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

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

S0040-4020(14)01761-X

DOI:

10.1016/j.tet.2014.12.057

Reference:

TET 26278

To appear in:

Tetrahedron

Received Date: 21 October 2014 Revised Date:

1 December 2014

Accepted Date: 15 December 2014

Please cite this article as: Nechayev MA, Gorobets NY, Shishkina SV, Shishkin OV, Kovalenko SM, Microwave-assisted acid-catalyzed nucleophilic heteroaromatic substitution: the synthesis of 7-amino-6azaindoles, Tetrahedron (2015), doi: 10.1016/j.tet.2014.12.057. 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 Graphical Abstract

Leave this area blank for abstract info.

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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. Kovalenkoa a

National University of Pharmacy, Pushkinska Str. 53, Kharkiv 61002, Ukraine Enamine Ltd., Alexandra Matrosova Street, 23, Kiev 01103, Ukraine c SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine, fax: +380573409343, e-mail: [email protected]

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ACCEPTED MANUSCRIPT

Tetrahedron journal homepage: www.elsevier.com

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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. Kovalenkoa a

National University of Pharmacy, Pushkinska Str. 53, Kharkiv 61002, Ukraine Enamine Ltd., Alexandra Matrosova Street, 23, Kiev 01103, Ukraine c SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenina Ave 60, Kharkiv 61001, Ukraine, fax: +380573409343, e-mail: [email protected]

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ABSTRACT

Article history: Received Received in revised form Accepted Available online

Derivatives of 7-amino-6-azaindole containing variable substituent in the amino group were synthesized via acid-catalyzed nucleophilic heteroaromatic substitution (SNHetarH+) using 7chloro-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.

1. Introduction

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Keywords: 6-azaindole β-carboline microwave-assisted organic synthesis nucleophilic heteroaromatic substitution acidic catalysis

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ARTICLE INFO

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In the past 40 years the classical methods for the synthesis of indole core1 were effectively used for construction of indole azaanalogues.2-5 As a result, several new heterocyclic scaffolds were identified that possess a wide range of biological activities.6-10 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,11-15 HemetsbergerKnittel,16 Bartoli,17-20 or Larock21-26 reactions. On the other hand more specific methods that start from a pyrrole derivative are still much less explored and applicable.27-29 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 β-carboline family30,31 (Scheme 1). Another example is represented by the marine alkaloid Marinoquinoline A isolated recently from the gliding bacterium R. thailandica TISTR 1742.32 Nevertheless, different 7-amino-6azaindole derivatives are suggested for treating kinase-associated diseases,33,34 viral infections,35 such as HIV and AIDS,8,36-38 chronic pain,19,39 gastroesophageal reflux40-42 and cancer.43 The related 1-amino-ß-carboline derivatives were shown to be able to

2009 Elsevier Ltd. All rights reserved.

intercalate DNA helix44,45 and recognized as anticancer,45 antimalarial45,46 and antiprion46 agents.

Due to the continuous interest in novel approaches to the 2-pyridone ring formation,47-50 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 suitable starting material for the synthesis of substituted 7-amino-6-azaindoles avoiding a low yielding Bartoli reaction generally used in the synthesis of 5-halogeno-6azaindole intermediates.19,20,52 R1 R3

NH

N

2

R

N H

N

β-Carboline

Marinoquinoline A

Me

NH

N Alk

O

1

R1 = H, Br R2 = H, Me, Ph R3 = H, Me Scheme 1. Pyrrolo[2,3-c]pyridine-7-one scaffold 1 and related natural products.

2

Tetrahedron

Starting material

N

O

1a

Me

71

N

Cl

2a

M AN U

Me

NH

N

1b

EP

AC C

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 azaheterocycles54-56 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-amine

91

O

Ph

Me

Br

TE D

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 oC in butan1-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 10-20 min) to give the desired product 3a in 52% isolated yield (Table 2).

Yield, %

N

NH

2. Results and Discussions The synthesis of initial compounds 1a-d (Table 1) was accomplished starting from pyrrole-2-carboxylic acids as was previously described.51 The β-carboline derivative 1e was synthesized from indole-2-carboxylic acid using the same general procedures. Compounds 1a-e were transformed into required N1-substituted 7-chloro-6-azaindoles 2a-d and 1-chloro-9methyl-9H-β-carboline 2e by heating in POCl3 with good to excellent yields (Table 1) following the reported procedure for 2a.53

Product

SC

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.

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The main synthetic approach to 7-amino-6-azaindoles with piperazine in toluene, and this reaction was reported to be ACCEPTEDis MANUSCRIPT heteroaromatic nucleophilic substitution in 7-halogenated-61.8 times faster without the use of sodium carbonate as an acid scavenger.57 azaindole derivatives which is described mostly in patent literature and exampled by uncatalyzed reactions of 7-halogenoTable 1. Preparation and isolated yields of N1-substituted 76-azaindoles with amines in pyridine,43 acid-catalyzed chloro-6-azaindoles 2a-d. reactions,19,39,40 as well as using copper35-37,52 or palladium41 catalysts. Neat reagents were used to obtain related 1-amino-βcarboline 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 ß-carboline series.44,45

NH

N

76

O

Me

1c NH 92

Ph

N

O

Me 1d N

NH

88 N Me

O

1e

N Me

Cl

2e

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. As seen from Table 2 (Entries 1-4), the application of MSA taken in 0 to 1.0 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 4-6) led to the acceptable conditions (Entry 5).

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Table 2. Search for acceptable conditions for the nucleophilic substitution using representative 7-chloro-6-azaindole 2a, morpholine and aniline.

MeSO3H, equiv

Temperature, ºC

Time, min(a

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 1.0(c

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 70(b 75 67 24(d

SC

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

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a)

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Entry

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).

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 1-4).

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 5-7). Thus 2.0 equiv of triethylamine and 1.2 equiv of a reacting primary amine were used under the same reaction conditions (Method B).

TE D

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 nitrogen leading to 2aH+, 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, SNHetarH+.

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 8-15, Method C).

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Interestingly, the reaction of 2a with aniline already at 150 ºC during 30 min resulted in formation of the desired product (3p) in

Table 3. Preparation and isolated yields of 7-amino-6-azaindole derivatives 3a-p.

