Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the synthesis of 7-amino-6-azaindoles

Tetrahedron 71 (2015) 1311e1321

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Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the synthesis of 7-amino-6-azaindoles Maxim A. Nechayev a, b, Nikolay Yu. Gorobets c, *, Svetlana V. Shishkina c, Oleg V. Shishkin c, Sergiy M. Kovalenko a a b c

National University of Pharmacy, Pushkinska Str. 53, Kharkiv 61002, Ukraine Enamine Ltd., Alexandra Matrosova Street, 23, Kiev 01103, Ukraine SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 October 2014 Received in revised form 1 December 2014 Accepted 15 December 2014 Available online 30 December 2014

Derivatives of 7-amino-6-azaindole containing variable substituent in the amino group were synthesized via acid-catalyzed nucleophilic heteroaromatic substitution (SNHetarHþ) using 7-chloro-6-azaindoles as substrates and aliphatic and aromatic amines as nucleophiles. The protonation of the pyridine nitrogen in the starting 7-chloro-6-azaindoles is presumed to be the key stage of the reaction mechanism discussed. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: 6-Azaindole b-Carboline Microwave-assisted organic synthesis Nucleophilic heteroaromatic substitution Acidic catalysis

1. Introduction In the past 40 years the classical methods for the synthesis of indole core1 were effectively used for construction of indole azaanalogues.2e5 As a result, several new heterocyclic scaffolds were identified that possess a wide range of biological activities.6e10 Consequently, the development of novel practically useful approaches to the synthesis of this heterocyclic family has gained considerable attention. The most widely usable strategies to the azaindole core are based on the formation of pyrrole ring onto an existing pyridine fragment using the classical methods for indole synthesis such as Leimgruber-Batcho,11e15 Hemetsberger-Knittel,16 Bartoli,17e20 or Larock21e26 reactions. On the other hand more specific methods that start from a pyrrole derivative are still much less explored and applicable.27e29 6-Azaindoles are not found in natural sources ‘as they are’, but the fragment of 6-azaindole is presented in a considerable number of alkaloids of b-carboline family30,31 (Scheme 1). Another example is represented by the marine alkaloid Marinoquinoline A isolated recently from the gliding bacterium Rapidithrix thailandica TISTR 1742.32 Nevertheless, different 7-amino-6-azaindole derivatives are

* Corresponding author. Fax: þ380 573409343; e-mail address: gorobets@isc. kharkov.com (N.Yu. Gorobets). http://dx.doi.org/10.1016/j.tet.2014.12.057 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

Scheme 1. Pyrrolo[2,3-c]pyridine-7-one scaffold 1 and related natural products.

suggested for treating kinase-associated diseases,33,34 viral infections,35 such as HIV and AIDS,8,36e38 chronic pain,19,39 gastroesophageal reflux40e42 and cancer.43 The related 1-amino-bcarboline derivatives were shown to be able to intercalate DNA helix44,45 and recognized as anticancer,45 antimalarial45,46 and antiprion46 agents. Due to the continuous interest in novel approaches to the 2pyridone ring formation,47e50 we have recently developed an efficient synthesis of 1-substituted pyrrolo[2,3-c]pyridine-7-ones51 (1, Scheme 1). In current work we were intrigued by a possibility to apply these synthetically available heterocycles as a cheap and

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suitable starting material for the synthesis of substituted 7-amino6-azaindoles avoiding a low yielding Bartoli reaction generally used in the synthesis of 5-halogeno-6-azaindole intermediates.19,20,52 The main synthetic approach to 7-amino-6-azaindoles is heteroaromatic nucleophilic substitution in 7-halogenated-6azaindole derivatives, which is described mostly in patent literature and exampled by uncatalyzed reactions of 7-halogeno-6azaindoles with amines in pyridine,43 acid-catalyzed reactions,19,39,40 as well as using copper35e37,52 or palladium41 catalysts. Neat reagents were used to obtain related 1-amino-bcarboline derivatives.45,46 All these approaches require high reaction temperatures and long heating time up to 40 h. Since such reactions seems to be feasible only under vigorous conditions, the simplicity of introduction of the amine component into the azaindole ring using such methods is counterbalanced with the loss of chemical flexibility: application of metal catalysts, long reaction times and often low yields. The similar difficulties also refer to the b-carboline series.44,45 In the current work a novel efficient synthetic pathway to 7amino-6-azaindoles is presented using a combination of previously described pyrrole-2-carboxylic acid based synthesis of heterocyclic core 151 (Scheme 1) followed by its transformation into 7-chloro-6-azaindoles and acid-catalyzed heteroaromatic nucleophilic chlorine substitution with aliphatic and aromatic amines under microwave conditions.

Table 1 Preparation and isolated yields of N1-substituted 7-chloro-6-azaindoles 2aed

