NMR spectra of 10l in DMSO at T = 303 K. S33

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Figure S30. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 12a in DMSO at T = 303 K.

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Figure S31. 2D 1H-1H COSY NMR spectra of 12a in DMSO at T = 303 K. S35

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Figure S32. 2D 1H-13C HSQC NMR spectra of 12a in DMSO at T = 303 K. S36

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Figure S33. 2D 1H-13C HMBC NMR spectra of 12a in DMSO at T = 303 K. S37

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Figure S34. 1D 1H (a), 1H DPFGROE (b, c), and 1H TOCSY (d, e and f) NMR spectra of 12a in DMSO at T = 303 K. S38

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Figure S35. 2D 1H-15N HSQC NMR spectra of 12a in DMSO at T = 303 K. S39

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Figure S36. 2D 1H-15N HMBC NMR spectra of 12a in DMSO at T = 303 K. S40

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Figure S37. 1D 1H (a), 1H{19F} (b), 19F{1H} (c) and 13C{1H} (d) NMR spectra of 12b in DMSO at T = 303 K.

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Figure S38. 2D 1H-1H COSY NMR spectra of 12b in DMSO at T = 303 K. S42

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Figure S39. 2D 1H-13C HSQC NMR spectra of 12b in DMSO at T = 303 K. S43

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Figure S40. 2D 1H-13C HMBC NMR spectra of 12b in DMSO at T = 303 K. S44

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Figure S41. 1D 1H (a), 1H DPFGROE (b, c, d), and 1H TOCSY (e, f and g) NMR spectra of 12b in DMSO at T = 303 K. S45

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Figure S42. 2D 19F-1H HETCOR NMR spectra of 12b in DMSO at T = 303 K. S46

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Figure S43. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 17a in DMSO at T = 303 K.

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Figure S44. 2D 1H-1H COSY NMR spectra of 17a in DMSO at T = 303 K. S48

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Figure S45. 2D 1H-13C HSQC NMR spectra of 17a in DMSO at T = 303 K. S49

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Figure S46. 2D 1H-13C HMBC NMR spectra of 17a in DMSO at T = 303 K. S50

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Figure S47. 1D 1H TOCSY NMR spectra of 17a in DMSO at T = 303 K.

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Figure S48. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 17b in DMSO at T = 303 K. S52

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Figure S49. 2D 1H-1H COSY NMR spectra of 17b in DMSO at T = 303 K. S53

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Figure S50. 2D 1H-13C HSQC NMR spectra of 17b in DMSO at T = 303 K. S54

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Figure S51. 2D 1H-13C HMBC NMR spectra of 17b in DMSO at T = 303 K. S55

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Figure S52. 1D 1H DPFGNOE NMR spectra of 17b in DMSO at T = 303 K.

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Figure S53. 2D 1H-15N HMBC NMR spectra of 17b in DMSO at T = 303 K. S57

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Figure S54. 2D 19F-1H HETCOR NMR spectra of 17b in DMSO at T = 303 K. S58

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Figure S55. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 18a in DMSO at T = 303 K.

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Figure S56. 2D 1H-1H COSY NMR spectra of 18a in DMSO at T = 303 K. S60

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Figure S57. 2D 1H-13C HSQC NMR spectra of 18a in DMSO at T = 303 K. S61

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Figure S58. 2D 1H-13C HMBC NMR spectra of 18a in DMSO at T = 303 K. S62

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Figure S59. 1D 1H TOCSY NMR spectra of 18a in DMSO at T = 303 K.

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Figure S60. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 18b in CDCl3 at T = 303 K. S64

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Figure S61. 2D 1H-1H COSY NMR spectra of 18b in CDCl3 at T = 303 K. S65

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Figure S62. 2D 1H-13C HSQC NMR spectra of 18b in CDCl3 at T = 303 K. S66

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Figure S63. 2D 1H-13C HMBC NMR spectra of 18b in CDCl3 at T = 303 K. S67

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Figure S64. 1D 1H TOCSY NMR spectra of 18b in CDCl3 at T = 303 K.