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Starting compound

AC C

Entry

Method

Amine

Product

Yield, %

H N

A

81 O

Br Me

Br H N

Me

2 N Me 2c Cl

N

A

Me O

N

N

30 N

3b O

4

Tetrahedron

ACCEPTED MANUSCRIPT 3

H N

A

64

N

A

NH2

Me

N

Me

H2N

OMe

B

8

C

11

12

Me

EP

10

C

AC C

9

Me

C

Me

60

72

NH2 HCl

83

TE D

7

M AN U

NH2

Me

3d

SC

B

5

76

HN

RI PT

4

NH2 HCl

98

NH2 HCl

78

C

Me

NH2 HCl

C

Me

NH2 HCl

59

N

N

91 Ph

HN

3k Me

5

ACCEPTED MANUSCRIPT

14

C

15

C

NH2 HCl

Me

Me

H N

HCl Me

30a

N

M AN U

D

80

NH3 . HCl

NH2

16

69

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C

SC

13

N

Me

HN

Cl

79

3o

Cl

17

81

TE D

Ph NH2

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

AC C

EP

a

D

Scheme 2. Possible reaction mechanism for the acid-catalyzed nucleophilic heteroaromatic substitution (SNHetarH+) in 7-chloro6-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.61-65 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 precess to create a reasonable concentration of the free acid catalyzing the reaction. Namely, pH value of an aqueous solution of morpholinium/morpholine (3:1 molar ratio) is changed from 8.7 at 25.5 ºC to 6.3 at 200 ºC.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

6

Tetrahedron

N

Me

Cl acetone 40 oC, 12 h

2a

M AN U

I

N Me

2a

MeI

SC

N

RI PT

dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium (4b) iodides in about elevated temperatures even in the presence ofACCEPTED an aliphatic base MANUSCRIPT 10:1 molar ratio determined by LC/MS (Scheme 3). Similar excess. From this viewpoint, it is clear why the similar reaction halide exchange has been described previously in the case of the conditions could be applied for the reactions with primary and synthesis of 2-bromo-pyridine methiodide.66 The obtained secondary aliphatic amines, and why the excess of a reacting amine could be efficiently replaced with non-reacting mixture of 4a and 4b was considered to simulate intermediate triethylamine. Taking into account these facts one can assume 2aH+ in the reaction with nucleophile. It was treated with an excess of methylamine (20% methanolic solution) and the full that the rate of protonation of a relatively weak basic center, the pyridine nitrogen, in 2a leading to formation of a key consumption of the starting material was observed already within 10 min at r.t. yielding corresponding 1,6-dimethyl-7intermediate 2aH+ is increased under higher temperature allowing subsequent nucleophilic substitution. (methylamino)-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (5a). A similar result was obtained for the reaction of 4a and 4b with + Assuming that the formation of 2aH is a crucial reaction step excess of aniline (3.0 equiv) at 50 °C after 1 hour giving in the above discussed reaction mechanism SNHetarH+ we have corresponding iodide 5b. isolated this intermediate as hydrochloride salt (2a·HCl) to compare its structure with the structure of starting azaindole 2a.

N

NHR

Me

5a,b

N

Me

I Cl

4a (92%)

+

RNH2

N Me

MeOH

5a: r.t., 10 min 5b: 65 oC, 30 min

N Me

I N

I

Me

4b (8%)

TE D

5a R = Me, 5b R = Ph

EP

2a·HCl

AC C

Figure 1. Molecular structures of 2a and 2a·HCl according to X-ray diffraction data. Thermal ellipsoids are shown at the 50% probability level. 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 C6-N2 bond up to 1.338(2) Å is observed in 2a·HCl as compared to 1.300(2) Å ÷ 1.305(2) Å in 2a and the shortening of the C6-Cl1 bond up to 1.707(2) Å (its value in 2a is 1.749(2) Å ÷ 1.755(2) Å). The latest fact can be considered as an indirect confirmation of the increased positive charge on the pyridine ring. To confirm or disprove the assumption that the formation of intermediate 2aH+ is a key reaction step in the suggested reaction mechanism (Scheme 2) further additional experiments have been carried out. The use of an activated analog of 2a bearing a stable pyridinium moiety could be applied as a model of 2aH+, since the last is obviously unstable in the presence of base. For this purpose 7-chloro-6-azaindole 2a was quaternized with methyl iodide yielding a mixture of 7-chloro- (4a) and 7-iodo-1,6-

Scheme 3. The synthesis of pyridinium salts 4a and 4b and their following conversion with methylamine and aniline giving to 5a and 5b.

From these results one can assume that molecules containing 7-halo-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 α-halogenopyridines and α-halogenopyridinium salts with hydroxide anion. Namely, the rate constant ratio of these reactions for 2-chloropyridine and 2chloropiridinium 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 7chloro-6-azaindole 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

7

crushed ice (200 g) and then carefully neutralized with undesirable, it can be equally substituted byACCEPTED cheap and easily MANUSCRIPT potassium carbonate to pH~10. The resulting mixture was removable triethylamine used to liberate the nucleophilic reagent.

extracted with ethyl acetate (2 × 100 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 . 1 . 1 . 1 -B e n z y l -7 -c h l o r o -1 H -p y r r o l o [ 2 , 3 - c] p y r i d i n e (2 b )

RI PT

Brownish powder; yield 6.62 g. (91%); m.p. 75-76ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 4.7 Hz, 1H), 7.27 - 7.34 (m, 2H), 7.19 - 7.26 (m, 1H), 7.01 (d, J = 7.3 Hz, 2H), 6.73 (d, J = 1.6 Hz, 1H), 5.82 (s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 243.0; 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 . 1 . 2 . 3 -Br o m o -7 - c h l o r o -1 , 5 -d i m e t h y l -1 H p y r r o l o [ 2 , 3 -c] p y r i d i n e (2 c )

SC

Brownish powder; yield 5.92 g. (76%); m.p. 75-77 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.79 (s, 1H), 7.18 (s, 1H), 4.05 (s, 3H), 2.47 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 259.0, 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%.

M AN U

The active intermediate 2aH+ (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, 2aH+ 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 SNHetarH+ mechanism. Thus, the formation of the intermediate 2aH+ is most likely the ratelimiting factor. This statement has 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 2aH+ containing movable proton is obviously stronger than that for quaternary salt 4a. This difference also can decrease the reactivity of 2aH+ 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 6azaindole and can be applied for other ‘‘basic’’ heterocycles.