Starting material

Product

Yield, %

71

91

2. Results and discussions The synthesis of initial compounds 1aed (Table 1) was accomplished starting from pyrrole-2-carboxylic acids as was previously described.51 The b-carboline derivative 1e was synthesized from indole-2-carboxylic acid using the same general procedures. Compounds 1aee were transformed into required N1-substituted 7-chloro-6-azaindoles 2aed and 1-chloro-9-methyl-9H-b-carboline 2e by heating in POCl3 with good to excellent yields (Table 1) following the reported procedure for 2a.53 To find acceptable conditions for nucleophilic substitution, initially the excess of morpholine (5.0 equiv) was involved into reaction with 2a under microwave irradiation at 190  C in butan-1-ol. It was convenient to use this polar and high boiling point solvent to guarantee a satisfactory absorption of microwave power and the safe level of internal pressure inside a closed vial under such a high temperature. The reaction proceeded during 150 min until no more starting material was observed on a TLC plate (TLC control every 10e20 min) to give the desired product 3a in 52% isolated yield (Table 2). Reasoning about further direction of optimization, beside the usual requirements of high isolated yields, the following considerations have been taken into account. The reaction conditions should allow: avoiding less facile metal-catalyzed reaction conditions (a); ensuring the possibility to apply ‘small’ aliphatic amines (b). The ‘small’ aliphatic amines are the first option when a synthetic method is applied for medicinal chemistry purposes because the low molecular weights of the synthesized products are dictated by the leadlikeness criteria. On the other hand, they are volatile or even gaseous and would create additional pressure inside a sealed microwave vial under evaluated temperatures. Among available catalytic systems, we have examined the application of strong acidic catalysis as the simplest option for the beginning that also meets criteria (a) and (b). The application of such catalysis was previously described for nucleophilic substitution with anilines for particular aza-heterocycles54e56 including 7-chloro-6-azaindole derivatives19,39 with ‘active’ halogen and this process was reported to be autocatalytic, since hydrochloric acid is formed during the reaction. The autocatalytic character of a similar substitution was also observed in the reaction of 2-chloro-N-ethyl pyridin-3-

76

92

88

amine with piperazine in toluene, and this reaction was reported to be 1.8 times faster without the use of sodium carbonate as an acid scavenger.57 However, to our surprise, the use of acidic catalyst for nucleophilic (hetero)aromatic substitution58,59 is much less described in the literature comparing with application of different base- and transition metal-catalyzed approaches.60 Thus, the model microwave-assisted reactions of 2a with morpholine and aniline in the presence of methanesulfonic acid (MSA) were further studied.

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Table 2 Search for acceptable conditions for the nucleophilic substitution using representative 7-chloro-6-azaindole 2a, morpholine and aniline. The optimal conditions are highlighted in bold

Entry

MeSO3H, equiv

Temperature,  C

Time, mina

Amine, equiv

Isolated yield, %

1 2 3 4 5 6 7 8 9

None 0.2 0.5 1.0 1.0 1.0 1.0 0.2 1.0c

190 190 190 190 190 190 160 160 200

150 90 60 40 40 40 30 40 300

5.0 5.0 5.0 5.0 3.0 2.0 3.0 1.5 1.3

52 54 67 80 81 70b 75 67 24d

a b c d

Full conversion of starting material according to TLC. After evaporation of the solvent the mixture was neutralized with sodium carbonate. 2.2 equiv of NEt3 were added. The yield was determined by LCMS analysis.

As seen from Table 2 (Entries 1e4), the application of MSA taken in 0e1.0 equiv resulted in shortening of the reaction time from 150 to 40 min and increasing the isolated yield from 52 to 80%. Further optimization of the morpholine amount (Table 2, Entries 4e6) led to the acceptable conditions (Entry 5). These conditions were successfully applied for cheap liquid water soluble amines (the excess of amine is removed during aqueous workup, Method A, Table 3, Entries 1e4).

In those cases where the application of the amine in excess is undesirable due to its high cost or poor solubility in water, the excess of reacting amine was replaced with a cheap base, triethylamine, that can be easily removed from the reaction mixture (Table 3, Entries 5e7). Thus 2.0 equiv of triethylamine and 1.2 equiv of a reacting primary amine were used under the same reaction conditions (Method B).

Table 3 Preparation and isolated yields of 7-amino-6-azaindole derivatives 3aep Entry

Starting compound

Method

Amine

Product

Yield, %

1

A

81

2

A

30

3

A

H N

64

(continued on next page)

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Table 3 (continued ) Entry

4

Starting compound

Method

A

Amine

Product

NH2

Me

Yield, %

76

H2N

5

B

60

OMe

NH2 7

B

72

8

C

Me

9

C

Me

10

C

Me

11

C

Me

NH2 HCl

83

NH2 HCl

98

NH2 HCl

78

NH2 HCl

59

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Table 3 (continued ) Entry

Starting compound

Method

Amine

Product

Yield, %

12

C

Me

NH2 HCl

91

13

C

Me

NH2 HCl

69

14

C

15

C

Me

H N

HCl Me

NH3 . HCl

80

30a

NH2 16

D

79

Cl

17

D

81

Ph NH2 a

The compound was not isolated, the yield was determined form LC/MS data.

Also, gaseous or low boiling point amines available as hydrochlorides were successfully applied in the reaction (3.0 equiv of the amine hydrochloride instead of using MSA) in the presence of 2.2 equiv of triethylamine (Table 3, Entries 8e15, Method C). Interestingly, the reaction of 2a with aniline already at 150  C during 30 min resulted in formation of the desired product (3p) in 75% isolated yield (Table 2, Entry 7). Attempts to decrease the catalyst amount or substitute the aniline excess with triethylamine

(even under higher temperature) led to the yield lowering in both cases (Entries 8, 9). Thus, the initial conditions (Table 2, Entries 7) for the reaction with aniline were applied for aromatic amines as Method D (Table 3, Entries 16, 17). Apparently the presence of both the excess of organic base and the strong inorganic acid is required to promote the reaction efficiently (Table 2). According to the previously proposed mechanism for a similar transformation54 after protonation of the pyridine

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nitrogen leading to 2aHD, this already ‘activated’ for aromatic nucleophilic substitution substrate can effectively react with N-nucleophile to give reaction product 3 after elimination of hydrogen chloride (Scheme 2). In view of the important role of the protonation of the heterocyclic fragment, a specific abbreviation for this mechanism type is proposed here, SNHetarHþ.

To confirm or disprove the assumption that the formation of intermediate 2aHD is a key reaction step in the suggested reaction mechanism (Scheme 2) further additional experiments have been carried out. The use of an activated analogue of 2a bearing a stable pyridinium moiety could be applied as a model of 2aHD, since the last is obviously unstable in the presence of base. For this purpose

Scheme 2. Possible reaction mechanism for the acid-catalyzed nucleophilic heteroaromatic substitution (SNHetarHþ) in 7-chloro-6-azaindole 2a.

