Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels-Alder reaction versus aryne-mediated domino process

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L. Nikonov, A. F. Khasanov, K. Giri, S. Santra, I. S. Kovalev, E. V. Nosova, S. Gundala , P. V. Venkatapuram,

G. V. Zyryanov, A. Majee and O. N. Chupakhin, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB00847G.

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Takeharu Haino et al.

Solvent-induced emission of organogels based on tris(phenylisoxazolyl)

benzene

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Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with

arynes: Inverse demand aza-Diels-Alder reaction versus aryne-

mediated domino process†

Received 00th January 20xx,

Accepted 00th January 20xx

Dmitry S. Kopchuk,^a,bIgor L. Nikonov,^aAlbert F. Khasanov,^aKousik Giri,^c‖ Sougata Santra,*^aIgor S.

Kovalev,^aEmiliya V. Nosova,^a,bSravya Gundala,^aPadmavathi Venkatapuram,^dGrigory

V. Zyryanov,^a,bAdinath Majee,^eOleg N. Chupakhin^a,b

DOI: 10.1039/x0xx00000x

www.rsc.org/

The interactions between substituted 5-R-3-(pyridyl-2)-1,2,4-triazines with in situ generated substituted aryne

intermediates have been studied. The reaction afforded either inverse demand (ID) aza-Diels-Alder products or 1,2,4-

triazine ring rearrangement (domino) products as major ones depending on the nature of both the substituents at the C5

position of 1,2,4-triazine core or in the aryne moiety. The structures of the key products were confirmed based on X-ray

data. Based on the density functional theoretical (DFT) studies of the Diels-Alder transition state geometries the influence

of the nature of arynes on the direction of the 1,2,4-triazine transformation has been proposed.

and 1,2,4-triazinoxides.⁸Recently, we reported the

interactions of arynes with 6-aryl-3-(2-pyridyl)-1,2,4-triazines

Introduction

1

, bearing a hydrogen atom or aromatic substituents at the C5

The in situ generated aryne intermediates have been attracted

attention in synthetic organic chemistry, including total

synthesis¹and chemistry of materials²since their discovery

more than a century ago.³Now, the aryne-based methodology

is well recognized as a convenient, one-pot synthetic approach

to a great number of compounds with various applications,

and most of them could not be obtained by using traditional

synthetic methods.⁴However, the fundamental mechanistic

path of the aryne-mediated transformations (such as the

control and understanding the selectivity in the nucleophilic

substitution in the aryne core or aryne involving cycloaddition

reactions) remains an important area of research.⁵Moreover,

the discussions on the mechanistic aspects of the interactions

of arynes or hetarynes with aza-heterocycles are very rare.⁶To

the best of our knowledge, no studies have been put forth to

predict/analize the possible reaction pathway in the

interactions between aza-heterocyclic substrates and arynes

based on the first or last ones structures. It is worthy to

mention that some reports were published previously on the

interactions of 1,2,4,5-tetrazines and 1,2,4-triazines with

certain aryne dienophiles to afford the corresponding

isoquinolines via inverse demand (ID) aza-Diels-Alder

reaction,⁷as well as some other interactions between arynes

position,^9-11as well as a cyano-substituent at the C5-position.¹²

It has been found that in most cases these reactions led to

domino products, namely, 1H-(1,2,3-triazol-1-yl)pyrido[1,2-

a]indoles

2, while the expected 1-(2-pyridyl)isoquinolines 3

were isolated only as by-products in low yields (Table 1).

However, the isoquinolines were obtained as major products

when 5-cyano-3-(2-pyridyl)-1,2,4-triazines were used as

starting compounds,¹²where the pyrido[1,2-a]indoles were

isolated as by-products. It is worthy to mention that these

products are of wide interest due to their broad spectrum of

biological activities, in particular cytostatic,¹³antiviral,¹⁴etc.

(Figure 1), as well as their unique fluorescent properties.¹⁵

Isoquinolines¹⁶and their metal coordinated complexes¹⁷also

possess biological activities, and the isoquinoline moety is

widely presented in alkaloids.¹⁸

Figure 1 Some biologically-active pyrido[1,2-a]indoles

In this work we wish to disclose our studies on the

interactions of 1,2,4-triazines with arynes, particularly to

analyze the influence of the nature of the substituent in the

C5-position of 6-aryl-3-(2-pyridyl)-1,2,4-triazines, as well as the

nature of aryne intermediates on the reaction pathway and on

the type of the products formed.

^a.Department of Organic and Biomolecular Chemistry, Chemical Engineering

Institute, Ural Federal University, 19 Mira Str., Yekaterinburg, K-2, 620002,

Russian Federation. E-mail: sougatasantra85@gmail.com; ssantra@urfu.ru

^b.I. Ya. Postovskiy Institute of Organic Synthesis, Ural Division of the Russian

Academy of Sciences, 22 S. Kovalevskoy Str., Yekaterinburg, 620219, Russian

Federation.

^c.Centre for Computational Sciences, School of Basic and Applied Sciences, Central

University of Punjab, City Campus, Mansa Road, Bathinda-151001, India.

^d.Department of Chemistry, Sri Venkateswara University, Tirupati-517502, Andhra

Pradesh, India

^e.Department of Chemistry, Visva-Bharati (A Central University), Santiniketan-

731235, India

†Electronic Supplementary Information (ESI) available: Copies of ¹H and ¹³C NMR

spectra of the synthesized compounds (PDF), Crystallographic data for compounds

Results and discussion

Based on the literature, a commonly accepted mechanism for

ID aza-Diels-Alder reaction and previously reported^9-11aryne-

mediated rearrangement of 1,2,4-triazines (domino reaction)

are presented in Scheme 1.

2d

Cartesian coordinates (Angstroms) and total energies (hartree) of the geometry-

optimized structures of all computed compounds (PDF). See

DOI: 10.1039/x0xx00000x

, 2j & 3c (CIF), DFT calculations and all computed structures (as .cif file),

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formation of acetophenone hydrazone

previously described procedure,²⁹and followed by the reaction

of with pyridine-2-carbaldehyde in boiling acetic acid. 6H-

1,2,4-Triazine 4i was obtained by the reaction between the

corresponding arylglyoxal and amidrazone according to the

previously reported method.³⁰

7 by using the

Table 1 Our previous studies

7

8

9

In the course of our work, we also analyzed the possible

methods for the in situ generation of various³¹arynes from the

viewpoint of their convenient use in the following interactions

with 1,2,4-triazines. Among the common methods for the

aryne generation only two were found to be the most suitable

based on the synthetic availability of the reagents: one is via

the dehydrohalogenation reactions of monohalogenaryls in

presence of strong bases (e.g. t-BuOK, NaNH₂, etc.), and

another one is via the diazotization reaction of anthranilic acid

derivatives. At first we tested the monohalogenaryl-based

method, and only few isoquinolines were isolated in low yields

as a result of the reactions with substituted 1,2,4-triazines in

an autoclave.³²Unfortunately, further detailed analysis of the

reaction mixture composition revealed the presence of the

significant amount of 1,2,4-triazine ring decomposition

products, most probably, for the presence of strong base.³³

Therefore, this method was found to be inappropriate for the

aryne generation by the reactions with 1,2,4-triazines, and in

our further experiments we used anthranilic acid-based

methodology. Anthranilic acid is the cheapest commercially

available precursor for the in situ generation of simplest aryne,

namely 1,2-dehydrobenzene (benzyne). In addition, 4,5-

difluoro- and 4,5-dimethoxy-1,2-dehydrobenzenes (Figure 2)

were tested, and their precursors were synthesized by means

of optimized methods.

Triazine

Ar

R

Х

H

Product 2

2a⁴

2g⁵

2j⁶

Product 3

1а

Ph

-

F

OMe

H

3d⁶

1b

1c

Ph

H

2b⁴

2k⁶

2c⁴

-

OMe

H

3e⁶

-

Biphenyl-2,2′-diyl

F

2i⁵

-

OMe

H

2l⁶

3f⁶

3a⁷

3g⁶

3b⁷

3c⁷

-

1d

Ph

CN

2d⁷

OMe

H

-

1e

1f

Tol

CN

H

2e⁷

2f⁷

4-BrC₆H₄

4-FC₆H₄

H

1g

F

2h⁵

Thus, as we can suggest, for the both pathways the formal

1,3-diaddition product (I1) is a key intermediate for the

reaction between aryne dienophile and 1,2,4-triazine diene

(Scheme 1). Depending on the electronic factors of both the

1,2,4-triazine and the aryne the subsequent transformation

would afford either the classical ID aza-Diels-Alder product

along with the elimination of N₂molecule and/or the 1,2,4-

triazine ring rearrangement (domino) products, namely

pyrido[1,2-a]indoles (via the intermediate I2).