4. Experimental section

AC C

EP

TE D

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 1a-d and compound 2a are identical to those described in the literature.51,53 The preparation of compound 1e is described in Supporting Information. Copies of NMR spectra were prepared using ACD/NMR Processor software (academic edition) and can be found in Supporting Information. LC/MS spectra were recorded using a chromatography/mass spectrometric system that consists of high-performance liquid chromatograph equipped with a diode-matrix and massselective detector. Ionization method, chemical ionization under atmospheric pressure (APCI). Ionization mode, simultaneous scanning of positive ions in the mass range of 80–1000 m/z. According to HPLC MS and 1H NMR spectra data, all synthesized compounds have purity >95%. For all microwave-assisted reaction Emrys Creator (Biotage) equipped with magnetic stirrer, pressure sensor and IRtemperature 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. 4.1. General procedure for synthesis of 7-chloro-1H-pyrrolo[2,3c]pyridines (2a-2e)[22]

Oxocompound 1a-e (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 r.t. and added to

4 . 1 . 3 . 7 -C h l o r o -1 - m e t h y l -2 -p h e n y l -1 H -p y r r o l o [ 2 , 3 c] p y r i d i n e (2 d )

Brown solid, yield 6.70 g. (92%); m.p. 79-80 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.93 (d, J = 4.7 Hz, 1H), 7.48 - 7.68 (m, 6H), 6.72 (s, 1H), 3.99 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 243.0; 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 . 1 . 4 . 1 -C h l o r o -9 - m e t h y l -9 H -p y r i d o [ 3 , 4 -b] in d o l e (2 e )

White solid; yield 5.73 g. (88%); m.p. 115-116 ºC; 1H NMR (500 MHz, DMSO-d6) δ 8.17 (d, J = 6.8 Hz, 1H), 7.95 - 8.12 (m, 2H), 7.51 - 7.72 (m, 2H), 7.28 (br. s, 1H), 4.07 (s, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 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/z = 217.2; 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%. 4.2. General procedure for microwave assisted chlorine substitution in N1-substituted 7–chloro-6-azaindoles and 1chloro-9-methyl-9H-β-carboline

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 ºC for 40 min. After cooling the reaction mixture was worked-up as described below. 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 ºC for 40 min. After cooling the reaction mixture was worked-up as described below. Method C. In a microwave process vial a mixture of N1substituted 7-chloro-6-azaindole or 1-chloro-9-methyl-9H-βcarboline (3.0 mmol), a reacting amine hydrochloride (9.0

8

Tetrahedron

Hz, 1H), 7.10 (d, J = 6.5 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), mmol) and triethylamine (6.6 mmol, 670 ACCEPTED mg) was diluted MANUSCRIPT 6.56 (d, J = 2.3 Hz, 1H), 4.90 (d, J = 5.2 Hz, 2H), 4.27 (s, with butan-1-ol up to 5 mL total volume of the reaction 3H), 3.71 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 159.1, mixture. Then the reaction vessel was sealed and irradiated with microwaves at 190 ºC for 40 min. After cooling the 143.0, 138.5, 135.1, 129.5, 129.3, 125.3, 118.8, 114.3, 108.0, reaction mixture were worked-up as described below. 103.0, 55.5, 44.7, 37.8; LC/MS: m/z = 268.2.

4 . 2 . 1 . 1 -M e t h y l -7 -( m o r p h o l i n -4 -y l ) -1 H -p y r r o l o [ 2 , 3 c] p y r i d i n e (3 a )

4 . 2 . 7 . N , 1 -d i m e t h y l -1 H -p y r r o l o [ 2 , 3 -c] p y r i d i n -7 a m i n e (3 g )

White powder; yield 0.40 g. (83%); m.p. 103-104 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J = 5.5 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 6.76 (d, J = 5.8 Hz, 1H), 6.25 (d, J = 2.5 Hz, 1H), 5.98 (br. s, 1H), 4.06 (s, 3H), 2.91 (d, J = 1.0 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 147.6, 136.0, 132.9, 131.9, 121.5, 106.3, 99.8, 36.3, 28.6; LC/MS: m/z = 162.2 [M+H]+; Anal. Calcd for C9H11N3: C 67.06%, H 6.88%, N 26.07%; found: C 67.04%, H 6.89%, N 26.05%.

M AN U

Brownish powder; yield 0.53 g. (81%); m.p. 107-108 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J = 4.9 Hz, 1H), 7.43 (s, 1H), 7.24 (d, J = 4.7 Hz, 1H), 6.4613 (s, 1H), 4.07 (s, 3H), 3.81 (br. s, 4H), 3.09 (br. s, 4H); C NMR (126 MHz, DMSO-d6) δ 150.4, 136.2, 135.4, 134.2, 125.9, 112.6, 101.2, 66.6, 52.2, 35.4; LC/MS: m/z = 218.2; 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%.

Brownish solid; yield 0.47 g. (72%); m.p. 75-76 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.55 (d, J = 5.5 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 6.25 (d, J = 2.2 Hz, 1H), 5.50 (d, J = 5.5 Hz, 1H), 4.36 (d, J = 6.3 Hz, 1H), 4.08 (s, 3H), 1.89 - 2.14 (m, 2H), 1.65 - 1.82 (m, 2H), 1.48 - 1.64 (m, 4H); 13C NMR (126 MHz, DMSO-d6) δ 146.9, 136.0, 133.1, 132.0, 121.7, 106.5, 99.8, 52.5, 36.2, 32.7, 23.6; LC/MS: m/z = 216.1; Anal. Calcd for C13H17N3: C 72.52%, H 7.96%, N 19.52%; found: C 72.54%, H 7.99%, N 19.49%.

RI PT

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 (2×10 mL). The extracts were combined, dried over potassium carbonate and evaporated to dryness. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane 1:1 v/v) to afford targeted compound after evaporation.

4 . 2 . 6 . N -c y c l o p e n t y l -1 - m e t h y l -1 H -p y r r o l o [ 2 , 3 c] p y r i d i n -7 -a m i n e (3 f)

SC

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 ºC for 30 min. After cooling the reaction mixture were worked-up as described below.