In the previous works54,56 such reactions were concluded to be general for aromatic but not for aliphatic amines under acidic conditions at 100  C. In the case of aromatic amines, the reaction proceeded rapidly already at this relatively low temperature because of the lower basicity of the aromatic amines allowing considerable hydrolysis of its conjugate acid simultaneously liberating the free amine and mineral acid.56 In the present work, the aromatic amines also reacted under lower temperature without addition of an extra base. Base strength of amines at high temperatures is well-studied in the literature.61e65 Because of the higher basicity of the aliphatic amines compared with aromatic ones the solvolysis of their conjugate acids requires higher temperatures. This solvolysis is necessary for the studied process to create a reasonable concentration of the free acid catalyzing the reaction. Namely, pH value of an aqueous solution of morpholinium/morpholine (3:1 M ratio) is changed from 8.7 at 25.5  C to 6.3 at 200  C.65 Moreover, the difference in basicities of amines have been shown earlier to decrease at elevated temperatures in aqueous solution, and even reversals in relative base strengths were seen.63 Thus, the protonation rate of a relatively weak at the ambient temperature base 2 can be significantly increased at the elevated temperatures even in the presence of an aliphatic base excess. From this viewpoint, it is clear why the similar reaction conditions could be applied for the reactions with primary and secondary aliphatic amines, and why the excess of a reacting amine could be efficiently replaced with nonreacting triethylamine. Taking into account these facts one can assume that the rate of protonation of a relatively weak basic center, the pyridine nitrogen, in 2a leading to formation of a key intermediate 2aHD is increased under higher temperature allowing subsequent nucleophilic substitution. Assuming that the formation of 2aHD is a crucial reaction step in the above discussed reaction mechanism SNHetarHþ we have isolated this intermediate as hydrochloride salt (2a$HCl) to compare its structure with the structure of starting azaindole 2a. X-ray diffraction study of 2a and its salt 2a$HCl (Fig. 1) indicates that the protonation leads to increase of delocalization of electrons within the pyridine ring. Elongation of the C6eN2 bond up to 1.338(2)  A is observed in 2a$HCl as compared to 1.300(2)  Ae1.305(2)  A in 2a and the shortening of the C6eCl1 bond up to 1.707(2)  A (its value in 2a is 1.749(2)  Ae1.755(2)  A). The latest fact can be considered as an indirect confirmation of the increased positive charge on the pyridine ring.

Fig. 1. Molecular structures of 2a and 2a$HCl according to X-ray diffraction data. Thermal ellipsoids are shown at the 50% probability level.

7-chloro-6-azaindole 2a was quaternized with methyl iodide yielding a mixture of 7-chloro- (4a) and 7-iodo-1,6-dimethyl-1Hpyrrolo[2,3-c]pyridin-6-ium (4b) iodides in about 10:1 M ratio determined by LC/MS (Scheme 3). Similar halide exchange has been described previously in the case of the synthesis of 2-bromo-pyridine methiodide.66 The obtained mixture of 4a and 4b was considered to simulate intermediate 2aHD in the reaction with nucleophile. It was treated with an excess of methylamine (20% methanolic solution) and the full consumption of the starting

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another two indirect confirmations. The aromatic amines are generally considered to be weaker nucleophiles, but they react at lower temperatures (i) that correlates with the lower base strength of these amines. As depicted in Scheme 3, the mixture of quaternized salts 4a and 4b quickly reacts with both methylamine and aniline showing the positive charge ‘fixed’ onto the heterocyclic core allows extreme acceleration of the nucleophilic substitution (ii). This is probably not an ideal model of the final step in the reaction mechanism, because of the solvation effects of the reaction media onto intermediate 2aHD containing movable proton is obviously stronger than that for quaternary salt 4a. This difference also can decrease the reactivity of 2aHD under the applied reaction conditions compared to the model quaternary salt. We believe that the microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution is a powerful method for the introduction of not only aromatic but also aliphatic amine residues into the heterocyclic cores that are not limited by 6-azaindole and can be applied for other ‘basic’ heterocycles. Scheme 3. The synthesis of pyridinium salts 4a and 4b and their following conversion with methylamine and aniline giving to 5a and 5b.

4. Experimental section 4.1. General

material was observed already within 10 min at rt yielding corresponding 1,6-dimethyl-7-(methylamino)-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (5a). A similar result was obtained for the reaction of 4a and 4b with excess of aniline (3.0 equiv) at 50  C after 1 h giving corresponding iodide 5b. From these results one can assume that molecules containing 7halo-1H-pyrrolo[2,3-c]pyridin-6-ium fragment possess extremely high reactivity towards nucleophiles. These results are also in good agreement with our proposed reaction mechanism (Scheme 2) and the data earlier obtained for aromatic nucleophilic substitution in a-halogenopyridines and a-halogenopyridinium salts with hydroxide anion. Namely, the rate constant ratio of these reactions for 2-chloropyridine and 2-chloropiridinium iodide was defined to be 1:2.6$108.66 3. Conclusion Thus, we have developed an effective pyrrole-2-carboxylic acids based synthetic strategy towards 7-amino-6-azaindoles with variable substituents. Application of a strong mineral acid as catalyst at high temperature in the final reaction step allows 7-chloro-6azaindole derivatives 2 to be used as substrates for nucleophilic substitution even without any activating electron withdrawing groups in their molecules, vice versa, in the presence of an electron donating fused pyrrole ring. The activation of the heteroaromatic system towards the nucleophilic substitution proceeds via protonation of the pyridine nitrogen. However, the application of a strong acid, at the same time, decreases the equilibrium concentration of the reacting nucleophile, especially in the case of aliphatic amines, which have higher basicity compared to the aromatic ones. That is why an excess of the reacting amine has to be generally applied. In those cases, where the application of the reacting amine excess is undesirable, it can be equally substituted by cheap and easily removable triethylamine used to liberate the nucleophilic reagent. The active intermediate 2aHD (Scheme 2) can be easily obtained in a preparative manner as hydrochloride 2a$HCl, but it is obviously unstable in the presence of aliphatic amines. Nevertheless, at the evaluated temperatures under conditions stated in this paper, 2aHD is presumably formed in a reasonable concentration allowing the reaction to progress. Once formed, the activated intermediate can efficiently react with nucleophiles following the discussed SNHetarHþ mechanism. Thus, the formation of the intermediate 2aHD is most likely the rate-limiting factor. This statement has