Thus,

a

synthetic precursor of 4,5-difluoro-1,2-

dehydrobenzene, 2-amino-4,5-difluorobenzoic acid, was

synthesized according to the optimized conditions by our

procedure via the oxidation of the previously described 5,6-

1,2,4-Triazines and their N-oxides could be easily

functionalized by means of the nucleophilic substitution of

leaving groups (S_N^ipso) or by the nucleophilic substitution of

hydrogen (S_N^H). For highly π-deficient systems, such as 1,2,4-

triazines,¹⁹the S_N^H-based processes look more attractive

especially based on the principles of atom economy²⁰and

green chemistry.²¹

difluoro-1H-indole-2,3-dione³⁴

2 with hydrogen peroxide in an

alkaline medium.

Thus, as a first step, using the previously reported S_N^H- or

S_N^ipso-based procedures we prepared several 5-substituted

Figure 2 Structures of used aryne intermediates

1,2,4-triazines

1

and

4

as starting materials. Thus, 5-

as well as 5-

phenylethynyl substituted 1,2,4-triazine 4a ²²

,

The

synthetic

precursor

of

4,5-dimethoxy-1,2-

cyano-1,2,4-triazines 1d-e¹⁶were prepared starting from 1,2,4-

triazine-4-oxides 5a-b²³(Scheme 2). According to the

previously reported methods the ipso-substitution of the

cyano group by the residues of methanol,²⁴nitromethane²⁵

and pyrrolidine in triazines 1d-e (via solvent-free procedure²⁶)

afforded the compounds 4b-d. 5-(Indolyl-3)-substituted 1,2,4-

triazine 4g was obtained by an optimized procedure²⁷as a

result of oxidative nucleophilic substitution of the hydrogen by

the indole moiety in presence of trifluoroacetic acid. The

styryl-substituted 1,2,4-triazine 4h was synthesized according

dehydrobenzene, 2-amino-4,5-dimethoxybenzoic acid

obtained from the commercially available veratric acid

8

was

9

. For

this acid and its methyl ester 10, the previously reported

methods³⁵were used for the chemoselective introduction of

the nitro group into the C2-position of the benzene ring. Thus,

the nitration of the ester 10 proceeded very smoothly, and

subsequent hydrolysis of compound 11 afforded the 2-

nitroveratric acid 12 (Scheme 3). In the both steps the yields of

the products were very high, and the procedures are easily

realizable. In the final step, the reduction of 12 (by the

hydrogen gas over the 10% palladium on activated carbon)

to the reported procedure²⁸starting from 1,2,4-triazine 1b

.

5-Methyl-1,2,4-triazine 4e was easily prepared starting

afforded the desired 2-amino-4,5-dimethoxybenzoic acid

8 in

from the commercially available propiophenone

6 via the

97% yield. It is worthy to mention that we also tried to carry

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out the direct nitration of veratric acid according to a reported procedure allowed to obtain the desired product in up to 73%

procedure;³⁶however, the reaction afforded the desired yield.

product 12 in very low yield. The modification of the original

Scheme 1 A Commonly accepted ID aza-Diels-Alder reaction mechanism affording isoqionolines, and the benzyne-mediated rearrengement of 1,2,4-triazines (Domino Reaction)

Affording Pyrido[1,2-a]indoles.

Scheme 2 Synthetic approaches towards 5-substituted 1,2,4-triazines. Reagents and conditions: i) phenylacetylene, n-BuLi, THF, -78 °C, 20 min, then AcCl; ii) sodium, methanol, 65

°C, 2 min, then 20 °C, 1 h; iii) pyrrolidine, neat, 150 °C, 3 h, 1 h; iv) acetone cyanohydrin, Et₃N, DCM, reflux, 30 min; v) pyridine-2-carbaldehyde, ethanol, 20 °C, 10 h, then AcOH, 118

°C, 5 min; vi) indole, CF₃COOH, 1,2-dichloroethane, 20 °C, 12 h, then Na₂CO₃, 20 °C, 10 min, then DDQ, DCM, 20 °C, 30 min; vii) BuLi, phenylacetylene, THF/toluene (1:9), -78 °C, 5

min, then 20 °C, overnight, then methanol, 20 °C; viii) ethanol, reflux, 10 h.

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Table 2 Interactions between arynes and 5-R-3-(pyridyl-2)-1,2,4-triazines

R₂

R₁

X

N

R₂

R₁

N

R₂

R₁

N

+

N

i

N

X

1a-f

4a-f

3a-f

16a-c

2a-l

15a-q

X

Reagents and conditions: i) anthranilic acid, iso-amyl nitrite, toluene/1,4-

dioxane (4:1), reflux, 1.5 h.

Pyridoindole Isoquinoline

X

Triazine

R₂

R₁

Scheme 3 Synthesis of 3,4-dimethoxyanthranilic acid. Reagents and conditions: i)

methanol, H₂SO₄, 65 °C, 10 h; ii) HNO₃(40%), 20 °C, 24 h; iii) NaOH, ethanol, 1 h, 78 °C,

then HCl, 20 °C; iv) HNO₃(conc.), 20 °C, 12 h; v) H₂, Pd/C, methanol, 20 °C, 6 h.

(yield^a)

2a (49%)

2b (49%)

2c (60%)

2d (4%)

2e (3%)

2f ^b

(yield^a)

H

1а

1b

1c

1d

1e

1f

Ph

H

-

Next, the reactions of arynes with 6-aryl-5-R-1,2,4-triazines

were studied. Similarly to 6-aryl-5-R-3-(pyridyl-2)-1,2,4-

Biphenyl-2,2′-diyl

-

Ph

Tol

CN

3a (36%)

3b (31%)

3c (39%)

16a (12%)

triazines 1a-c, 1g (R = H or R = Ar) the introduction of electron-

donor substituents at the C5-position of 1,2,4-triazine moiety

did not alter the reaction pathway for all three arynes. Thus,

by the reactions with all three arynes, 5-methoxy- and 5-

pyrrolidino-1,2,4-triazines 4b,d afforded the corresponding

1,2,4-triazine ring rearrangement products (domino) as the

only products, namely pyrido[1,2-a]indoles 15 (Table 2). 6H-

1,2,4-Triazine 4i also reacted with benzyne to afford 1,2,4-

triazine rearrangement product 15g. The introduction of

electron-rich substituent, such as indole, at the C5-postion of

the 1,2,4-triazine moiety (4g) also did not alter the reaction

pathway, although the yield of the product 15e was much

lower, and extensive tarring of the reaction mixture was

observed.

4-BrC₆H₄

Ph

CN

4a

Ph-ethynyl

Pyrrolidin

e-1-yl

15a (28%)

4b

4c

4e

Ph

15b (35%)

-

OMe

15c (40%)

-

Complex mixture of

products

15d (49%)

CH₂NO₂

4f

4g

4h

Ph

Me

Indol-3-yl

Styryl

4-

-

15e (18%)

15f (31%)

-

16b (3%)

4i

H

15g (25%)

-

MeOC₆H₄

H

1h

1a

1b

1g

1d

1e

4a

4-NO₂C₆H₄

Ph

15h (40%)

2g (37%)

2h (45%)

2i (35%)

-

F

Ph

The introduction of electron-withdrawing substituents,

such as phenylethynyl-, phenylvinyl- or cyanogroup, at the C5-

position altered the direction of the main transformation of

the 1,2,4-triazine ring (Table 2). As reported previously¹²1-(2-

Biphenyl-2,2′-diyl

4-FC₆H₄

Ph

H

CN

15i (37%)

15j (45%)

15k (41%)

Tol

CN

pyridyl)-3-cyanoisoquinolines

products in the reaction of 5-cyano-1,2,4-triazines 1d,e with

1,2-dehydrobenzene, and pyrido[1,2-a]indoles were isolated

3 were isolated as major

Ph

Ph-ethynyl

Pyrrolidin

e-1-yl

OMe

4b

4d

4f

Ph

Tol

Ph

15l (40%)

-

2

15m (49%)

only as minor products. Moreover, in the reaction with less

electrophilic aryne, 4,5-dimethoxy-1,2-dehydrobenzene, the

Complex mixture of

products

15n (42%)

Me

rearrangement products

2 were not detected at all in the

4h

1a

1b

1c

1d

1e

4a

Ph

Styryl

Ph

-

reaction mixture, and the yield of isoquinoline 3g was found to

be noticeably lower compared to that observed for

unsubstituted aryne.¹²We found that the similar reaction of 5-

OMe

2j (26%)

3d (7%)

H

2k (25%)

-

Biphenyl-2,2′-diyl

2l (44%)

3e^b

phenylethynyl- and 5-styryl-3-(pyridyl-2)-1,2,4-triazines 4a,h

Ph

Tol

Ph

CN

-

3f (10%)

16c (14%)

with benzyne afforded pyrido[1,2-a]indoles 15a,f as major

products along with isoquinolines 16a,b as minor ones (in 12%

and 3% yields respectively).