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Figure S65. 2D 19F-1H HETCOR NMR spectra of 18b in CDCl3 at T = 303 K. S69

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Calculations.

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Figure S66. Calculated vs. experimental 13C chemical shifts for 7a. S70

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Figure S67. Calculated vs. experimental 15N chemical shifts for 7a.

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Figure S68. Calculated vs. experimental 13C chemical shifts for 7b. S72

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Figure S69. Calculated vs. experimental 15N chemical shifts for 7b.

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Figure S70. Calculated vs. experimental 13C chemical shifts for 8a.

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Figure S71. Calculated vs. experimental 13C chemical shifts for 8b.

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Figure S72. Calculated vs. experimental 13C chemical shifts for 10g.

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Figure S73. Calculated vs. experimental 13C chemical shifts for 10h.

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Figure S74. Calculated vs. experimental 13C chemical shifts for 10l.

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Figure S75. Calculated vs. experimental 13C chemical shifts for 12a.

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Figure S76. Calculated vs. experimental 13C chemical shifts for 12b.

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Figure S77. Calculated vs. experimental 13C chemical shifts for 17a.

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Figure S78. Calculated vs. experimental 13C chemical shifts for 17b.

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Figure S79. Calculated vs. experimental 13C chemical shifts for 18a.

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Figure S80. Calculated vs. experimental 13C chemical shifts for 18b.

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SUPPORTING INFORMATION FOR:

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Friedländer reaction/quinoxalinone-benzimidazole rearrangement sequence: expeditious entry to diverse quinoline derivatives with the benzimidazole moieties

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Vakhid A. Mamedov,* Saniya F. Kadyrova, Nataliya A. Zhukova, Venera R. Galimullina, Fedor M. Polyancev, Shamil K. Latypov

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A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of Russian Academy of Sciences, Arbuzov str. 8, 420088 Kazan, Russian Federation [email protected]

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Table of Contents

General Methods References

Page S4 S5 S6

Figure S2. 2D 1H-1H COSY NMR spectra of 7a in DMSO at T = 303 K.

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Figure S3. 2D 1H-13C HSQC NMR spectra of 7a in DMSO at T = 303 K.

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Figure S4. 2D 1H-13C HMBC NMR spectra of 7a in DMSO at T = 303 K.

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Figure S1. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 7a in DMSO at T = 303 K

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Figure S5. 1D H (a), H DPFGNOE (b), and H TOCSY (c, d) NMR spectra of 7a in DMSO at T = 303 K.

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Figure S6. 2D 1H-15N HSQC NMR spectra of 7a in DMSO at T = 303 K.

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Figure S7. 2D 1H-15N HMBC NMR spectra of 7a in DMSO at T = 303 K.

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Figure S8. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 7b in DMSO at T = 303 K.

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Figure S9. 2D 1H-1H COSY NMR spectra of 7b in DMSO at T = 303 K.

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Figure S11. 2D 1H-13C HMBC NMR spectra of 7b in DMSO at T = 303 K.

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Figure S12. 1D 1H (a), 1H DPFGNOE (b), and 1H TOCSY (c, d) NMR spectra of 7b in DMSO at T = 303 K.

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Figure S13. 2D 1H-15N HSQC NMR spectra of 7b in DMSO at T = 303 K.

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Figure S14. 2D 1H-15N HMBC NMR spectra of 7b in DMSO at T = 303 K. 19

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Figure S15. 2D F- H HETCOR NMR spectra of 7b in DMSO at T = 303 K.

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Figure S10. 2D 1H-13C HSQC NMR spectra of 7b in DMSO at T = 303 K.

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Figure S17. 2D 1H-1H COSY NMR spectra of 8a in DMSO at T = 303 K.

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Figure S18. 2D 1H-13C HSQC NMR spectra of 8a in DMSO at T = 303 K.

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Figure S16. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 8a in DMSO at T = 303 K.

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Figure S19. 2D 1H-13C HMBC NMR spectra of 8a in DMSO at T = 303 K.

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Figure S20. 1D 1H DPFGNOE NMR spectra of 8a in DMSO at T = 303 K.