4 . 2 . 2 . 4 -(3 - Br o m o -1 , 5 -d i m e t h y l -1 H -p y r r o l o [ 2 , 3 c] p y r i d i n -7 -y l ) m o r p h o l i n e (3 b )

TE D

Yellowish solid; yield 0.12 g. (30%); m.p. 153-154 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.60 (s, 1H), 6.91 (s, 1H), 4.02 (s, 3H), 3.73 - 3.85 (m, 4H), 2.97 - 3.18 (m, 4H), 2.43 (s, 3H); 13 C NMR (126 MHz, DMSO-d6) δ 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/z = 310.0, 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 . 2 . 3 . 1 -M e t h y l -2 -p h e n y l -7 - (p y r r o l i d i n -1 - y l )-1 H p y r r o l o [ 2 , 3 -c] p y r i d i n e (3 c )

AC C

EP

Yellow solid; yield 0.22 g. (64%); m.p. 83-84 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, J = 5.5 Hz, 1H), 7.65 (d, J = 7.4 Hz, 2H), 7.51 (t, J = 7.1 Hz, 2H), 7.41 - 7.48 (m, 1H), 7.09 (d, J = 5.2 Hz, 1H), 6.59 (s,131H), 3.85 (s, 3H), 3.38 - 3.45 (m, 4H), 1.73 - 1.98 (m, 4H); C NMR (126 MHz, DMSOd6) δ 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/z = 278.2 [M+H]+; Anal. Calcd for C18H19N3: C 77.95%, H 6.90%, N 15.15%; found: C 77.93%, H 6.91%, N 15.12%. 4 . 2 . 4 . 1 -M e t h y l -N -p r o p y l -1 H -p y r r o l o [ 2 , 3 - c] p y r i d i n 7 -a m i n e (3 d )

White solid; yield 0.43 g. (76%); m.p. 88-89 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J = 5.5 Hz, 1H), 7.20 (d, J = 2.6 Hz, 1H), 6.77 (d, J = 5.7 Hz, 1H), 6.26 (d, J = 2.9 Hz, 1H), 5.81 - 5.92 (m, 1H), 4.09 (s, 3H), 3.27 -133.54 (m, 2H), 1.55 - 1.78 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); C NMR (126 MHz, DMSO-d6) δ 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/z = 190.2; Anal. Calcd for C11H15N3: C 69.81%, H 7.99%, N 22.20%; found: C 69.80%, H 7.82%, N 22.17%. 4 . 2 . 5 . N - (4 - m e t h o x y b e n z y l ) -1 -m e t h y l -1 H p y r r o l o [ 2 , 3 -c] p y r i d i n -7 - a m i n e (3 e • H C l )

Was purified by recrystallization from ethanol as hydrochloride. White solid; yield 0.55 g. (60%); m.p. 179-180 ºC; 1H NMR (500 MHz, DMSO-d6) δ 8.47 (br. s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 6.2

4 . 2 . 8 . 1 -B e n z y l - N - m e t h y l -1 H -p y r r o l o [ 2 , 3 - c] p y r i d i n 7 -a m i n e (3 h )

Yellow oil; yield 0.48 g. (98%); 1H NMR (500 MHz, DMSOd6) δ 7.63 (d, J = 5.5 Hz, 1H), 7.42 (d, J = 2.9 Hz, 1H), 7.26 7.32 (m, 2H), 7.21 - 7.26 (m, 1H), 7.05 (d, J = 7.01 Hz, 2H), 6.84 (d, J = 5.5 Hz, 1H), 6.40 (d, J = 2.9 Hz, 1H), 5.76 (d, J = 4.9 Hz, 1H), 5.68 (s, 2H), 2.85 (d, J = 4.4 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 238.2 [M+H]+; Anal. Calcd for C15H15N3: C 75.92%, H 6.37%, N 17.71%; found: C 75.90%, H 6.37%, N 17.69%. 4 . 2 . 9 . N , 9 -d i m e t h y l -9 H -p y r i d o [ 3 , 4 -b] i n d o l -1 -a m i n e (3 i )

Yellowish powder; yield 0.38 g. (78%); m.p. 153-154 ºC; 1H NMR (500 MHz, DMSO-d6) δ 8.07 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 4.9 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 4.9 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 6.38 (br. s, 1H), 4.14 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 212.1; Anal. Calcd for C13H13N3: C 73.91%, H 6.20%, N 19.89%; found: C 73.94%, H 6.22%, N 19.88%. 4 . 2 . 1 0 . N - Et h y l -1 -m e t h y l -1 H -p y r r o l o [ 2 , 3 - c] p y r i d i n 7 -a m i n e (3 j )

White powder; yield 0.31 g. (59%); m.p. 85-86 ºC; 1H NMR (500 MHz, DMSO-d6) δ 7.54 (d, J = 5.5 Hz, 1H), 7.19 (d, J = 2.7 Hz, 1H), 6.75 (d, J = 5.5 Hz, 1H), 6.24 (d, J = 3.0 Hz, 1H), 5.85 (br. s, 1H), 4.07 (s, 3H), 3.3113 - 3.54 (m, J = 5.6, 7.00 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H); C NMR (126 MHz, DMSO-d6) δ 147.0, 136.0, 133.1, 131.9, 121.4, 106.3, 99.8, 36.3, 35.7, 15.1; LC/MS: m/z = 176.2 [M+H]+; Anal. Calcd for C10H13N3: C 68.54%, H 7.48%, N 23.98%; found: C 68.52%, H 7.50%, N 23.97%. 4 . 2 . 1 1 . 1 -B e n z y l - N - e t h y l -1 H -p y r r o l o [ 2 , 3 -c] p y r i d i n 7 -a m i n e (3 k )

Yellow oil; yield 0.47 g. (91%); 1H NMR (500 MHz, DMSOd6) δ 7.56 (d, J = 5.5 Hz, 1H), 7.45 (d, J = 2.7 Hz, 1H), 7.26 7.33 (m, 2H), 7.21 - 7.26 (m, 1H), 7.04 (d, J = 7.1 Hz, 2H), 6.80 (d, J = 5.5 Hz, 1H), 6.37 (d, J = 3.0 Hz, 1H), 5.66 (s, 2H), 5.40 (br. s, 1H), 3.27 - 3.35 (m, 2H), 1.00 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, DMSO-d6) δ 146.3, 139.2, 136.4, 134.0, 132.4, 128.7, 127.5, 126.3, 120.6, 106.3, 100.9, 51.6,

9

1

4 . 2 . 1 4 . N - (4 - c h l o r o p h e n y l )-1 -m e t h y l -1 H p y r r o l o [ 2 , 3 -c] p y r i d i n -7 - a m i n e (3 o )

White solid; yield 0.61 g. (79%); m.p. 123-124 ºC; 1H NMR (500 MHz, DMSO-d6) δ 8.33 (br. s, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.40 (br. s, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 4.9 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), 4.07 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 258.1 [M+H] ; 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%.