-

Ph-ethynyl

Pyrrolidin

e-1-yl

Tarring

4b

Ph

15o (25%)

-

4c

4f

Ph

OMe

Tarring

Me

15p (28%)

15q (30%)

-

4h

Styryl

-

^aIsolated yields. ^bDetected by mass spectrometry

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Thus, in this reaction the amount of the classical ID aza-

Diels-Alder products, namely isoquinolines, is changed in

accordance with an acceptor strength of the substituent at the

C5-position of 1,2,4-triazine moiety, and the enhancement of

acceptor strength lies in the row “styryl group – phenylethynyl

group - cyano group” led to the increasing of the the amount

of isoquinolines in the composition of the products, thus

facilitating the course of the classical ID aza-Diels-Alder

reaction.

Scheme 4 Possible tautomeric equilibrium of compound 4e

In some cases the X-ray data were used as a key method

for establishing the structure of products. Thus, in order to

confirm the structure of the 1,2,4-triazine transformation

product obtained by the reaction of 4,5-dimethoxy-1,2-

dehydrobenzene,¹¹such as compound 2j, the X-ray diffraction

experiment was performed (Figure 3). According to the

collected XRD data, the compound is crystallized in the

centrosymmetric space-group. The molecule is a non-planar,

and the 1,2,3-triazol ring is turned towards the pyrido[1,2-

a]indole moiety on the angle of 57°. All bond distances and

angles in the molecule are within the standard values. In

particular, the single and double bonds in the pyridine ring of

the pyrido[1,2-a]indole (1.41 and 1.35 Å respectively) are well

distinguished (approximately on the 0.05 Å). The non-

hydrogen atoms of the methoxy-substituents are located in

the plane of the pyrido[1,2-a]indole moiety. In the crystal, the

molecules form one-dimensional structure, and the close

contacts are not detected with neighboring molecular chains

(See Figure S1 in ESI).

It is worthy to mention, that 1,2,4-triazine 4e, substituted

with nitromethane moiety at the C5-position was also tested in

the reaction with 1,2-dihydrobenzene. However, the reaction

led to the formation of a complex, inseparable mixture of

products and neither ID aza-Diels-Alder reaction product nor

1,2,4-triazine transformation product were detected. This is

probably due to the existence of compound 4e in two

tautomeric forms (Scheme 4). According to the ¹H NMR

spectroscopy, the form

B is the preferable, which was

confirmed based on the presence of one-proton singlet in the

6.59 ppm region.

In order to study the influence of electron-withdrawing

substituents at the C6-position of triazine moiety 6-(4-

nitrophenyl)-1,2,4-triazine 1h was reacted with 1,2-

dehydrobenzene; the reaction afforded only the

rearrangement product, namely pyrido[1,2-a]indole 15h, and

no classical ID aza-Diels-Alder reaction product (isoquinoline)

was detected.

Unlike, 1,2-dehydrobenzene and 4,5-dimethoxy-1,2-

dehydrobenzene (in reactions with 1,2,4-triazines 4a,c) the

interaction of 4,5-difluoro-1,2-dehydrobenzene with all 5-R-3-

(pyridyl-2)-1,2,4-triazines substituted with both the electron-

withdrawing or electron-donating groups afforded the

pyrido[1,2-a]indoles as the only products, and no

corresponding ID aza-Diels-Alder products (isoquinolines),

were detected. Likewise for 1,2-dehydrobenzene, the reaction

of 1,2,4-triazines with 1,2-dehydro-4,5-dimethoxybenzene

afforded the 1,2,4-triazine ring transformation products along

with ID aza-Diels-Alder products as minor ones. Table 2

summarizes all the data for the interaction between arynes

and 5-R-3-(pyridyl-2)-1,2,4-triazines obtained herein, as well as

some previously reported examples.

According to the XRD data of another transformation

product 2d, its molecule is non-planar (Figure 4). The phenyl

substituent is placed approximately in the plane of the 1,2,3-

triazole ring (with some deviation of the C-atom at the para-

position of the phenyl ring from the plane less than 0.2 Å). The

1,2,3-triazole ring is turned towards the pyrido[1,2-a]indole

tricyclic system on the angle of 52^o. In the crystal the

molecules form the centrosymmetric dimers with formation of

shortened π-π C…C contacts between tricyclic moieties. In

particular, the observed contacts between pyrido[1,2-a]indole

tricyclic systems with symmetry transformation [-1-x, -y, 1-z]

are: the C(1)…C(14) contact is equal to 3.266 Å, and the

contact C(13)…C(13) is less efficient and equal to 3.309 Å (See

Figures S2-S3 in ESI). The N-atom of the CN-group in the dimer

forms a weak intermolecular H-bond of the N…HC type with

carbon atom of C(20) of the pyrido[1,2-a]indole tricyclic

system, in order to stabilize the conformation of the molecule.

The 4-Ph-5-CN-1,2,3-triazole moiety also forms some

shortened intermolecular π-π C…C contacts (See Figures S2-S3

in ESI), however, the interatomic distances for these contacts

are greater than for discussed above.

The structures of all new products were confirmed based

1

on the data of H, ¹³C NMR spectroscopy, elemental analysis

and in some cases IR spectra. In all cases, there is a clear

correlation with the data for analogous compounds with other

substituents reported earlier. In some cases, one can note the

presence of characteristic signals of the corresponding

substituents in the structure of the products. In particular, for

the phenylethynyl substituents in the ¹³C NMR spectrum, the

characteristic signals of sp-hybridized carbon atoms were

observed in the region of 76.2-102.7 ppm.

In accordance with XRD data, the molecule of isoquinoline

3c is non-planar (Figure 5). The 4-bromophenyl-substituent is

turned towards the heterocyclic moiety on the angle of 56^o,

and the pyridine ring is turned towards the isoquinoline

moiety on the angle of -47^owith anticlinal placing of the N-

atoms of the heterocyclic rings. In the crystal the molecules of

3c form stacks with intermolecular distances of 3.4-3.9 Å (See

Figure S4 in ESI).

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As we previously mentioned,¹¹in the ¹H NMR spectra of instead of only one two-proton singlet at around 7.00 ppm.

some products of the reactions between 1,2,4-triazines and However, in CD₃CN a typical resonance peak of the styrene

1,2-dehydro-4,5-dimethoxy-benzene

(dimethoxyaryne), moiety was observed, and the trans-configuration was

namely 2j-2l, at room temperature, the signals of the aromatic confirmed based on the coupling constant data (J = 15.5 Hz).

protons of the C5-aryl substituent, as well as the signals of the

protons of one of the methoxy groups of the pyrido[1,2-

a]indole moiety are observed as broadened singlets (Figure 6).

We assumed that the rotation of the dimethoxy-substituted

pyrido[1,2-a]indole moiety is somehow hampered with respect

to the diaryl-substituted 1,2,3-triazole moiety due to one

methoxy group pointed towards the aromatic substituent of

the 1,2,3-triazole moiety. To confirm that case we measured

the ¹H NMR spectra for the most representative compound 2k

at the temperature of -56 °C (217K) (Figure 6). As it can be

seen that the lowering of the temperature significantly

reduces the speed of the rotation around the C-N bond

between the pyrido[1,2-a]indole and 1,2,3-triazole moieties,

and only one set of sharp peaks could be observed.

Figure 3 Crystal Structure of pyrido[1,2-a]indole 2j (CCDC # 1562139

)

Figure 6 ¹H NMR Spectra of compound 2k in CDCl₃at different temperatures

DFT-supported evaluation of the Diels−Alder vs domino reactivity

of the arynes in reactions with 1,2,4-triazines

In Diels–Alder reactions two new bonds are simultaneously

formed between the diene and dienophile in a [π⁴s + π²s]

fashion. The reaction kinetics is governed by the energy

differences between the HOMO and LUMO; the smaller the

energy differences between the Frontier Molecular Orbitals

(FMO) the faster the reaction.³⁷Here the present reported ID

aza-Diels–Alder reactions were governed by the

HOMO_dienophile–LUMO_dienegap.³⁸In order to analyze the above

experimental results, particularly to estimate the influence of

the substituents in the both aryne intermediates and 1,2,4-

triazines, the theoretical calculations of the HOMO and LUMO

energies and the HOMO-LUMO gap for arynes (dienophiles)

and 1,2,4-triazines (dienes) were carried out (Table 3). The

obtained results of the density functional theoretical (DFT)

calculation suggest that compared to the HOMO of benzyne (-

9.69 eV)³⁹the introduction of the both fluorine atom and

methoxy-group strongly increases the HOMO level of aryne

dienophile compare to 1,2-dehydrobenzene (benzyne), which

decreases the HOMO_aryne–LUMO_{1,2,4-triazine}gap. Thus, based on

Figure 4 Crystal structure of pyrido[1,2-a]indole 2d (CCDC # 1562142)