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Figure S22. 2D 1H-15N HMBC NMR spectra of 8a in DMSO at T = 303 K.

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Figure S23. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S24. 2D 1H-1H COSY NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S25. 2D 1H-13C HSQC NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S26. 2D 1H-13C HMBC NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S21. 2D H- N HSQC NMR spectra of 8a in DMSO at T = 303 K.

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Figure S27. 1D H DPFGNOE NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S28. 2D 1H-15N HSQC NMR spectra of 8a in DMSO at T = 303 K.

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Figure S29. 2D 1H-15N HMBC NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S30. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 8b in DMSO at T = 303 K.

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Figure S31. 2D 1H-1H COSY NMR spectra of 8b in DMSO at T = 303 K.

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Figure S32. 2D H- C HSQC NMR spectra of 8b in DMSO at T = 303 K. Figure S33. 2D H- C HMBC NMR spectra of 8b in DMSO at T = 303 K. S2

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Figure S35. 2D 1H-15N HSQC NMR spectra of 8b in DMSO at T = 303 K.

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Figure S36. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10a in DMSO at T = 303 K.

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Figure S37. 2D 1H-1H COSY NMR spectra of 10a in DMSO at T = 303 K.

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Figure S38. 2D 1H-13C HSQC NMR spectra of 10a in DMSO at T = 303 K. 1

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Figure S39. 2D H- C HMBC NMR spectra of 10a in DMSO at T = 303 K.

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Figure S34. 1D 1H DPFGNOE NMR spectra of 8b in DMSO at T = 303 K.

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Figure S41. 2D 1H-1H COSY NMR spectra of 10b in DMSO at T = 303 K.

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Figure S42. 2D 1H-13C HSQC NMR spectra of 10b in DMSO at T = 303 K.

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Figure S40. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10b in DMSO at T = 303 K.

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Figure S43. 2D 1H-13C HMBC NMR spectra of 10b in DMSO at T = 303 K.

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Figure S44. 1D 1H DPFGNOE NMR spectra of 10b in DMSO at T = 303 K.

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Figure S46. 2D 1H-15N HMBC NMR spectra of 10b in DMSO at T = 303 K.

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Figure S47. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10c in DMSO at T = 303 K.

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Figure S48. 2D 1H-1H COSY NMR spectra of 10c in DMSO at T = 303 K.

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Figure S49. 2D 1H-13C HSQC NMR spectra of 10c in DMSO at T = 303 K.

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Figure S50. 2D 1H-13C HMBC NMR spectra of 10c in DMSO at T = 303 K.

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Figure S45. 2D H- N HSQC NMR spectra of 10b in DMSO at T = 303 K.

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Figure S51. 1D H (a), C DEPT (b) and C{ H} (c) NMR spectra of 10d in DMSO at T = 303 K.

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Figure S52. 2D 1H-1H COSY NMR spectra of 10d in DMSO at T = 303 K.

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Figure S53. 2D 1H-13C HSQC NMR spectra of 10d in DMSO at T = 303 K.

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Figure S54. 2D 1H-13C HMBC NMR spectra of 10d in DMSO at T = 303 K.

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Figure S55. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10e in DMSO at T = 303 K.

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Figure S56. 2D H- H COSY NMR spectra of 10e in DMSO at T = 303 K. Figure S57. 2D H- C HSQC NMR spectra of 10e in DMSO at T = 303 K. S3

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Figure S59. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10f in DMSO at T = 303 K.

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Figure S60. 2D 1H-1H COSY NMR spectra of 10f in DMSO at T = 303 K.

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Figure S61. 2D 1H-13C HSQC NMR spectra of 10f in DMSO at T = 303 K.

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Figure S62. 2D 1H-13C HMBC NMR spectra of 10f in DMSO at T = 303 K. 1

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Figure S58. 2D 1H-13C HMBC NMR spectra of 10e in DMSO at T = 303 K.

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Figure S64. 2D 1H-1H COSY NMR spectra of 10g in DMSO at T = 303 K.