TE D

4 . 2 . 1 5 . 1 -M e t h y l -N -p h e n y l -1 H -p y r r o l o [ 2 , 3 c] p y r i d i n -7 -a m i n e (3 p )

EP

White solid; yield 0.5 g. (79%); m.p. 134-135 ºC; 1H NMR (500 MHz, DMSO-d6) δ 8.17 (br. s, 1H), 7.71 (d, J = 5.2 Hz, 1H), 7.39 (br. s, 1H), 7.30 (d, J = 7.7 Hz, 2H), 7.21 (t, J = 7.4 Hz, 2H), 7.14 (d, J = 5.2 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H), 6.41 (br. s, 1H), 4.06 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 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/z = 224.2 [M+H] ; Anal. Calcd for C14H13N3: C 75.31%, H 5.87%, N 18.82%; found: C 75.32%, H 5.89%, N 18.84%.

AC C

4.3. Reaction of 2a with methyl iodide. Synthesis of 7-chloro-1,6dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (4a) and 7-iodo1,6-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 r.t. under vacuum. According to LC/MS analysis the resulting solid is a mixture of 7-chloro-1,6-dimethyl-1Hpyrrolo[2,3-c]pyridin-6-ium iodide (92%) 4a and 7-iodo-1,6dimethyl-1H-pyrrolo[2,3-c]pyridin-6-ium iodide (8%) 4b. Total yield 7.13 g (77%). 4 . 3 . 1 . 7 -c h l o r o -1 , 6 -d i m e t h y l -1 H -p y r r o l o [ 2 , 3 c] p y r i d i n -6 -i u m i o d i d e (4 a )

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 r.t. and the residue was recrystallised 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, m.p. >150 ºC (decomposition); 1H NMR (500 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J = 5.8 Hz, 1H), 7.29 (s, 2H), 6.84 - 7.0513 (m, 2H), 6.75 (d, J = 6.6 Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H); C NMR (126 MHz, DMSOd6) δ 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/z = 238.2 [M]+.

M AN U

Yellow oil; yield 0.42 g. (80%); H NMR (500 MHz, DMSOd6) δ 7.77 (d, J = 5.5 Hz, 1H), 7.40 (d, J = 3.1 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 6.44 (d, J = 2.9 Hz, 1H), 4.04 (s, 3H), 2.79 (s, 6H); 13C NMR (126 MHz, DMSO-d6) δ 151.5, 136.0, 135.1, 133.9, +125.7, 111.9, 101.2, 43.6, 35.2; LC/MS: m/z = 176.2 [M+H] ; Anal. Calcd for C10H13N3: C 68.54%, H 7.48%, N 23.98%; found: C 68.55%, H 7.45%, N 23.97%.

4.5. Synthesis of 1,6-dimethyl-7-(phenylamino)-1H-pyrrolo[2,3c]pyridin-6-ium iodide (5b)

SC

4 . 2 . 1 3 . N , N , 1 -t r i m e t h y l -1 H -p y r r o l o [ 2 , 3 - c] p y r i d i n 7 -a m i n e (3 m )

RI PT

35.6, 14.8; LC/MS: m/z = 252.2 [M+H]+; ACCEPTED Anal. Calcd for MANUSCRIPT 4.4. Synthesis of 1,6-dimethyl-7-(methylamino)-1H-pyrrolo[2,3C16H17N3: C 76.46%, H 6.82%, N 16.72%; found: C 76.43%, c]pyridin-6-ium iodide (5a) H 6.83%, N 16.70%. The mixture of compounds 4a and 4b (200 mg) was added in one portion to 10 mL of the 20% methanolic solution of 4 . 2 . 1 2 . N -e t h y l -9 -m e t h y l -9 H -p y r i d o [ 3 , 4 -b] i n d o l -1 methylamine and stirred at r.t. for 5 min. The clear solution a m i n e (3 l ) was evaporated on a rotary evaporator at r.t. to afford 5a as a 1 White solid; yield 0.36 g. (69%); m.p. 100-101 ºC; H NMR white solid. The analytical sample of 5a was prepared by (500 MHz, DMSO-d6) δ 8.07 (d, J = 8.0 Hz, 1H), 7.84 (d, J = suspending the obtained solid in a small amount of cold water 5.2 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), followed by filtration and drying under vacuum at r.t. (the 7.35 (d, J = 5.2 Hz, 1H), 7.19 (t, J = 7.3 Hz, 1H), 6.18 (br. s, compound should be stored under argon atmosphere while 1H), 4.14 (s, 3H), 3.45 - 3.62 (m, 2H), 1.28 (t, J = 7.0 Hz, darkens upon standing on air). Brownish solid, m.p. >150 ºC 3H); 13C NMR (126 MHz, DMSO-d6) δ 147.1, 141.2, 136.5, (decomposition); 1H NMR (500 MHz, DMSO-d6) δ 7.92 (s, 127.2, 126.9, 125.0, 121.1, 120.9, 119.1, 110.2, 105.2, 36.1, 1H), 7.83 (d, J = 4.1 Hz, 1H), 7.44 (d, J = 4.9 Hz, 1H), 6.70 32.1, 15.0; LC/MS: m/z = 226.2; Anal. Calcd for C14H15N3: C (s, 2H), 4.14 (s, 3H), 4.02 (s, 3H), 3.16 (s, 3H); 13C NMR 74.64%, H 6.71%, N 18.65%; found: C 74.67%, H 6.70%, N (126 MHz, DMSO-d6) δ 146.8, 140.6, 136.2, 132.2, 123.6, 18.66%. 110.6, 102.9, 42.2, 36.9, 36.2; LC/MS: m/z = 176.1 [M]+.