All starting materials were commercially available from Enamine Ltd., and were used without additional purification. Melting points are uncorrected. 1H NMR spectra were recorded on a Bruker Avance drx 500 (500 MHz) spectrometer with TMS as an internal standard. 13C NMR (126 MHz) were performed on the 500 MHz spectrometer. The synthesis and spectral characteristics of compounds 1aed and compound 2a are identical to those described in the literature.51,53 The preparation of compound 1e is described in Supplementary data. Copies of NMR spectra were prepared using ACD/NMR Processor software (academic edition) and can be found in Supplementary data. LC/MS spectra were recorded using a chromatography/mass spectrometric system that consists of high-performance liquid chromatograph equipped with a diodematrix and mass-selective detector. Ionization method, chemical ionization under atmospheric pressure (APCI). Ionization mode, simultaneous scanning of positive ions in the mass range of 80e1000 m/z. According to HPLC MS and 1H NMR spectra data, all synthesized compounds have purity >95%. For all microwaveassisted reaction Emrys Creator (Biotage) equipped with magnetic stirrer, pressure sensor and IR-temperature sensor was used. The reactions were carried out using microwave process vials for 5 mL maximal reaction volume. The microwave absorption level was set as ‘high’ meaning that initial MW power was limited by 150 W. The reaction time corresponds to the time of irradiating at set temperature (fixed hold time). During all experiments, the maximal internal pressure never excided the safety limit of 20 bar. 4.2. General procedure for synthesis of 7-chloro-1H-pyrrolo [2,3-c]pyridines (2ae2e)22 Oxocompound 1aee (30.0 mmol) was added portion wise to phosphorus oxychloride (13.8 g, 90.0 mmol) and heated at 100  C for 2 h, the mixture was cooled to rt and added to crushed ice (200 g) and then carefully neutralized with potassium carbonate to pHw10. The resulting mixture was extracted with ethyl acetate (2100 mL), combined extracts were evaporated and the residue was flash-chromatographed on silica-gel (using EtOAc as eluent) yielding the targeted compound after evaporation. 4.2.1. 1-Benzyl-7-chloro-1H-pyrrolo[2,3-c]pyridine (2b). Brownish powder; yield 6.62 g (91%); mp 75e76  C; 1H NMR (500 MHz, DMSO-d6) d 7.93 (d, J¼5.2 Hz, 1H), 7.86 (d, J¼1.8 Hz, 1H), 7.62 (d, J¼4.7 Hz, 1H), 7.27e7.34 (m, 2H), 7.19e7.26 (m, 1H), 7.01 (d,

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J¼7.3 Hz, 2H), 6.73 (d, J¼1.6 Hz, 1H), 5.82 (s, 2H); 13C NMR (126 MHz, DMSO-d6) d 139.4, 137.8, 137.1, 136.5, 133.3, 129.1, 128.5, 127.8, 126.3, 116.0, 102.3, 51.4; LC/MS: m/z¼243.0; Anal. Calcd for C14H11ClN2: C 69.28%, H 4.57%, Cl 14.61%, N 11.54%; found: C 69.26%, H 4.55%, N 11.57%. 4.2.2. 3-Bromo-7-chloro-1,5-dimethyl-1H-pyrrolo[2,3-c]pyridine (2c). Brownish powder; yield 5.92 g (76%); mp 75e77  C; 1H NMR (500 MHz, DMSO-d6) d 7.79 (s, 1H), 7.18 (s, 1H), 4.05 (s, 3H), 2.47 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.0, 135.9, 135.6(CH), 132.4, 127.1, 111.8(CH), 87.0, 36.8(CH3), 23.3(CH3); LC/MS: m/z¼259.0, 261.0; Anal. Calcd for C9H8BrClN2: C 41.65%, H 3.11%, Br 30.79%, Cl 13.66%, N 10.79%; found: C 41.68%, H 3.14%, N 10.77%. 4.2.3. 7-Chloro-1-methyl-2-phenyl-1H-pyrrolo[2,3-c]pyridine (2d). Brown solid, yield 6.70 g (92%); mp 79e80  C; 1H NMR (500 MHz, DMSO-d6) d 7.93 (d, J¼4.7 Hz, 1H), 7.48e7.68 (m, 6H), 6.72 (s, 1H), 3.99 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.1, 138.0, 135.9, 133.7, 131.3, 130.6, 130.1, 129.6, 129.3, 115.4, 102.4, 34.7; LC/MS: m/z¼243.0; Anal. Calcd for C14H11ClN2: C 69.28%, H 4.57%, Cl 14.61%, N 11.54%; found: C 69.29%, H 4.54%, N 11.51%. 4.2.4. 1-Chloro-9-methyl-9H-pyrido[3,4-b]indole (2e). White solid; yield 5.73 g (88%); mp 115e116  C; 1H NMR (500 MHz, DMSO-d6) d 8.17 (d, J¼6.8 Hz, 1H), 7.95e8.12 (m, 2H), 7.51e7.72 (m, 2H), 7.28 (br s, 1H), 4.07 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 142.4, 137.8, 132.6, 132.5, 131.4, 129.4, 122.0, 120.7, 120.3, 115.1, 110.9, 32.0; LC/ MS: m/z¼217.2; Anal. Calcd for C12H9ClN2: C 66.52%, H 4.19%, Cl 16.36%, N 12.93%; found: C 66.49%, H 4.21%, N 12.92%.