Figure 5 Crystal structure of isoquinoline 3c (CCDC # 1562138)

Additionally, in CDCl₃in ¹H NMR spectra of pyrido[1,2-

a]indoles 15f, 15n, 15q with a stylbene residue we did not

observe the characteristic signals of this moiety as two

characteristic doublets were observed at around 7.00 ppm

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the lowest values for the HOMO-LUMO gap, the most favorable in case of benzyne. From another hand the

favorable looks ID aza-Diels-Alder reaction between 1,2,4- nucleophilic addition to arynes occurs at the reaction site with

triazines 1d,4a,4b and 4,5-difluoro-1,2-dehydrobenzene (Table the highest contribution of LUMO.⁴⁰Here, opposite to the

3). However, in our experiments with all 1,2,4-triazines, even HOMO orbitals, the predominant localization of the LUMO's

those substituted with cyano-group at the C5-position of the orbital lobes at the "triple bond's" 4,5-difluoro-1,2-dehydro-

1,2,4-triazine moiety we observed either the formation of benzene carbons (Figure S10, ESI) leads to the conclusion that

1,2,4-triazine ring rearrangement products (domino products), a nucleophilic attack (by the lone pair of pyridine atom of

such as pyrido[1,2-a]indoles with no ID aza-Diels-Alder 1,2,4-triazine, Scheme 1) is considerably more favorable than

products or observed no reaction at all (Table 2). Some our in case of benzyne at these particular positions. In fact, based

additional findings, namely DFT calculations of localization of on DFT calculations (Table 3) the LUMO energy of 4,5-difluoro-

HOMO orbital lobs in benzyne and 4,5-difluoro-1,2-dehydro- 1,2-dehydro-benzene is 0.87 eV (20.06 kcal/mol) which is

benzene, have demonstrated the predominant localization of lower than that of benzyne and 4,5-dimethoxy-1,2-dehydro-

the HOMO's orbital lobes at the "triple bond's" carbons, while benzene and that makes the formation of addition products at

in 4,5-difluoro-1,2-dehydro-benzene the HOMO's orbital lobes the “triple bond” of the 4,5-difluoro-1,2-dehydro-benzene to

are mainly localized at the “HC-CF-CF-CH” moiety of aryne be the most favorable.

molecule (Figure S9, ESI). This suggests that the cycloaddition

process with LUMO orbitals of 1,2,4-triazine would be more

Table 3 The HOMO-LUMO calculations for the 1,2,4-Triazines 1a, 4a, 4b and arynes

Benzyne³⁹

4,5-Dimethoxy-

1,2-dehydro-

benzene

4,5-Difluoro-

1,2-dehydro-

benzene

1d

4a

4b

E_LUMO, eV

E_HOMO, eV

0.64

0.95

1.58

1.42

1.38

0.87

-8.95

-8.35

-8.18

-9.69

-9.25

-10.09

∆E, eV, (E_{HOMOdienophile}–E_LUMOdiene

)

Benzyne

9.05

8.61

8.74

8.30

8.11

7.67

-

4,5-Dimethoxy-1,2-

dehydro-benzene

4,5-Difluoro-1,2-

dehydro-benzene

9.45

9.14

8.51

The transition structures for the Diels−Alder/domino

reactions between the most representative 1,2,4-triazine 1d

and benzyne and 4,5-difluoro-1,2-dehydro-benzene are shown

in Figure 7 (please also see ESI, Figure S5-S8 & S11-S12). Herein

the activation enthalpy (ΔH^⧧), activation free energy (ΔG^⧧), and

reaction free energy (ΔG_rxn) for each combination were

calculated. Based on the calculated ΔH^⧧, ΔG^⧧and ΔG_rxnvalues

the interaction between 1d and benzyne affording ID Diels-

Alder product (TS1) requires 2.768 kcal/mol less energy than

the required energy for domino product (TS2). In case of 4,5-

difluoro-1,2-dehydro-benzene both interactions will proceed

with very close activation free energies, namely 8.550 kcal/mol

Table 4 The activation enthalpy (ΔH^⧧), activation free energy (ΔG^⧧) and reaction free

energy (ΔG_rxn) for the interaction of 1d and arynes

Transition

state

ΔH^⧧

ΔG^⧧

ΔG_rxn

k₂(M^-1s^-1)

1,2-Dehydro-benzene

TS1

TS2

-3.887

-2.040

8.826

-141.039

-81.913

2.10x10⁶

1.97x10⁴

11.594

4,5-Difluoro-1,2-dehydro-benzene

TS3

TS4

-4.300

-4.715

8.550

9.004

-144.821

-83.901

3.36x10⁶

1.56x10⁶

Next, the interaction/distortion analysis^41-42was performed

on all possible transition states (TS1-TS4). Figure 8 illustartes

the graphs obtained for the interactions between 1,2,4-triazine

1a and benzyne or 4,5-difluoro-1,2-dehydro-benzene. It can be

clearly seen that distortion energies for the interactions

between 1d and arynes affording domino products are always

larger than that for ID Diels−Alder products and that is

(

TS3) and 9.004 kcal/mol (TS4) and that is also very close to

the values calculated for the TS3 (8.826 kcal/mol) in case of

benzyne. In other words, based on the literature,⁴¹the

formation of products via TS1,TS3-TS4 would proceed with a

very similar reaction rates. To prove this the second order rate

constants were computed by using the Eyring transition state

theory at 298K (Table 4) and, except TS2, they all are lying in

the same range of 1.5-3.3x10⁶M^-1s^-1.

assuming the late transition states (TS2,

TS4).⁴¹In these

interactions the contribution of the distortion energy of diene

1d is almost same, while the distortion energy of the benzyne

is 1.5 times higher than the distortion energy of the 4,5-

difluoro-1,2-dehydro-benzene. Additionally, for the interaction

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with the last one both aryne and 1d are almost equally better predistorted for the domino reaction. Finally, the

contributed to the tolal ΔE^#_dist, while in case of benzyne the interaction between 1d and 4,5-difluoro-1,2-dehydro-benzene

contribution of benzyne (pre)distortion is much larger. In ID proceeds with most negative interaction energy affording the

Diels−Alder process the diene 1d has the largest contribution domino product, an that is also assuming the lowest activation

in the ΔE^#and it is almost the same for the both benzyne energy.⁴¹Thus, according to the DFT studies, in the interaction

dist

and 4,5-difluoro-1,2-dehydro-benzene, and the contribution of between 4,5-difluoro-1,2-dehydro-benzene and 1,2,4-triazine

two last ones is very small. By summarizing of all above, it may 1d the domino reaction is the only process due to the both

assume that the 4,5-difluoro-1,2-dehydro-benzene is much electronic and steric effects.

Figure 7 M06-2X/6-31G(d) - optimized transition state structures for the reaction of 1,2,4-triazine (1a) with benzyne (TS 1-2) and difluoro-benzene (TS3-4)

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Figure 8 Graph of distortion, interaction, and activation energies for transition states of reactions between the most representative 1,2,4-triazine 1d and benzyne or 4,5-difluoro-

1,2-dehydro-benzene (green: distortion energy of aryne, blue: distortion energy of 1d, red: interaction energy, black: activation energy, in kcal/mol).

by comparing the yields of isoquinoline formed in the series of

5-phenylethynyl-, 5-styryl- and 5-cyano-1,2,4-triazines. 4,5-

CONCLUSIONS

Difluoro-1,2-dehydrobenzene is the only exception to this

Thus, in this article the main features of the interactions of 3-

(2-pyridyl)-1,2,4-triazines with aryne intermediates, such as

1,2-dehydrobenzene and its 4,5-difluoro- and 4,5-demethoxy

substituted derivatives, have been studied. It was found that

3-(2-pyridyl)-1,2,4-triazines, which are 5-unsubstituted or

substituted with electron-donating substituents at the C5

position, such as aryl, methoxygroup, pyrrolidyl residue, react

with all three arynes to afford the 1,2,4-triazine ring

rearrangement (domino) products, namely pyrido[1,2-

a]indoles, as major products. In case of the less electrophilic

4,5-dimethoxy-1,2-dehydrobenzene along with the triazine

ring rearrangement products, the formation of the classical ID

aza-Diels-Alder reaction products took place, however, the

yields were not exceeding 7%. Upon the introduction of the

electron-withdrawing substituents at the C5-position of 3-(2-

pyridyl)-1,2,4-triazine, the formation of the expected

isoquinoline derivatives takes place to a major extent, and the

greater the acceptor character of the introduced residue the

higher the yield of the isoquinolines formed. This is confirmed

pattern, and in all cases the only products were exclusively

pyrido[1,2-a]indoles as domino products. Based on the DFT

calculations and the interaction/distortion analysis it was

suggested that the presence of two fluorine atoms in this

aryne provides its high electrophilicity and/or high

“predistortion” for the domino reactions. The structures of the

three key products were confirmed based on the X-ray data.