1 H NMR (500 MHz, DMSO-d6) δ 8.52 (d, J = 6.9 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.10 (d, J = 6.613Hz, 1H), 6.96 (d, J = 2.7 Hz, 1H), 4.34 (s, 3H), 4.25 (s, 3H); C NMR (126 MHz, DMSO-d6) δ 145.3, 138.5, 135.3, 132.9, 129.1, 116.2, 103.1, 45.7, 37.5; For 7-iodo-1,6-dimethyl-1H-pyrrolo[2,3-c]pyridin6-ium iodide admixture (4a) the resulted signals in 1H NMR (500 MHz, DMSO-d6) δ (other signals are overlapped with signals of the main product 4a) LC/MS (mix): m/z = 181.1 (4a), 273.0 (4b).

4.6. X-Ray diffraction study

The crystals of 2a (C8H7N2Cl) are monoclinic. At 293 K a = 14.0663(9), b = 15.1942(9), c = 7.5353(5) Å, β = 104.388(6)° , V = 1560.0(2) Å3 3, Mr = 166.61, Z = 8, space group P21/c, dcalc= 1.419 g/cm , µ(MoKα) = 0.417 mm-1, F(000) = 688. Intensities of 15619 reflections (4546 independent, Rint = 0.043) were measured on the«Xcalibur-3» diffractometer (graphite monochromated MoKα radiation, CCD detector, ωscaning, 2Θmax = 60°). The crystals of 2a·HCl (C8H8N2Cl2) are monoclinic. At 293 K a = 8.487(2), b 3= 13.020(1), c = 8.5440(8) Å, β = 103.55(2)°, V = 917.8(3)3 Å , Mr = 203.06, Z = 4, space-1 group P21/n, dcalc= 1.470 g/cm , µ(MoKα) = 0.650 mm , F(000) = 416. Intensities of 4702 reflections (2663 independent, Rint = 0.017) were measured on the«Xcalibur-3» diffractometer (graphite monochromated MoKα radiation, CCD detector, ωscaning, 2Θmax = 60°). 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 nonhydrogen atoms using 4493 (2a), 2580 (2a·HCl) reflections was converged to: wR2 = 0.120 (R1 = 0.050 for 2409 reflections with F>4σ(F), S = 0.937) for structure 2a and wR2 = 0.103 (R1 = 0.039 for 1873 reflections with F>4σ(F), S = 0.963) 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: +44-1223-336033; e-mail: [email protected]) and are available on request quoting the deposition numbers CCDC 961706 for 2a and CCDC 961707 for 2a·HCl).

Acknowledgments

10

Tetrahedron

Authors are very thankful to Prof. Nikolay O. Mchedlov- MANUSCRIPT 22. Wensbo, D.; Eriksson, A.; Jeschke, T.; Annby, U.; Gronowitz, ACCEPTED Petrossyan, (V. N. Karazin Kharkiv National University) for his S.; Cohen, L. A. Tetrahedron Lett. 1993, 34, 2823. valuable discussion of the physico-chemical aspects of this work. 23. Ujjainwalla, F.; Warner, D. Tetrahedron Lett. 1998, 39, 5355.

References and notes

7. 8.

9.

10. 11.

12.

13. 14. 15. 16. 17. 18.

19.

20. 21.

M AN U

5. 6.

TE D

4.

EP

3.

Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. Popowycz, F.; Mérour, J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689. Popowycz, F.; Routier, S.; Joseph, B.; Mérour, J.-Y. Tetrahedron 2007, 63, 1031. Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. Rev. 2007, 36, 1120. Zhao, S.-B.; Wang, S. Chem. Soc. Rev. 2010, 39, 3142. Hyaric, M.; Viera, d. A. M.; Nora, d. S. M. V. Quim. Nova 2002, 25, 1165. Scios Inc. Exp. Opin. Ther. Patents 2005, 15, 227. Kadow, J. F.; Bender, J.; Regueiro-Ren, A.; Ueda, Y.; Wang, T.; Yeung, K.-S.; Meanwell, N. A. In Antiviral Drugs: From Basic Discovery through Clinical Trials; Kazmierski, W. M. Ed.; John Wiley & Sons, Inc., 2011; pp. 149. Plewe, M. B.; Johnson, T. W. In HIV-1 Integrase: Mechanism and Inhibitor Design; Neamati, N. Ed.; John Wiley & Sons, Inc., 2011; pp. 265. Matter, H.; Scheiper, B.; Steinhagen, H.; Böcskei, Z.; Fleury, V.; McCort, G. Bioorg. Med. Chem. Lett. 2011, 21, 5487. Filla, S. A.; Mathes, B. M.; Johnson, K. W.; Phebus, L. A.; Cohen, M. L.; Nelson, D. L.; Zgombick, J. M.; Erickson, J. A.; Schenck, K. W.; Wainscott, D. B. J. Med. Chem. 2003, 46, 3060. Plewe, M. B.; Butler, S. L.; R. Dress, K.; Hu, Q.; Johnson, T. W.; Kuehler, J. E.; Kuki, A.; Lam, H.; Liu, W.; Nowlin, D. J. Med. Chem. 2009, 52, 7211. Andaloussi, M.; Moreau, E.; Chavignon, O.; Teulade, J. C. Tetrahedron Lett. 2007, 48, 8392. Linz, S.; Müller, J.; Hübner, H.; Gmeiner, P.; Troschütz, R. Bioorg. Med. Chem. 2009, 17, 4448. Zhu, J.; Wong, H.; Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. Tetrahedron Lett. 2006, 47, 5653. Roy, P. J.; Dufresne, C.; Lachance, N.; Leclerc, J. P.; Boisvert, M.; Wang, Z.; Leblanc, Y. Synthesis 2005, 2751. Yoon, Y.; Kim, D. H.; Lee, B. M.; Kim, T. K.; Cha, M. H.; Sim, J. Y.; Kim, J. G. Bioorg. Med. Chem. Lett. 2010, 20, 5237. Blaazer, A. R.; Lange, J. H. M.; van der Neut, M. A. W.; Mulder, A.; den Boon, F. S.; Werkman, T. R.; Kruse, C. G.; Wadman, W. J. Eur. J. Med. Chem. 2011, 46, 5086. Giblin, G. M. P.; Billinton, A.; Briggs, M.; Brown, A. J.; Chessell, I. P.; Clayton, N. M.; Eatherton, A. J.; Goldsmith, P.; Haslam, C.; Johnson, M. R.; Mitchell, W. L.; Naylor, A.; Perboni, A.; Slingsby, B. P.; Wilson, A. W. J. Med. Chem. 2009, 52, 5785. Zhang, Z.; Yang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T. J. Org. Chem. 2002, 67, 2345. Walsh, T. F.; Toupence, R. B.; Ujjainwalla, F.; Young, J. R.; Goulet, M. T. Tetrahedron 2001, 57, 5233.