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Figure S65. 2D 1H-13C HSQC NMR spectra of 10g in DMSO at T = 303 K.

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Figure S66. 2D 1H-13C HMBC NMR spectra of 10g in DMSO at T = 303 K.

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Figure S63. 1D H (a), H{ F} (b), F{ H} (c), C DEPT (d) and C{ H} (e) NMR spectra of 10g in DMSO at T = 303 K.

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Figure S67. 1D 1H DPFGNOE NMR spectra of 10g in DMSO at T = 303 K.

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Figure S68. 2D 1H-15N HSQC NMR spectra of 10g in DMSO at T = 303 K.

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Figure S69. 2D H- N HMBC NMR spectra of 10g in DMSO at T = 303 K.

General Methods

All NMR experiments were performed with a 600 and 400 spectrometers equipped with a 5 mm diameter gradient inverse broad band probehead and a

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pulsed gradient unit capable of producing magnetic field pulse gradients in the z-direction of 53.5 G·cm-1. Frequencies are 600 and 400 MHz for 1H

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NMR, 150 and 100 MHz for 13C NMR, 60 MHz for 15N NMR (at 600) experiments, and 376 MHz (at 400) for 19F NMR experiments were carried out using standard Bruker pulse programs. The pulse widths were 7 µs (90°) and 12 µs (90°) for 1H at 600 and 400, 12 µs (90°) and 9 µs (90°) for 13C at 600 and 400, 26 µs (90°) for

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N at 600 and 20 µs (90°) for

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F at 400, respectively. Typically 16K and 64K data points were collected for one-

dimensional proton and carbon/nitrogen/fluorine spectra, respectively. 2D experiments parameters were as follows. For 1H–1H correlations (COSY): relaxation delay 1.5 s, data matrix 1K x 2K (256 experiments to 0.5K, zero filling in F1, 1K in F2), 2 transients in each experiment. For 1H-13C correlations (HSQC): optimized for J = 145 Hz, relaxation delay 2.5 s, data matrix 0.5K x 2K (256 experiments to 0.5K, zero filling in F1, 2K in F2), 16 transients in each experiment. For 1H-13C long range correlations (HMBC): optimized for J = 8Hz, relaxation delay 2.5 s, data matrix 0.5K x 2K S4

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(256 experiments to 0.5K, zero filling in F1, 2K in F2), 48 transients in each experiment. For 19F-1H correlations (HETCORR): optimized for J = 20 Hz, relaxation delay 3 s, data matrix 64 x 2K (64 experiments in F1, 2K in F2), 8 transients in each experiment. For 1H-15N correlations (HSQC): optimized for J = 96 Hz, relaxation delay 2 s, data matrix 64 x 2K (64 experiments in F1, 2K in F2), 64 transients in each experiment. For 1H-15N long

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range correlations (HMBC): optimized for J = 8Hz, relaxation delay 2 s, data matrix 0.5K x 2K (256 experiments to 0.5K, zero filling in F1, 2K in F2), 256 transients in each experiment. All 2D spectra were weighted with sine-bell squared and shifted (π/2 in both dimensions) window functions, and processed with the Bruker software package. DPFGNOE, DPFGROE and TOCSY spectra were obtained using a spectral width of 20.03 ppm to give a

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digital resolution of 0.73 Hz per point, an RD of 8.00 s and an AT of 1.36 s. A Hermite-shaped pulse was used for selective excitation. Calculations

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The quantum chemical calculations were performed using Gaussian 98w software package. Full geometry optimizations have been carried out within the framework of DFT (B3LYP) method using 6-31G(d) basis sets. Chemical shifts (CSs) were calculated by the GIAO method at the same level of theory. All data were referred to TMS (1H and

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C) and NH3 (15N) chemical shifts, which were calculated under the same conditions. The chemical

shifts of carbons connected directly to chlorine and bromine atoms were excluded from consideration due GIAO calculatuons do not reproduce

References

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correctly influence of third group elements vicinal to carbon under consideration.1,2

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(1) Balandina, A. A.; Kalinin, A. A.; Mamedov, V. A.; Figadere, B.; Latypov, Sh. K. Magn. Res. Chem. 2005, 43, 816-828.