4.3. General procedure for microwave assisted chlorine substitution in N1-substituted 7-chloro-6-azaindoles and 1chloro-9-methyl-9H-b-carboline 4.3.1. Method A. In a microwave process vial a mixture of N1substituted 7-chloro-6-azaindole (3.0 mmol) and a reacting amine (9.0 mmol) was diluted with butan-1-ol up to 5 mL total volume of the reaction mixture. Then methanesulfonic acid (3.0 mmol, 290 mg) was added and the reaction vessel was sealed and irradiated with microwaves at 190  C for 40 min. After cooling the reaction mixture was worked-up as described below. 4.3.2. Method B. In a microwave process vial a mixture of N1substituted 7-chloro-6-azaindole (3.0 mmol), a reacting amine (3.6 mmol), and triethylamine (6.0 mmol, 610 mg) was diluted with butan-1-ol up to 5 mL total volume of the reaction mixture. Then methanesulfonic acid (3.0 mmol, 290 mg) was added and the reaction vessel was sealed and irradiated with microwaves at 190  C for 40 min. After cooling the reaction mixture was worked-up as described below. 4.3.3. Method C. In a microwave process vial a mixture of N1substituted 7-chloro-6-azaindole or 1-chloro-9-methyl-9H-b-carboline (3.0 mmol), a reacting amine hydrochloride (9.0 mmol) and triethylamine (6.6 mmol, 670 mg) was diluted with butan-1-ol up to 5 mL total volume of the reaction mixture. Then the reaction vessel was sealed and irradiated with microwaves at 190  C for 40 min. After cooling the reaction mixture were worked-up as described below. 4.3.4. Method D. In a microwave process vial a mixture of N1substituted 7-chloro-6-azaindole (3.0 mmol) and an aromatic amine (9.0 mmol) was diluted with butan-1-ol up to 5 mL total volume of the reaction mixture. Then methanesulfonic acid (3.0 mmol, 290 mg) was added and the reaction vessel was sealed

and irradiated with microwaves at 160  C for 30 min. After cooling the reaction mixture were worked-up as described below. 4.3.5. Work-up procedure. The obtained reaction mixture was diluted with water (20 mL), potassium carbonate (5.0 g) was added to the mixture followed by extraction with ethyl acetate (210 mL). The extracts were combined, dried over potassium carbonate and evaporated to dryness. The residue was purified by column chromatography on silica gel (ethyl acetateehexane 1:1 v/v) to afford targeted compound after evaporation. 4.3.6. 1-Methyl-7-(morpholin-4-yl)-1H-pyrrolo[2,3-c]pyridine (3a). Brownish powder; yield 0.53 g (81%); mp 107e108  C; 1H NMR (500 MHz, DMSO-d6) d 7.80 (d, J¼4.9 Hz, 1H), 7.43 (s, 1H), 7.24 (d, J¼4.7 Hz, 1H), 6.46 (s, 1H), 4.07 (s, 3H), 3.81 (br s, 4H), 3.09 (br s, 4H); 13C NMR (126 MHz, DMSO-d6) d 150.4, 136.2, 135.4, 134.2, 125.9, 112.6, 101.2, 66.6, 52.2, 35.4; LC/MS: m/z¼218.2; Anal. Calcd for C12H15N3O: C 66.34%, H 6.96%, N 19.34%, O 7.36%; found: C 66.36%, H 6.99%, N 19.32%. 4.3.7. 4-(3-Bromo-1,5-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)morpholine (3b). Yellowish solid; yield 0.12 g (30%); mp 153e154  C; 1H NMR (500 MHz, DMSO-d6) d 7.60 (s, 1H), 6.91 (s, 1H), 4.02 (s, 3H), 3.73e3.85 (m, 4H), 2.97e3.18 (m, 4H), 2.43 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 149.6, 145.2, 134.8, 133.2, 124.0, 108.0, 87.6, 66.5, 52.1, 35.6, 24.1; LC/MS: m/z¼310.0, 312.0; Anal. Calcd for C13H16BrN3O: C 50.34%, H 5.20%, Br 25.76%, N 13.55%, O 5.16%; found: C 50.36%, H 5.18%, N 13.58%. 4.3.8. 1-Methyl-2-phenyl-7-(pyrrolidin-1-yl)-1H-pyrrolo[2,3-c]pyridine (3c). Yellow solid; yield 0.22 g (64%); mp 83e84  C; 1H NMR (500 MHz, DMSO-d6) d 7.75 (d, J¼5.5 Hz, 1H), 7.65 (d, J¼7.4 Hz, 2H), 7.51 (t, J¼7.1 Hz, 2H), 7.41e7.48 (m, 1H), 7.09 (d, J¼5.2 Hz, 1H), 6.59 (s, 1H), 3.85 (s, 3H), 3.38e3.45 (m, 4H), 1.73e1.98 (m, 4H); 13C NMR (126 MHz, DMSO-d6) d 149.0, 145.7, 136.3, 134.2, 131.8, 129.2, 128.8, 128.5, 127.7, 109.9, 101.9, 50.5, 33.6, 23.9; LC/MS: m/z¼278.2 [MþH]þ; Anal. Calcd for C18H19N3: C 77.95%, H 6.90%, N 15.15%; found: C 77.93%, H 6.91%, N 15.12%. 4.3.9. 1-Methyl-N-propyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3d). White solid; yield 0.43 g (76%); mp 88e89  C; 1H NMR (500 MHz, DMSO-d6) d 7.56 (d, J¼5.5 Hz, 1H), 7.20 (d, J¼2.6 Hz, 1H), 6.77 (d, J¼5.7 Hz, 1H), 6.26 (d, J¼2.9 Hz, 1H), 5.81e5.92 (m, 1H), 4.09 (s, 3H), 3.27e3.54 (m, 2H), 1.55e1.78 (m, 2H), 0.97 (t, J¼7.4 Hz, 3H); 13 C NMR (126 MHz, DMSO-d6) d 147.4, 136.4, 133.5, 132.3, 121.8, 106.6, 100.2, 43.3, 36.7, 22.8, 12.1; LC/MS: m/z¼190.2; Anal. Calcd for C11H15N3: C 69.81%, H 7.99%, N 22.20%; found: C 69.80%, H 7.82%, N 22.17%. 4.3.10. N-(4-Methoxybenzyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-7amine (3e$HCl). Was purified by recrystallization from ethanol as hydrochloride. White solid; yield 0.55 g (60%); mp 179e180  C; 1H NMR (500 MHz, DMSO-d6) d 8.47 (br s, 1H), 7.75 (d, J¼2.1 Hz, 1H), 7.51 (d, J¼8.0 Hz, 2H), 7.39 (d, J¼6.2 Hz, 1H), 7.10 (d, J¼6.5 Hz, 1H), 6.89 (d, J¼8.3 Hz, 2H), 6.56 (d, J¼2.3 Hz, 1H), 4.90 (d, J¼5.2 Hz, 2H), 4.27 (s, 3H), 3.71 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 159.1, 143.0, 138.5, 135.1, 129.5, 129.3, 125.3, 118.8, 114.3, 108.0, 103.0, 55.5, 44.7, 37.8; LC/MS: m/z¼268.2. 4.3.11. N-Cyclopentyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3f). Brownish solid; yield 0.47 g (72%); mp 75e76  C; 1H NMR (500 MHz, DMSO-d6) d 7.55 (d, J¼5.5 Hz, 1H), 7.20 (d, J¼1.9 Hz, 1H), 6.77 (d, J¼5.2 Hz, 1H), 6.25 (d, J¼2.2 Hz, 1H), 5.50 (d, J¼5.5 Hz, 1H), 4.36 (d, J¼6.3 Hz, 1H), 4.08 (s, 3H), 1.89e2.14 (m, 2H), 1.65e1.82 (m, 2H), 1.48e1.64 (m, 4H); 13C NMR (126 MHz, DMSO-d6) d 146.9, 136.0, 133.1, 132.0, 121.7, 106.5, 99.8, 52.5, 36.2, 32.7, 23.6; LC/MS:

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m/z¼216.1; Anal. Calcd for C13H17N3: C 72.52%, H 7.96%, N 19.52%; found: C 72.54%, H 7.99%, N 19.49%. 4.3.12. N,1-Dimethyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3g). White powder; yield 0.40 g (83%); mp 103e104  C; 1H NMR (500 MHz, DMSO-d6) d 7.56 (d, J¼5.5 Hz, 1H), 7.19 (d, J¼1.9 Hz, 1H), 6.76 (d, J¼5.8 Hz, 1H), 6.25 (d, J¼2.5 Hz, 1H), 5.98 (br s, 1H), 4.06 (s, 3H), 2.91 (d, J¼1.0 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.6, 136.0, 132.9, 131.9, 121.5, 106.3, 99.8, 36.3, 28.6; LC/MS: m/z¼162.2 [MþH]þ; Anal. Calcd for C9H11N3: C 67.06%, H 6.88%, N 26.07%; found: C 67.04%, H 6.89%, N 26.05%. 4.3.13. 1-Benzyl-N-methyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3h). Yellow oil; yield 0.48 g (98%); 1H NMR (500 MHz, DMSO-d6) d 7.63 (d, J¼5.5 Hz, 1H), 7.42 (d, J¼2.9 Hz, 1H), 7.26e7.32 (m, 2H), 7.21e7.26 (m, 1H), 7.05 (d, J¼7.01 Hz, 2H), 6.84 (d, J¼5.5 Hz, 1H), 6.40 (d, J¼2.9 Hz, 1H), 5.76 (d, J¼4.9 Hz, 1H), 5.68 (s, 2H), 2.85 (d, J¼4.4 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.5, 139.6, 136.8, 134.2, 132.5, 129.0, 128.9, 127.8, 126.8, 121.2, 106.7, 101.6, 51.9, 29.0; LC/MS: m/z¼238.2 [MþH]þ; Anal. Calcd for C15H15N3: C 75.92%, H 6.37%, N 17.71%; found: C 75.90%, H 6.37%, N 17.69%. 4.3.14. N,9-Dimethyl-9H-pyrido[3,4-b]indol-1-amine (3i). Yellowish powder; yield 0.38 g (78%); mp 153e154  C; 1H NMR (500 MHz, DMSO-d6) d 8.07 (d, J¼7.7 Hz, 1H), 7.85 (d, J¼4.9 Hz, 1H), 7.61 (d, J¼8.2 Hz, 1H), 7.50 (t, J¼7.6 Hz, 1H), 7.36 (d, J¼4.9 Hz, 1H), 7.19 (t, J¼7.3 Hz, 1H), 6.38 (br s, 1H), 4.14 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.5, 141.1, 136.0, 127.0, 126.9, 124.9, 121.1, 121.0, 119.2, 110.3, 105.2, 32.1, 29.0; LC/MS: m/z¼212.1; Anal. Calcd for C13H13N3: C 73.91%, H 6.20%, N 19.89%; found: C 73.94%, H 6.22%, N 19.88%. 4.3.15. N-Ethyl-1-methyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3j). White powder; yield 0.31 g (59%); mp 85e86  C; 1H NMR (500 MHz, DMSO-d6) d 7.54 (d, J¼5.5 Hz, 1H), 7.19 (d, J¼2.7 Hz, 1H), 6.75 (d, J¼5.5 Hz, 1H), 6.24 (d, J¼3.0 Hz, 1H), 5.85 (br s, 1H), 4.07 (s, 3H), 3.31e3.54 (m, J¼5.6, 7.00 Hz, 2H), 1.22 (t, J¼7.1 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.0, 136.0, 133.1, 131.9, 121.4, 106.3, 99.8, 36.3, 35.7, 15.1; LC/MS: m/z¼176.2 [MþH]þ; Anal. Calcd for C10H13N3: C 68.54%, H 7.48%, N 23.98%; found: C 68.52%, H 7.50%, N 23.97%. 4.3.16. 1-Benzyl-N-ethyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3k). Yellow oil; yield 0.47 g (91%); 1H NMR (500 MHz, DMSO-d6) d 7.56 (d, J¼5.5 Hz, 1H), 7.45 (d, J¼2.7 Hz, 1H), 7.26e7.33 (m, 2H), 7.21e7.26 (m, 1H), 7.04 (d, J¼7.1 Hz, 2H), 6.80 (d, J¼5.5 Hz, 1H), 6.37 (d, J¼3.0 Hz, 1H), 5.66 (s, 2H), 5.40 (br s, 1H), 3.27e3.35 (m, 2H), 1.00 (t, J¼7.1 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) d 146.3, 139.2, 136.4, 134.0, 132.4, 128.7, 127.5, 126.3, 120.6, 106.3, 100.9, 51.6, 35.6, 14.8; LC/MS: m/z¼252.2 [MþH]þ; Anal. Calcd for C16H17N3: C 76.46%, H 6.82%, N 16.72%; found: C 76.43%, H 6.83%, N 16.70%. 4 . 3 .17 . N - E t hyl - 9 - m e t h yl - 9 H - p y r i d o [ 3 , 4 - b ] i n d o l - 1 - a m i n e (3l). White solid; yield 0.36 g (69%); mp 100e101  C; 1H NMR (500 MHz, DMSO-d6) d 8.07 (d, J¼8.0 Hz, 1H), 7.84 (d, J¼5.2 Hz, 1H), 7.61 (d, J¼8.2 Hz, 1H), 7.50 (t, J¼7.6 Hz, 1H), 7.35 (d, J¼5.2 Hz, 1H), 7.19 (t, J¼7.3 Hz, 1H), 6.18 (br s, 1H), 4.14 (s, 3H), 3.45e3.62 (m, 2H), 1.28 (t, J¼7.0 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) d 147.1, 141.2, 136.5, 127.2, 126.9, 125.0, 121.1, 120.9, 119.1, 110.2, 105.2, 36.1, 32.1, 15.0; LC/MS: m/z¼226.2; Anal. Calcd for C14H15N3: C 74.64%, H 6.71%, N 18.65%; found: C 74.67%, H 6.70%, N 18.66%. 4.3.18. N,N,1-Trimethyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3m). Yellow oil; yield 0.42 g (80%); 1H NMR (500 MHz, DMSOd6) d 7.77 (d, J¼5.5 Hz, 1H), 7.40 (d, J¼3.1 Hz, 1H), 7.17 (d, J¼5.2 Hz, 1H), 6.44 (d, J¼2.9 Hz, 1H), 4.04 (s, 3H), 2.79 (s, 6H); 13C