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24. Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42, 6441. 25. Riether, D.; Harcken, C.; Razavi, H.; Kuzmich, D.; Gilmore, T.; Bentzien, J. r.; Pack, E. J.; Souza, D.; Nelson, R. M.; Kukulka, A.; Fadra, T. N.; Zuvela-Jelaska, L.; Pelletier, J.; Dinallo, R.; Panzenbeck, M.; Torcellini, C.; Nabozny, G. H.; Thomson, D. S. J. Med. Chem. 2010, 53, 6681. 26. Livecchi, M.; Calvet, G.; Schmidt, F. J. Org. Chem. 2012, 77, 5006. 27. Rousseau, J.-F.; Dodd, R. H. J. Org. Chem. 1998, 63, 2731. 28. Johnson, T. W.; Tanis, S. P.; Butler, S. L.; Dalvie, D.; DeLisle, D. M.; Dress, K. R.; Flahive, E. J.; Hu, Q.; Kuehler, J. E.; Kuki, A.; Liu, W.; McClellan, G. A.; Peng, Q.; Plewe, M. B.; Richardson, P. F.; Smith, G. L.; Solowiej, J.; Tran, K. T.; Wang, H.; Yu, X.; Zhang, J.; Zhu, H. J. Med. Chem. 2011, 54, 3393. 29. Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651. 30. Allen, J. R. F.; Holmstedt, B. R. Phytochemistry 1980, 19, 1573. 31. Herraiz, T. In Bioactive Compounds in Foods; Gilbert, J.; Şenyuva, H. Z. Eds.; Blackwell Publishing Ltd., 2009; pp. 199. 32. Yutthapong, S.; Sakulkeo, O.; Yuenyongsawad, S.; Kanjanaopas, A.; Ingkaninan, K.; Plubrukarn, A.; Suwanborirux, K. Marine Drugs 2008, 6, 578. 33. Das, S.; Brown, J. W.; Dong, Q.; Gong, X.; Kaldor, S. W.; Liu, Y.; Paraselli, B. R.; Scorah, N.; Stafford, J. A.; Wallace, M. B. Int. Patent Appl. 044779A1, 2007; Chem. Abstr. 2007, 146, 441771. 34. Brown, J. W.; Dong, Q.; Gangloff, A. R.; Paraselli, B. R.; Stafford, J. A.; Scorah, N.; Salsbury, J. S.; Das, S. Int. Patent Appl. 129401A1, 2009; Chem. Abstr. 2009, 151, 491106. 35. Kadow, J. F.; Regueiro-Ren, A. US Patent Appl. 0142298A1, 2006; Chem. Abstr. 2006, 145, 103690 36. Wang, T.; Kadow, J. F.; Meanwell, N. A.; Yeung, K.-S.; Zhang, Z.; Yin, Z.; Qiu, Z.; Deon, D. H.; James, C. A.; Ruediger, E. H.; Bachand, C. Int. Patent Appl. 0186292A1, 2004; Chem. Abstr. 2004, 141, 296001. 37. Regueiro-Ren, A.; Swidorski, J.; Liu, Z.; Wang, T.; Zhang, Z.; Hamann, L. G.; Meanwell, N. A.; Carini, D. J.; Li, W. Int. Patent Appl. 158396A1, 2009; Chem. Abstr. 2009, 152, 119660. 38. Kim, J. T.; Hamilton, A. D.; Bailey, C. M.; Domoal, R. A.; Wang, L.; Anderson, K. S.; Jorgensen, W. L. J. Am. Chem. Soc. 2006, 128, 15372. 39. Eatherton, A. J.; Giblin, G. M. P.; Johnson, M. R.; Mitchell, W. L.; Perboni, A.; Slingsby, B. P. Int. Patent Appl. 121140A1, 2005; Chem. Abstr. 2005, 144, 69741. 40. Choi, R.; Kim, J.-G.; Ahn, B.-N.; Lee, H.-W.; Yoon, S.-W.; Yoon, Y.-A.; Kim, D.-H.; Park, C.-S.; Han, S.-H.; Cha, M.-H.; Kang, H.-I. Int. Patent Appl. 025717A1, 2006; Chem. Abstr. 2006, 144, 292741. 41. Choi, R.; Kim, J.-G.; Ahn, B.-N.; Lee, H.-W.; Yoon, S.-W.; Yoon, Y.-A.; Kim, D.-H.; Park, C.-S.; Han, S.-H.; Cha, M.-H.; Kang, H.-I. Int. Patent Appl. 25716A1, 2006; Chem. Abstr. 2011, 155, 40964. 42. Hasuoka, A.; Arikawa, Y. Int. Patent Appl. 011670A1, 2006; Chem. Abstr. 2006, 144, 150354 43. Liou, J.-P.; Chang, J.-Y. Int. Patent Appl. 019634A2, 2011; Chem. Abstr. 2011, 154, 234673 44. Ma, C.; Cao, R.; Shi, B.; Zhou, X.; Ma, Q.; Sun, J.; Guo, L.; Yi, W.; Chen, Z.; Song, H. Eur. J. Med. Chem. 2010, 45, 5513.