EXPERIMENTAL SECTION

General informations

Unless otherwise indicated all common reagents and solvents

were used from commercial suppliers without further

1

purification. H, ¹³C and ¹⁹F NMR spectra were determined on

a 400 MHz spectrometer, 298 K, digital resolution ± 0.01 ppm,

1

using TMS as internal reference for H and ¹³C NMR or CFСl₃

for ¹⁹F NMR. The XRD analysises were accomplished on

standard procedure (MoK-irradiation, ω-scans with 1° step).

Empirical absorption corrections were applied using Olex2,⁴³

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the structures were solved with the Superflip⁴⁴structure (300 mg, 1.16 mmol) and pyrrolidine (0.095 mL, 1.16 mmol)

solution program using Charge Flipping and refined with the was stirred at 150 °C for 3 h in argon atmosphere. The product

ShelXL⁴⁵refinement package using Least Squares minimisation. was used in the next step without additional purification. ¹Н

The non-hydrogens atoms were refined in anisotropic NMR (400 MHz, DMSO-d₆): δ 1.87 (m, 2H, pyrrolidine), 3.43

approximation; the H-atoms were added in the calculated (brs, pyrrolidine), 7.41 (m, 1H, H-5 (Py)), 7.43-7.51 (m, 3H, Ph),

positions and were refined in isotropic approximation in the 7.62 (m, 2H, Ph), 7.86 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H, H-4 (Py)),

“rider” model.

8.56 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)), 8.85 (dd, J = 4.8, 1.8 Hz,

1H, H-6 (Py)); ¹³C NMR (100 MHz, CDCl₃): δ 25.3, 49.7, 123.9,

124.6, 128.2, 128.6, 128.8, 136.6, 137.2, 146.6, 150.0, 152.4,

154.2, 159.1. Anal. Calcd For C₁₈H₁₇N₅: C, 71.27; H, 5.65; N,

23.09%; Found: C, 71.21; H, 5.68; N, 23.02%.

Computational methods

The optimization of the geometrical structures and harmonic

vibrational analysis has been performed using the Gaussian 09

suite of programs.⁴⁶The DFT (M06-2x) method⁴⁷has been

used with the 6-311+G(d,p) basis set for all atoms as

implemented in the Gaussian 09 program. The minima and

transition states (TS) on the potential energy surface have

been confirmed by the analysis of the harmonic vibrational

frequencies. For thermochemistry analysis the frequency scale

factor 0.97 is used to compensate the harmonic

approximation. The ultrafine integration grid and tight

geometry optimizations were used to enhance the calculation

accuracy. All calculations have been performed for the

molecules in a singlet state. The frontier molecular orbitals

(FMOs) and their energies were computed at the HF/6-

311+G(d,p) level using the M06-2X/6-311+G(d,p) geometries.

Distortion and interaction energies, as well as intrinsic reaction

coordinates were carried out at the M06-2X/6-311+G(d,p)

level. Please also see ESI for details.

General method for the synthesis of 5-methoxy-1,2,4-

triazines (4c, 4d). Synthesis was fulfilled in accordance with

the improved method presented for the similar compounds.²⁴

Corresponding 5-cyano-1,2,4-triazine

1 (2 mmol) was added to

solution of sodium (50 mg) in methanol (10 mL). The resulting

mixture was heated to reflux and then stored at room

temperature for 1 h. Water (80 mL) was added and the

obtaining precipitate was filtered off. Analytical sample was

obtained by recrystallization (methanol).

5-Metoxy-6-phenyl-3-(2-pyridyl)-1,2,4-triazine (4c). Yield 315

1

mg (60%). M.p. 214-216 °C. Н NMR (400 MHz, DMSO-d₆): δ

4.25 (s, 3H, OMe), 7.52-7.59 (m, 4H, Ph, H-5 (Py)), 8.00 (ddd, J

= 7.8, 7.8, 1.8 Hz, 1H, H-4 (Py)), 8.11 (m, 2H, Ph), 8.53 (dd, J =

7.8, 0.8 Hz, 1H, H-3 (Py)), 8.81 (dd, 1H, J = 4.8, 1.8 Hz, H-6 (Py));

¹³C NMR (100 MHz, DMSO-d₆): δ 54.4, 123.8, 125.6, 128.4,

129.1, 130.3, 132.4, 137.3, 148.9, 150.0, 152.4, 160.4, 161.0.

Anal. Calcd For C₁₅H₁₂N₄O: C, 68.17; H, 4.58; N, 21.20%; Found

C, 68.01; H, 4.43; N, 20.98%.

Starting compounds: 1,2,4-triazines 1a ³⁰

1d-f ²²4a ²³4h ²⁹2-(4-methoxyphenyl)-2-oxoacetaldehyde 8 ⁴⁹

picolinimidohydrazide 9 ⁴⁸2-amino-4,5-difluorobenzoic acid¹⁰

, 1b, , ,

1h and 1g ²⁸1c ⁴⁸

,

5-Metoxy-3-(2-pyridyl)-6-tolyl-1,2,4-triazine (4d). Yield 360

1

mg (65%). M.p. 209-211 °C. Н NMR (DMSO-d₆): δ 2.45 (s, 3H,

,

were synthesized according to the previously reported

methods.

4,5-Dimethoxy-2-nitrobenzoic acid (12).³⁵Synthesis was

fulfilled in accordance with the optimized method. In a typical

Me), 4.23 (s, 3H, OMe), 7.33 (m, 2H, Tol), 7.54 (m, 1H, H-5

(Py)), 7.95-8.03 (m, 3H, Tol, H-4 (Py)), 8.50 (dd, J = 7.8, 0.8 Hz,

1H, H-3 (Py)), 8.79 (dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)). Anal. Calcd

For C₁₆H₁₄N₄O: C, 69.05; H, 5.07; N, 20.13%; Found: C, 68.89;

H, 4.92; N, 20.01%.

experimental procedure 4,5-dimethoxybenzioc acid

9 (3.00 g,

16.5 mmol) was dissolved in concentrated nitric acid (16.5 mL).

The resulting mixture was stirred at room temperature for 12

h. The obtained precipitation was filtered off, washed with

water and dried. The crude product was purified by

recrystallization (toluene). Yield 2.36 g (73%). M.p. 198-200 °С.

¹Н NMR (400 MHz, DMSO-d₆): δ 3.91 (s, 3H, MeO), 3.92 (s, 3H,

MeO), 7.21 (s, 1H, H-3), 7.46 (s, 1H, H-6), 13.26 (brs, 1Н,

СOOH).

2-Amino-4,5-dimethoxybenzoic acid (8).⁴⁹4,5-Dimethoxy-2-

nitrobenzoic acid 12 (2.36 g, 11.97 mmol) was dissolved in

methanol (40 mL), Pd/C (10%, 0.24 g) was added and the

resulting mixture was stirred at room temperature for 6 h

under hydrogen atmosphere (P = 10 atm.). The reaction mass

was filtered off from catalyst, the solvent from filtrate was

removed under reduced pressure. The product was used for

the aryne generation without additional purification. Yield 2.29

g (97%). M.p. 198-200 °С. ¹Н NMR (400 MHz, DMSO-d₆): δ 3.63

(s, 3H, MeO), 3.72 (s, 3H, MeO), 6.22 (s, 1H, H-3), 7.22 (s, 1H,

H-6).

(Z)-5-(nitromethylene)-6-phenyl-3-(pyridin-2-yl)-4,5-dihydro-

1,2,4-triazine (4e). Potassium hydroxyde (340 mg, 6.07 mmol)

was suspended in DMSO (3 mL). The cyanotriazine (225 mg,

0.87 mmol) and nitromethane (0.13 mL, 1.74 mmol) were

dissolved in THF (5 mL), the resulting solution was added

dropwise to the suspension of KOH at room temperature, then

the resulting mixture was stirred at room temperature for 1 h.

The resulting mixture was poured into ice/water. The

precipitate obtained was filtered off, washed with water and

dried. The product was used in the next step without

additional purification. Yield 167 mg (0.57 mmol, 65%). M.p.

224-226 °C. ¹Н NMR (400 MHz, DMSO-d₆): δ 6.59 (s, 1H,

CHNO₂), 7.43-7.54 (m, 4H, Ph, H-5 (Py)), 7.93 (ddd, J = 7.8, 7.8,

1.8 Hz, 1H, H-4 (Py)), 8.52 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)),

8.75 (dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)). Anal. Calcd For

C₁₅H₁₁N₅O₂: C, 61.43; H, 3.78; N, 23.88%; Found: C, 61.18; H,

3.59; N, 23.62%.