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(2) Claramunt, R. M.; Lopez, C.; Santa Maria, M. D.; Sanz, D.; Elguero, J. Progr. Nucl. Magn. Res. Spectr. 2006, 49, 169-206.

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Figure S1. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 7a in DMSO at T = 303 K. S6

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Figure S2. 2D 1H-1H COSY NMR spectra of 7a in DMSO at T = 303 K. S7

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Figure S3. 2D 1H-13C HSQC NMR spectra of 7a in DMSO at T = 303 K. S8

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Figure S4. 2D 1H-13C HMBC NMR spectra of 7a in DMSO at T = 303 K. S9

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Figure S5. 1D 1H (a), 1H DPFGNOE (b), and 1H TOCSY (c, d) NMR spectra of 7a in DMSO at T = 303 K.

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Figure S6. 2D 1H-15N HSQC NMR spectra of 7a in DMSO at T = 303 K. S11

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Figure S7. 2D 1H-15N HMBC NMR spectra of 7a in DMSO at T = 303 K. S12

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Figure S8. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 7b in DMSO at T = 303 K. S13

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Figure S9. 2D 1H-1H COSY NMR spectra of 7b in DMSO at T = 303 K. S14

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Figure S10. 2D 1H-13C HSQC NMR spectra of 7b in DMSO at T = 303 K. S15

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Figure S11. 2D 1H-13C HMBC NMR spectra of 7b in DMSO at T = 303 K. S16

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Figure S12. 1D 1H DPFGNOE NMR spectra of 7a in DMSO at T = 303K 1D 1H (a), 1H DPFGNOE (b), and 1H TOCSY (c, d) NMR spectra of 7b in DMSO at T = 303 K. S17

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Figure S13. 2D 1H-15N HSQC NMR spectra of 7b in DMSO at T = 303 K. S18

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Figure S14. 2D 1H-15N HMBC NMR spectra of 7b in DMSO at T = 303 K. S19

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Figure S15. 2D 19F-1H HETCOR NMR spectra of 7b in DMSO at T = 303 K. S20

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Figure S16. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 8a in DMSO at T = 303 K. S21

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Figure S17. 2D 1H-1H COSY NMR spectra of 8a in DMSO at T = 303 K. S22

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Figure S18. 2D 1H-13C HSQC NMR spectra of 8a in DMSO at T = 303 K. S23

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Figure S19. 2D 1H-13C HMBC NMR spectra of 8a in DMSO at T = 303 K. S24

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Figure S20. 1D 1H DPFGNOE NMR spectra of 8a in DMSO at T = 303 K. S25

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Figure S21. 2D 1H-15N HSQC NMR spectra of 8a in DMSO at T = 303 K. S26

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Figure S22. 2D 1H-15N HMBC NMR spectra of 8a in DMSO at T = 303 K. S27

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Figure S23. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S24. 2D 1H-1H COSY NMR spectra of 8a’ in DMSO at T = 303 K. S29

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Figure S25. 2D 1H-13C HSQC NMR spectra of 8a’ in DMSO at T = 303 K. S30

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Figure S26. 2D 1H-13C HMBC NMR spectra of 8a’ in DMSO at T = 303 K. S31

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Figure S27. 1D 1H DPFGNOE NMR spectra of 8a’ in DMSO at T = 303 K.

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Figure S28. 2D 1H-15N HSQC NMR spectra of 8a’ in DMSO at T = 303 K. S33

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Figure S29. 2D 1H-15N HMBC NMR spectra of 8a’ in DMSO at T = 303 K. S34

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Figure S30. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 8b in DMSO at T = 303 K.. S35

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Figure S31. 2D 1H-1H COSY NMR spectra of 8b in DMSO at T = 303 K. S36

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Figure S32. 2D 1H-13C HSQC NMR spectra of 8b in DMSO at T = 303 K. S37

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Figure S33. 2D 1H-13C HMBC NMR spectra of 8b in DMSO at T = 303 K. S38

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Figure S34. 1D 1H DPFGNOE NMR spectra of 8b in DMSO at T = 303 K.