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45. Boursereau, Y.; Coldham, I. Bioorg. Med. Chem. Lett. 2004, 14, MANUSCRIPT ACCEPTED 5841. 46. Thompson, M. J.; Louth, J. C.; Little, S. M.; Jackson, M. P.; Boursereau, Y.; Chen, B.; Coldham, I. ChemMedChem 2012, 7, 578. 47. Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757. 48. Yermolayev, S. A.; Gorobets, N. Y.; Desenko, S. M. J. Comb. Chem. 2009, 11, 44. 49. Yermolayev, S. A.; Gorobets, N. Y.; Lukinova, E. V.; Shishkin, O. V.; Shishkina, S. V.; Desenko, S. M. Tetrahedron 2008, 64, 4649. 50. Yermolayev, S. A.; Gorobets, N. Y.; Shishkin, O. V.; Shishkina, S. V.; Leadbeater, N. E. Tetrahedron 2011, 67, 2934. 51. Nechayev, M. A.; Gorobets, N. Y.; Borisov, A. V.; Kovalenko, S. M.; Tolmachev, A. A. Mol. Divers. 2012, 16, 749. 52. Lu, R.-J.; Tucker, J. A.; Zinevitch, T.; Kirichenko, O.; Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Pickens, J.; Tandel, S.; Brahmachary, E.; Yang, Y.; Wang, J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.; Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs, P.; Khasanov, A.; Ma, Y.-A.; Jeffries, C.; Liu, C.; Proskurina, T.; Zhu, T.; Chucholowski, A.; Li, R.; Sexton, C. J. Med. Chem. 2007, 50, 6535. 53. Nechayev, M. A.; Gorobets, N. Y.; Kovalenko, S. M.; Tolmachev, A. A. Synthesis 2013, 45, 919. 54. Banks, C. K. J. Am. Chem. Soc. 1944, 66, 1127. 55. Morley, J. S.; Simpson, J. C. E. J. Chem. Soc. 1949, 1014. 56. Maggiolo, A.; Phillips, A. P. J. Org. Chem. 1951, 16, 376. 57. Perrault, W. R.; Shephard, K. P.; LaPean, L. A.; Krook, M. A.; Dobrowolski, P. J.; Lyster, M. A.; McMillan, M. W.; Knoechel, D. J.; Evenson, G. N.; Watt, W.; Pearlman, B. A. Org. Process Res. Dev. 1997, 1, 106. 58. Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273. 59. Vlasov, V. M. Russ. Chem. Rev. 2003, 72, 681. 60. Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. 61. Hetzer, H. B.; Bates, R. G.; Robinson, R. A. J. Phys. Chem. 1966, 70, 2869. 62. Bolton, P. D.; Hall, F. M. Aust. J. Chem. 1967, 20, 1797. 63. Mesmer, R. E.; Hitch, B. F. J. Solution Chem. 1977, 6, 251. 64. Tremaine, P. R.; Shvedov, D.; Xiao, C. J. Phys. Chem. B 1997, 101, 409. 65. Ridley, M. K.; Xiao, C.; Palmer, D. A.; Wesolowski, D. J. J. Chem. Eng. Data 2000, 45, 502. 66. Barlin, G. B.; Benbow, J. A. J. Chem. Soc., Perkin Trans. 2 1974, 790. 67. Sheldrick G. M. SHELXTL PLUS. PC Version. A System of Computer Programs for the Determination of Crystal Structure from X-ray Diffraction Data. Rev. 5.1, 1998.

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Microwave-Assisted Acid-Catalyzed Nucleophilic Heteroaromatic Substitution: the Synthesis of 7-Amino-6-azaindoles

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Maxim A. Nechayev, Nikolay Yu. Gorobets, Svetlana V. Shishkina, Oleg V. Shishkin, Sergiy M. Kovalenko

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Indole-2carboxylic acid (100 mmol) was suspended in 200 mL of dry dioxane and heated to 60°C then CDI (100 mmol) was added portion wise. The reaction mixture was stirred at this

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temperature until no more liberation of CO2 is observed then 2,2-dimethoxyethanamine was added in one portion. The mixture was heated at 70°C for 3 hours. The solvent was removed on a rotary evaporator, residue was dissolved in 100 mL of ethyl acetate and extracted three times with 100 mL portions of water following by flash chromatography (ethyl acetate as eluent) yielding the compound . 1H NMR (500 MHz, DMSO-d6) δ 11.60 (br. s., 1H), 8.57 (br. s., 1H), 7.63 (d, J = 7.53 Hz, 1H), 7.46 (d, J = 7.78 Hz, 1H), 7.12 - 7.27 (m, 2H), 7.05 (t, J = 7.14 Hz, 1H), 4.54 (d, J = 5.19 Hz, 1H), 3.42 (br. s., 2H), 3.33 (d, J = 1.56 Hz, 6H);13C NMR (126 MHz, DMSO-d6) δ 161.7, 136.9, 132.0, 127.6, 123.8, 122.0, 120.2, 112.8, 103.3, 102.6, 53.8, 41.2;

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Synthesis of 9-methyl-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one 1e Amidoacetal (50 mmol) was dissolved in 40 mL of dry DMF and the mixture was cooled to 0°C. Sodium hydride (60% in mineral oil, 55 mmol) was added portion wise with stirring to the cooled solution. The mixture was stirred for 20 min and then heated to 50°C and stirred at this temperature for additional 30 min, then cooled to rt. Methyl iodide (55 mmol) was added portion

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wise in such a rate to keep temperature below 40°C and then the mixture was stirred at 50°C for 5 h. The resulted reaction mixture was extracted two times with hexane (30 mL) to remove mineral oil, DMF was evaporated under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate and extracted three times with 50 mL portions of water followed by flash chromatography (using ethyl acetate as an eluent) yielding the product as oily substance. This

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precipitate was filtered off, washed with MeOH (50 mL) and water (100 mL), then suspended in water (150 mL). Potassium carbonate was added to this suspension to make pH ~ 10 and the product was filtered off, washed with water to give compound 1e as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 11.33 (br. s., 1H), 8.03 (d, J = 7.53 Hz, 1H), 7.58 (d, J = 8.30 Hz, 1H), 7.49 (t, J = 7.53 Hz, 1H), 7.22 (t, J = 7.14 Hz, 1H), 7.09 (d, J = 6.49 Hz, 1H), 6.98 (d, J = 6.75 Hz, 1H), 4.24 (s, 3H);

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C NMR (126 MHz, DMSO-d6) δ 156.9, 140.7, 127.2, 127.0, 125.4, 125.1,

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