5-Methyl-6-phenyl-3-(2-pyridyl)-1,2,4-triazine

(4f).

The

hydrazone 7 (1 g, 5.64 mmol) was dissolved in ethanol (25 mL),

6-Phenyl-5-(pyrrolidin-1-yl)-3-(2-pyridyl)-1,2,4-triazine (4b).

The mixture of 5-cyano-6-phenyl-3-(2-pyridyl)-1,2,4-triazine 1d

pyridine-2-carbaldehyde (0.54 mL, 5.64 mmol) was added and

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the resulting mixture was kept at room temperature for 10 h. corresponding anthranilic acid (3.5 mmol) in dry 1,4-dioxane

Solvent was removed under reduced pressure. The glacial (15 mL) was added by means of dropping funnel for 30 min.

acetic acid was added to the residue and the resulting mixture The reaction mixture was heated under reflux for 1 h and then

was heated to reflux 5 times. Then the reaction mixture was cooled to room temperature. Then the reaction mass was

cooled to room temperature, solvent was removed under washed with potassium hydroxide solution (3M, 3 x 50 mL),

reduced pressure. The residue was tritutared with ethanol and dried with anhydrous sodium sulfate. Solvents were removed

the resulting precipitate was filtered off, washed with ethanol under reduced pressure. The products of reaction were

and dried. The analytical sample was obtained by separated by column chromatography (Silica gel,

recrystallization (ethanol). Yield 760 mg (54%). M.p. 195-197 corresponding eluent).

°C. ¹Н NMR (400 MHz, DMSO-d₆): δ 2.71 (s, 3H, Me), 7.53-7.61 10-(4,5-Diphenyl-1H-1,2,3-triazol-1-yl)pyrido[1,2-a]indole

(m, 4H, Ph, H-5 (Py)), 7.77 (m, 2H, Ph), 8.00 (ddd, J = 7.8, 7.8, (2a). Eluent: ethyl acetate/toluene (1:1), R_f= 0.8. Yield 190 mg

1

1.8 Hz, 1H, H-4 (Py)), 8.51 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)), (49%). M.p. 175-177 °C. Н NMR (400 MHz, CDCl₃): δ 6.56 (m,

8.81 (dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)). Anal. Calcd For C₁₅H₁₂N₄: 1H), 6.95 (m, 1Н), 7.10-7.24 (m, 5Н), 7.25-7.39 (m, 6Н), 7.42

C, 72.56; H, 4.87; N, 22.57%; Found: C, 72.39; H, 4.67; N, (m, 1H), 7.71 (m, 2Н), 7.85 (m, 1Н), 8.31 (m, 1Н); ¹³С NMR (100

22.33%.

MHz, CDCl₃): δ 101.4, 109.1, 110.4, 115.9, 117.5, 120.8, 124.1,

3-(6-Phenyl-3-(pyridin-2-yl)-1,2,4-triazin-5-yl)-1H-indole (4g). 124.2, 124.3, 124.6, 125.0, 127.4, 127.5, 127.6, 127.8, 127.9,

The starting triazine 1b (500 mg, 2.14 mmol) was dissolved in 128.3, 128.6, 128.7 (2С), 128.9, 129.1, 129.4, 130.5, 131.2,

1,2-dichloroethane (50 mL). Trifluoroacetic acid (0.49 mL, 6.42 132.3, 135.9, 143.9. Anal. Calcd For С₂₆Н₁₈N₄: С, 80.81; Н, 4.69;

mmol) and indole (250 mg, 2.14 mmol) were added and the N, 14.50%; Found: С, 80.62; Н, 4.55; N, 14.57%.

resulting mixture was stirred at room temperature for 24 h. 10-(4-Phenyl-1H-1,2,3-triazol-1-yl)pyrido[1,2-a]indole

(2b).

Then the resulting mixture was washed with water solution of Eluent: ethyl acetate/toluene (1:1), R_f= 0.8. Yield 150 mg

1

sodium carbonate, the precipitate formed was filtered off and (49%). M.p. 166-168 °C. Н NMR (400 MHz, CDCl₃): δ 6.68 (m,

dried. Then the obtained σ-adduct (600 mg, 1.71 mmol, 80% 1H), 7.12 (m, 1Н), 7.36-7.45 (m, 2Н, Ph), 7.46-7.54 (m, 3Н, Ph),

yield) was dissolved in DCM (40 mL), DDQ (430 mg, 1.88 mmol) 7.72 (m, 1H), 7.90 (m, 3Н), 8.24 (s, 1Н, H-5), 8.43 (m, 1Н); ¹³С

was added and the resulting mixture was stirred at room NMR (100 MHz, CDCl₃): δ 109.4, 110.6, 116.7, 117.3, 121.0,

temperature for 30 min. The product was separated by column 121.1, 123.1, 124.1, 124.6, 124.9, 125.9 (2С), 127.8, 128.2,

chromatography (neutral Al₂O₃, ethylacetate as eluent). Yield 128.9, 130.5, 130.7, 146.3. Anal. Calcd For С₂₀Н₁₄N₄: С, 77.40;

412 mg (total yield 55%). M.р. > 250 °C. ¹Н NMR (400 MHz, Н, 4.55; N, 18.05%; found: С, 77.31; Н, 4.42; N, 17.87%.

DMSO-d₆): δ 6.89 (brs, 1H, H-2 (indole)), 7.17-7.22 (m, 2H, 1-(Pyrido[1,2-a]indol-10-yl)-1H-phenantro[9,10-

indole), 7.41 (m, 1H, indole), 7.55-7.61 (m, 4H, Ph, H-5 (Py)), d][1,2,3]triazole (2c). Eluent: ethyl acetate/toluene (1:1), R_f=

1

7.70 (m, 2H, Ph), 8.04 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H,H-4 (Py)), 0.8. Yield 230 mg (60%). M.p. 233-235 °C. Н NMR (400 MHz,

8.57 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)), 8.71 (m, 1H, indole), CDCl₃): δ 6.70 (m, 1H), 7.03 (m, 1Н), 7.15-7.25 (m, 2Н), 7.35-

8.89 (dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)), 11.66 (brs, 1H, NH). 7.45 (m, 3Н), 7.60 (m, 2Н), 7.74 (m, 1Н), 7.83 (m, 1Н), 8.06 (m,

Anal. Calcd For C₂₂H₁₅N₅: C, 75.63; H, 4.33; N, 20.04%; Found: 1Н), 8.52 (m, 1Н), 8.66-8.76 (m, 2Н), 8.99 (m, 1Н); ¹³С NMR

C, 75.53; H, 4.50; N, 19.92%.

(100 MHz, CDCl₃): δ 102.4, 109.5, 110.8, 116.2, 117.9, 120.7,

5-(4-Methoxyphenyl)-3-(pyridin-2-yl)-1,2,4-triazine

(4h)

.

121.3, 122.9, 123.0, 123.5, 124.0, 124.4, 124.7, 125.1, 125.2,

Picolinimidohydrazide

9

(1 g, 7.34 mmol) and 2-(4- 125.3, 127.1, 127.2, 127.7, 128.2 (2С), 129.1, 130.2, 131.1,

(1.2 g, 7.34 mmol) were 132.8, 141.4. Anal. Calcd For С₂₆Н₁₆N₄: С, 81.23; Н, 4.20; N,

methoxyphenyl)-2-oxoacetaldehyde

8

dissolved in ethanol (60 mL). The resulting mixture was stirred 14.57%; Found: С, 81.02; Н, 4.11; N, 14.34%.

under reflux for 5 h and cooled to room temperature. Water 10-(5-Cyano-4-phenyl-1H-1,2,3-triazol-1-yl)pyrido[1,2-

(300 mL) was added and the resulting mixture was stirred at a]indole (2d). Eluent: DCM/ethyl acetate (7:5), R_f= 0.8. Yield

room temperature for 1 h. The precipitate formed was filtered 0.013 g (4%). M.p. 196-198 °C. ¹Н NMR (400 MHz, CDCl₃): δ

off, washed with water and dried. The analytical sample was 6.78 (td, J = 6.6, 6.6, 1.0 Hz, 1H), 7.22 (ddd, J = 9.4, 6.5, 1.0 Hz,

obtained by recrystallization (ethanol). Yield 1.57 g (81%). M.p. 1H), 7.45 (m, 1H), 7.48-7.61 (m, 5H), 7.75 (m, 1H), 8.00 (m,

1

> 250 °C. Н NMR (400 MHz, DMSO-d₆): δ 3.91 (s, 3H, OMe), 1H), 8.22 (m, 2H), 8.50 (m, 1H). Anal. Calcd For С₂₁Н₁₃N₅: C,

7.12 (m, 2H, 4-methoxyphenyl), 7.56 (m, 1H, H-5 (Py)), 8.00 75.21; H, 3.91; N, 20.88%; Found: C, 74.98; H, 3.94; N, 20.73%.