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NMR (126 MHz, DMSO-d6) d 151.5, 136.0, 135.1, 133.9, 125.7, 111.9, 101.2, 43.6, 35.2; LC/MS: m/z¼176.2 [MþH]þ; Anal. Calcd for C10H13N3: C 68.54%, H 7.48%, N 23.98%; found: C 68.55%, H 7.45%, N 23.97%. 4.3.19. N-(4-Chlorophenyl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-7amine (3o). White solid; yield 0.61 g (79%); mp 123e124  C; 1H NMR (500 MHz, DMSO-d6) d 8.33 (br s, 1H), 7.72 (d, J¼4.9 Hz, 1H), 7.40 (br s, 1H), 7.35 (d, J¼8.8 Hz, 2H), 7.25 (d, J¼8.5 Hz, 2H), 7.16 (d, J¼4.9 Hz, 1H), 6.42 (d, J¼2.5 Hz, 1H), 4.07 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 142.5, 141.9, 135.6, 135.0, 133.9, 128.3, 124.2, 123.1, 119.4, 110.9, 100.3, 35.9; LC/MS: m/z¼258.1 [MþH]þ; Anal. Calcd for C14H12ClN3: C 65.25%, H 4.69%, Cl 13.76%, N 16.30%; found: C 65.22%, H 4.66%, N 16.28%. 4.3.20. 1-Methyl-N-phenyl-1H-pyrrolo[2,3-c]pyridin-7-amine (3p). White solid; yield 0.5 g (79%); mp 134e135  C; 1H NMR (500 MHz, DMSO-d6) d 8.17 (br s, 1H), 7.71 (d, J¼5.2 Hz, 1H), 7.39 (br s, 1H), 7.30 (d, J¼7.7 Hz, 2H), 7.21 (t, J¼7.4 Hz, 2H), 7.14 (d, J¼5.2 Hz, 1H), 6.84 (t, J¼7.0 Hz, 1H), 6.41 (br s, 1H), 4.06 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 143.7, 142.4, 135.8, 134.9, 133.7, 128.5, 124.3, 119.8, 117.9, 110.6, 100.2, 35.8; LC/MS: m/z¼224.2 [MþH]þ; Anal. Calcd for C14H13N3: C 75.31%, H 5.87%, N 18.82%; found: C 75.32%, H 5.89%, N 18.84%. 4.4. Reaction of 2a with methyl iodide. Synthesis of 7-chloro1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (4a) and 7-iodo-1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (4b) Compound 2a (5 g, 30 mmol) was dissolved in dry acetone (100 mL) followed by addition of methyl iodide (3 equiv, 4.3 g). The mixture was heated at 40  C for 12 h. The precipitated product was filtered off, washed with dry acetone and dried at rt under vacuum. According to LC/MS analysis the resulting solid is a mixture of 7chloro-1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (92%) 4a and 7-iodo-1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (8%) 4b. Total yield 7.13 g (77%). 4.4.1. 7-Chloro-1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (4a). 1H NMR (500 MHz, DMSO-d6) d 8.52 (d, J¼6.9 Hz, 1H), 8.33 (d, J¼2.5 Hz, 1H), 8.10 (d, J¼6.6 Hz, 1H), 6.96 (d, J¼2.7 Hz, 1H), 4.34 (s, 3H), 4.25 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 145.3, 138.5, 135.3, 132.9, 129.1, 116.2, 103.1, 45.7, 37.5; For 7-iodo-1,6-dimethyl1H-pyrrolo[2,3-c]pyridin-6-ium iodide admixture (4a) the resulted signals in 1H NMR (500 MHz, DMSO-d6) d (other signals are overlapped with signals of the main product 4a) LC/MS (mix): m/ z¼181.1 (4a), 273.0 (4b). 4.5. Synthesis of 1,6-dimethyl-7-(methylamino)-1H-pyrrolo [2,3-c]pyridin-6-ium iodide (5a) The mixture of compounds 4a and 4b (200 mg) was added in one portion to 10 mL of the 20% methanolic solution of methylamine and stirred at rt for 5 min. The clear solution was evaporated on a rotary evaporator at rt to afford 5a as a white solid. The analytical sample of 5a was prepared by suspending the obtained solid in a small amount of cold water followed by filtration and drying under vacuum at rt (the compound should be stored under argon atmosphere while darkens upon standing on air). Brownish solid, mp >150  C (decomposition); 1H NMR (500 MHz, DMSO-d6) d 7.92 (s, 1H), 7.83 (d, J¼4.1 Hz, 1H), 7.44 (d, J¼4.9 Hz, 1H), 6.70 (s, 2H), 4.14 (s, 3H), 4.02 (s, 3H), 3.16 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 146.8, 140.6, 136.2, 132.2, 123.6, 110.6, 102.9, 42.2, 36.9, 36.2; LC/ MS: m/z¼176.1 [M]þ.