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Figure S35. 2D 1H-15N HSQC NMR spectra of 8b in DMSO at T = 303 K. S40

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Figure S36. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10a in DMSO at T = 303 K.

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Figure S37. 2D 1H-1H COSY NMR spectra of 10a in DMSO at T = 303 K. S42

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Figure S38. 2D 1H-13C HSQC NMR spectra of 10a in DMSO at T = 303 K. S43

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Figure S39. 2D 1H-13C HMBC NMR spectra of 10a in DMSO at T = 303 K. S44

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Figure S40. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10b in DMSO at T = 303 K. S45

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Figure S41. 2D 1H-1H COSY NMR spectra of 10b in DMSO at T = 303 K. S46

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Figure S42. 2D 1H-13C HSQC NMR spectra of 10b in DMSO at T = 303 K. S47

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Figure S43. 2D 1H-13C HMBC NMR spectra of 10b in DMSO at T = 303 K. S48

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Figure S44. 1D 1H DPFGNOE NMR spectra of 10b in DMSO at T = 303 K. S49

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Figure S45. 2D 1H-15N HSQC NMR spectra of 10b in DMSO at T = 303 K. S50

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Figure S46. 2D 1H-15N HMBC NMR spectra of 10b in DMSO at T = 303 K. S51

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Figure S47. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10c in DMSO at T = 303 K.

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Figure S48. 2D 1H-1H COSY NMR spectra of 10c in DMSO at T = 303 K. S53

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Figure S49. 2D 1H-13C HSQC NMR spectra of 10c in DMSO at T = 303 K. S54

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Figure S50. 2D 1H-13C HMBC NMR spectra of 10c in DMSO at T = 303 K. S55

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Figure S51. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10d in DMSO at T = 303 K.

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Figure S52. 2D 1H-1H COSY NMR spectra of 10d in DMSO at T = 303 K. S57

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Figure S53. 2D 1H-13C HSQC NMR spectra of 10d in DMSO at T = 303 K. S58

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Figure S54. 2D 1H-13C HMBC NMR spectra of 10d in DMSO at T = 303 K. S59

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Figure S55. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10e in DMSO at T = 303 K. S60

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Figure S56. 2D 1H-1H COSY NMR spectra of 10e in DMSO at T = 303 K. S61

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Figure S57. 2D 1H-13C HSQC NMR spectra of 10e in DMSO at T = 303 K. S62

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Figure S58. 2D 1H-13C HMBC NMR spectra of 10e in DMSO at T = 303 K. S63

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Figure S59. 1D 1H (a), 13C DEPT (b) and 13C{1H} (c) NMR spectra of 10f in DMSO at T = 303 K. S64

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Figure S60. 2D 1H-1H COSY NMR spectra of 10f in DMSO at T = 303 K. S65

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Figure S61. 2D 1H-13C HSQC NMR spectra of 10f in DMSO at T = 303 K. S66

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Figure S62. 2D 1H-13C HMBC NMR spectra of 10f in DMSO at T = 303 K. S67

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Figure S63. 1D 1H (a), 1H{19F} (b), 19F{1H} (c), 13C DEPT (d) and 13C{1H} (e) NMR spectra of 10g in DMSO at T = 303 K. S68

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Figure S64. 2D 1H-1H COSY NMR spectra of 10g in DMSO at T = 303 K. S69

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Figure S65. 2D 1H-13C HSQC NMR spectra of 10g in DMSO at T = 303 K. S70

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Figure S66. 2D 1H-13C HMBC NMR spectra of 10g in DMSO at T = 303 K. S71

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Figure S67. 1D 1H DPFGNOE NMR spectra of 10g in DMSO at T = 303 K.

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Figure S68. 2D 1H-15N HSQC NMR spectra of 10g in DMSO at T = 303 K. S73

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Figure S69. 2D 1H-15N HMBC NMR spectra of 10g in DMSO at T = 303 K. S74