(ddd, J = 7.8, 7.8, 1.8 Hz, 1H, H-4 (Py)), 8.44 (m, 2H, 4- CCDC # 1562142 contains the supplementary crystallographic

methoxyphenyl), 8.53 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)), 8.82 data for this compound.

(dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)), 9.96 (s, 1H, H-5). Anal. Calcd 10-(5-Cyano-4-tolyl-1H-1,2,3-triazol-1-yl)pyrido[1,2-a]indole

For C₁₅H₁₂N₄O: C, 68.17; H, 4.58; N, 21.20%; Found: C, 68.01; (2e). Eluent: DCM/ethyl acetate (7:5), R_f= 0.8. Yield 0.013 g

H, 4.69; N, 20.98%.

(3%). M.p. 196-198 °C. IR-spectra, (neat, υ/cm^-1): 2232 (CN). ¹Н

NMR (400 MHz, СDСl₃): δ 2.46 (s, 3H, Me), 6.77 (ddd, J = 7.0,

7.0, 1.0 Hz, 1H), 7.21 (m, 1H), 7.37 (m, 2H, Tol), 7.44 (m, 1H),

7.48-7.56 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 8.00 (d, J = 8.3 Hz,

1H), 8.11 (m, 2H, Tol), 8.48 (d, J = 7.0 Hz, 1H); ¹³С NMR (100

MHz, CDCl₃): δ 21.5, 110.0, 110.3, 110.7, 115.9, 117.2, 117.4,

121.7, 123.7, 124.4, 125.1, 125.1, 125.9, 126.6, 128.1, 130.0,

General method for interaction of 1,2,4-triazines with aryne

intermediates. Corresponding 1,2,4-triazine

1 or 4 (1 mmol)

was suspended in dry toluene (60 mL). Isoamyl nitrite (0.47

mL, 3.5 mmol) was added to this mixture. The resulting

mixture was stirred under reflux while solution of

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Journal Name

131.9, 140.6, 146.3. Anal. Calcd For C₂₂H₁₅N₅: C, 75.63; H, 4.33; 1Н), 7.19 (brs, 1Н), 7.32 (s, 1H), 7.38 (m, 1H), 7.45-7.55 (m,

N, 20.04%; Found: C, 75.54; H, 4.23; N, 20.09%.

3Н), 7.98 (m, 2H), 8.18 (s, 1H), 8.24 (brs, 1H); ¹Н NMR (CDCl₃, –

2,3-Difluoro-10-(4,5-diphenyl-1H-1,2,3-triazol-1-yl)pyrido[1,2- 56 °C): δ 3.95 (s, 3H, OMe), 4.02 (s, 3H, ОМе), 6.64 (t, J = 6.5,

a]indole (2g). Eluent: ethyl acetate/DCM (3:1), R_f= 0.8. Yield 6.5 Hz, 1Н), 7.00 (td, J = 7.5, 7.5, 1.9 Hz, 1Н), 7.10 (s, 1Н), 7.29

1

0.153 g (37%). M.p. 172-174 °C. Н NMR (400 MHz, CDCl₃): δ (s, 1H), 7.38-7.56 (m, 4H), 7.99 (m, 2H), 8.24 (s, 1H), 8.28 (d, J =

6.64 (ddd, J = 7.5, 6.8, 1.3 Hz, 1Н), 6.99 (ddd, J = 9.8, 6.5, 1.0 7.1 Hz, 1H); ¹³С NMR (CDCl₃): δ 56.3, 56.4, 93.1, 97.8, 103.1,

Hz, 1Н), 7.13 (dd, J = 10.4, 7.6 Hz, 1H), 7.19 (m, 4Н), 7.21-7.26 109.1, 115.9, 117.3, 121.1, 121.7, 122.5, 123.3, 125.8, 128.3,

(m, 2Н), 7.30-7.39 (m, 3Н), 7.63-7.72 (m, 3Н), 8.17 (dd, J = 8.2, 129.0, 129.1, 130.7, 146.9, 147.5, 149.0. Anal. Calcd For

1.0 Hz, 1Н); ¹⁹F NMR (CDCl₃): δ -141.95 (d, J = 20.7 Hz, 1F), - С₂₂Н₁₈N₄O₂: C, 71.34; H, 4.90; N, 15.13%; Found: C, 71.30; H,

138.97 (d, J = 20.7 Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): δ 99.0 4.81; N, 15.02%.

(d, J = 21.3 Hz), 103.9 (d, J = 21.3 Hz), 109.9, 115.9, 120.7 (d, J = 1-(2,3-Dimethoxypyrido[1,2-a]indol-10-yl)-1Н-

8.5 Hz), 122.5 (d, J = 8.5 Hz), 123.9, 124.6, 127.4, 127.5, 128.0, phenanthro[9,10-d][1,2,3]triazole (2l). Eluent: DCM/ethyl

1

128.6, 128.9, 129.3, 129.3, 130.9, 133.4 (d, J = 3.2 Hz), 135.8, acetate (3:1), R_f= 0.8. Yield 0.195 g (44%) M.p. 210-212 °C. Н

144.1, 147.0 (dd, J = 220.8, 14.6 Hz), 149.4 (dd, J = 222.4, 15.4 NMR (400 MHz, CDCl₃): δ 3.72 (s, 3H, OMe), 4.00–4.15 (brs,

Hz). Anal. Calcd For С₂₆Н₁₆F₂N₄: С, 73.93; Н, 3.82; N, 13.26%; 3H, ОМе), 6.70 (brs, 1Н), 6.75 (brs, 1Н), 6.90-7.00 (brs, 1Н),

Found: C, 73.78; Н, 3.72; N, 12.99%.

7.12-7.20 (brs, 1Н), 7.20-7.28 (m, 1H), 7.47 (s, 1H), 7.57-7.65

1-(2,3-Difluoropyrido[1,2-a]indol-10-yl)-1H-phenantro[9,10-

(m, 2Н), 7.72-7.80 (td, J = 8.5, 7.5, 1.5 Hz, 1Н), 7.80-7.87 (td, J =

d][1,2,3]triazole (2h). Eluent: ethyl acetate/DCM (3:1), R_f= 0.8. 7.5, 7.5, 1.0 Hz, 1H), 8.39 (brs, 1Н), 8.68-8.71 (dd, J = 8.4, 1.0,

Yield 0.19 g (45%). M.p. 196-198 °C. ¹Н NMR (400 MHz, CDCl₃): 1H), 8.71-8.74 (dd, J = 8.4, 1.0 Hz, 1H), 8.93–9.00 (dd, J = 8.0,

δ 6.76 (m, 1Н), 7.06 (m, 1Н), 7.12-7.28 (m, 3Н), 7.52 (m, 1Н), 1.0 Hz, 1H); ¹³С NMR (100 MHz, CDCl₃): δ 56.1, 56.5, 93.4, 97.9,

7.63 (m, 1Н), 7.75 (m, 1Н), 7.80-7.90 (m, 2Н), 8.38 (dt, J = 7.4, 102.1, 109.4, 116.0, 119.2, 120.6, 122.1, 122.9, 122.9, 123.0,

1.0, 1.0 Hz, 1H), 8.70 (d, J = 8.2 Hz, 1Н), 8.74 (d, J = 8.2 Hz, 1Н), 123.4, 123.5, 124.0, 125.2, 127.1, 127.3, 127.8, 128.2, 129.1,

8.96 (dd, J = 8.2, 1.0 Hz, 1Н); ¹⁹F NMR (375.5 MHz, CDCl₃): - δ 130.2, 131.1, 131.6, 141.3, 146.9, 149.2. Anal. Calcd For

141.29 (d, J = 20.4 Hz, 1F), -138.18 (d, J = 20.4 Hz, 1F); ¹³C NMR С₂₈Н₂₀N₄O₂: C, 75.66; H, 4.54; N, 12.60%; Found: C, 75.56; H,

(100 MHz, CDCl₃): δ 99.5 (d, J = 22.8 Hz), 104.4 (d, J = 21.6 Hz), 4.56; N, 12.50%.

105.2, 110.3, 116.3, 120.4, 121.0 (d, J = 8.5 Hz), 122.5, 122.9 3-Cyano-4-phenyl-1-(2-pyridyl)isoquinoline

(3a).

Eluent:

(d, J = 8.5 Hz), 123.0, 123.4, 124.2, 125.2 (d, J = 3.7 Hz), 127.2, DCM/ethyl acetate (7:5), R_f= 0.6. Yield 0.111 g (36%). M.p.