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4.6. Synthesis of 1,6-dimethyl-7-(phenylamino)-1H-pyrrolo [2,3-c]pyridin-6-ium iodide (5b) The mixture of compounds 4a, 4b (300 mg) and aniline (0.45 g, 5 equiv) were heated at reflux in 20 mL of MeOH for 30 min. The clear solution was evaporated on a rotary evaporator at rt and the residue was recrystallized from a small amount of water to afford 5b (220 mg, 62%) as a white solid (the compound should be stored under argon atmosphere while darkens upon standing on air). Brownish solid, mp >150  C (decomposition); 1H NMR (500 MHz, DMSO-d6) d 9.38 (s, 1H), 8.33 (d, J¼5.5 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J¼5.8 Hz, 1H), 7.29 (s, 2H), 6.84e7.05 (m, 2H), 6.75 (d, J¼6.6 Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H); 13C NMR (126 MHz, DMSO-d6) d 143.6, 143.0, 139.0, 137.8, 134.0, 130.0, 128.2, 121.5, 115.5, 114.9, 103.2, 42.2, 36.1; LC/MS: m/z¼238.2 [M]þ. 4.7. X-ray diffraction study The crystals of 2a (C8H7N2Cl) are monoclinic. At 293 K a¼14.0663(9), b¼15.1942(9), c¼7.5353(5)  A, b¼104.388(6) , V¼1560.0(2)  A3, Mr¼166.61, Z¼8, space group P21/c, dcalcd¼1.419 g/ cm3, m(MoKa)¼0.417 mm1, F(000)¼688. Intensities of 15,619 reflections (4546 independent, Rint¼0.043) were measured on the «Xcalibur-3» diffractometer (graphite monochromated MoKa radiation, CCD detector, u-scanning, 2Qmax¼60 ). The crystals of 2a$HCl (C8H8N2Cl2) are monoclinic. At 293 K  a¼8.487(2), b¼13.020(1), c¼8.5440(8) A, b¼103.55(2) , 3  V¼917.8(3) A , Mr¼203.06, Z¼4, space group P21/n, dcalcd¼1.470 g/ cm3, m(MoKa)¼0.650 mm1, F(000)¼416. Intensities of 4702 reflections (2663 independent, Rint¼0.017) were measured on the «Xcalibur-3» diffractometer (graphite monochromated MoKa radiation, CCD detector, u-scanning, 2Qmax¼60 ). The structures were solved by direct method using SHELXTL package.67 Position of the hydrogen atoms were located from electron density difference maps and refined in isotropic approximation. Full-matrix least-squares refinement of the structures against F2 in anisotropic approximation for non-hydrogen atoms using 4493 (2a), 2580 (2a$HCl) reflections was converged to: wR2¼0.120 (R1¼0.050 for 2409 reflections with F>4s(F), S¼0.937) for structure 2a and wR2¼0.103 (R1¼0.039 for 1873 reflections with F>4s(F), S¼0.963) for structure 2a$HCl. The final atomic coordinates, and crystallographic data for molecules 2a and 2a$HCl have been deposited to with the Cambridge Crystallographic Data Centre, 12 Union Road, CB2 1EZ, UK (fax: þ44-1223-336033; email: [email protected]) and are available on request quoting the deposition numbers CCDC 961706 for 2a and CCDC 961707 for 2a$HCl). Acknowledgements Authors are very thankful to Prof. Nikolay O. MchedlovPetrossyan, (V. N. Karazin Kharkiv National University) for his valuable discussion of the physico-chemical aspects of this work. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.tet.2014.12.057. References and notes 1. 2. 3. 4.

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