1

127.3, 127.9, 128.3, 129.1, 130.1, 131.2, 134.0 (d, J = 3.0 Hz), 171-173 ºC. IR-spectra (neat, υ/cm^-1): 2227 (CN). Н NMR (400

136.1, 141.5, 147.3 (dd, J = 221.0, 16.8 Hz), 149.1, 149.8 (dd, J MHz, DMSO-d₆): δ 7.53-7.60 (m, 3H, Ph), 7.62-7.69 (m, 3H, Ph,

= 223.0, 15.3 Hz). Anal. Calcd For С₂₆Н₁₄F₂N₄: С, 74.28; Н, 3.36; H-5 (py)), 7.74 (m, 1H, isoquin.), 7.82-7.87 (m, 2H, isoquin.),

N, 13.33%, found: С, 74.11; Н, 3.18; N, 12.95%.

8.06 (ddd, J = 7.8, 7.8, 2.0 Hz, 1H, Н-4 (py)), 8.12 (dd, J = 7.8,

0.8 Hz, 1Н, Н-3 (py)), 8.80 (dd, J = 4.8, 2.0 Hz, 1Н, Н-6 (py)),

2,3-Difluoro-10-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-

yl)pyrido[1,2-a]indole (2i). Eluent: ethyl acetate/DCM (3:1), R_f8.92 (m, 1H, isoquin.); ¹³С NMR (100 MHz, CDCl₃): δ 117.6,

= 0.8. Yield 0.127 g (35%). M.p. 159-161 °C. ¹Н NMR (400 MHz, 123.9, 125.4, 125.6, 126.5, 127.5, 128.6, 128.9, 129.4, 130.1,

CDCl₃): δ 6.71 (ddd, J = 6.9, 6.9, 1.0 Hz, 1Н), 7.12 (ddd, J = 9.5, 130.2, 131.4, 133.8, 135.9, 137.3, 140.5, 148.7, 157.0. Anal.

6.6, 1.2 Hz, 1Н), 7.18 (m, 2Н, 4-FC₆H₅), 7.55-7.65 (m, 2Н), 7.76 Calcd For С₂₁Н₁₃N₃: C, 82.07; H, 4.26; N, 13.67%; Found: C,

(dd, J = 9.8, 6.4 Hz, 1H), 7.94 (m, 2Н, 4-FC₆H₅), 8.13 (s, 1Н, Н-4), 82.07; H, 4.26; N, 13.62%.

8.25 (m, 1Н); ¹⁹F NMR (375.5 MHz, CDCl₃): δ -141.25 (d, 1F, J 3-Cyano-1-(2-pyridyl)-4-tolylisoquinoline

(3b).

Eluent:

20.4 Hz), -138.46 (d, 1F, J = 20.4 Hz), -113.18 (s, 1F). Anal. Calcd DCM/ethyl acetate (7:5), R_f= 0.6. Yield 0.119 g (31%). M.p.

1

For С₂₀Н₁₁F₃N₄: С, 65.94, Н, 3.04, N, 15.38%; Found: С, 65.82; 213-215 °C. IR-spectra (neat, υ/cm^-1): 2224 (CN). H NMR (400

Н, 2.89; N, 15.13%.

MHz, CDCl₃): δ 2.50 (s, 3H, Me), 7.42 (m, 4H, Tol), 7.47 (m, 1H,

2,3-Dimethoxy-10-(4,5-diphenyl-1Н-1,2,3-triazol-1-

H-5 (py)), 7.71-7.79 (m, 2H, isoquin.), 7.83 (m, 1H, isoquin.),

yl)pyrido[1,2-a]indole (2j). Eluent: DCM/ethyl acetate (3:2), R_f7.97 (ddd, J = 7.8, 7.8, 2.0 Hz, 1Н, Н-4 (py)), 8.13 (dd, J = 7.8,

= 0.6. Yield 0.116 g (26%). M.p. 201-203 °C. ¹Н NMR (400 MHz, 0.8 Hz, 1Н, Н-3 (py)), 8.80-8.86 (m, 2H, isoquin., H-6 (py)) ; ¹³С

CDCl₃): δ 3.78 (s, 3H, OMe), 4.00 (brs, 3H, ОМе), 6.58 (brs, 1Н), NMR (100 MHz, CDCl₃): δ 21.4, 117.8, 123.9, 125.4, 125.6,

6.69 (brs, 1Н), 6.79-6.92 (brs, 1Н), 7.12-7.29 (m, 7Н), 7.30-7.42 126.6, 127.5, 128.5, 129.6, 130.0, 130.1, 130.7, 131.3, 136.0,

(m, 3H), 7.72 (m, 2H), 8.18 (brs, 1Н). ¹³С NMR (100 MHz, 137.3, 139.4, 140.6, 148.6, 157.0, 158.0. Anal. Calcd For

CDCl₃): δ 56.1, 56.4, 93.1, 97.9, 101.4, 109.0, 116.0, 118.7, С₂₁Н₁₂BrN₃: C, 82.22; H, 4.70; N, 13.07%; Found: C, 82.05; H,

121.7, 122.3, 123.2, 127.5, 127.9, 127.9, 128.5, 128.7, 129.1, 4.54; N, 12.93%.

129.4, 131.1, 131.2, 135.5, 143.9, 146.6, 148.7. Anal. Calcd For 4-(4-Bromophenyl)-3-cyano-1-(2-pyridyl)isoquinoline

(3c).

С₂₈Н₂₂N₄O₂: C, 75.32; H, 4.97; N, 12.55%; Found: C, 75.26; H, Eluent: DCM/ethyl acetate (7:5), R_f= 0.65. Yield 0.150 g (39%).

1

4.89; N, 12.53%. CCDC # 1562139 contains the supplementary M.p. 213-215 °C. IR-spectra (neat, υ/cm^-1): 2224 (CN). H NMR

crystallographic data for this compound.

(400 MHz, CDCl₃): δ 7.41 (m, 2H, 4-BrPh), 7.48 (m, 1H, H-5

2,3-Dimethoxy-10-(4-phenyl-1Н-1,2,3-triazole-1-yl)pyrido[1,2- (py)), 7.72-7.81 (m, 5H, 4-BrPh, isoquin.), 7.97 (ddd, J = 7.8,

a]indole (2k). Eluent: DCM/ethyl acetate (3:1), R_f= 0.8. Yield 7.8, 2.0 Hz, 1Н, Н-4 (py)), 8.14 (dd, J = 7.8, 0.8 Hz, 1Н, Н-3 (py)),

0.093 g (25%). M.p. 189-191 °C. ¹Н NMR (CDCl₃, +27 °C): δ 3.96 8.82 (dd, J = 4.8, 2.0 Hz, 1Н, Н-6 (py)), 8.86 (m, 1H, isoquin.);

(s, 3H, OMe), 4.03 (brs, 3H, ОМе), 6.61 (brs, 1Н), 6.98 (brs, ¹³С NMR (100 MHz, CDCl₃): δ 117.4, 124.0, 124.1, 125.3, 125.6,

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126.1, 127.4, 128.8, 130.3, 131.6, 131.8, 132.3, 132.7, 135.6, 3.64 (s, 3H, OMe), 6.68 (td, J = 6.6, 6.6, 1.0 Hz, 1H), 7.11 (ddd, J

137.3, 139.2, 148.7, 156.8, 158.5. Anal. Calcd For С₂₁Н₁₂BrN₃: = 9.3, 6.5, 1.0 Hz, 1H), 7.33-7.43 (m, 2H), 7.45-7.54 (m, 4H),

C, 65.30; H, 3.13; N, 10.88%; Found: C, 65.11; H, 2.97; N, 7.78 (m, 1H), 7.97 (m, 1H), 8.06 (m, 2H), 8.44 (m, 1H); ¹³C NMR

10.56%. CCDC

# 1562138 contains the supplementary (100 MHz, CDCl₃): δ 61.6, 109.4, 110.5, 116.5, 118.0, 121.1,

crystallographic data for this compound. Crystallographic data 124.2, 124.3, 124.6, 124.9, 125.7, 127.7, 128.1, 128.8, 130.6,

are collected in ESI.

131.2, 131.5, 149.4. Anal. Calcd For С₂₁Н₁₆N₄O: C, 74.10; H,

4.74; N, 16.46%; Found: C, 73.91; H, 4.61; N, 16.29%.

6,7-Dimethoxy-1-(pyridin-2-yl)-3,4-diphenylisoquinoline (3d)

.

Eluent: DCM/ethyl acetate (3:2), R_f= 0.4. Yield 0.029 mg (7%). 10-(3-Methyl-4-phenyl-1H-1,2,3-triazol-1-yl)pyrido[1,2-

M.p. 182-184 °C. ¹Н NMR (400 MHz, CDCl₃): δ 3.78 (s, 3H, a]indole (15d). Eluent: DCM/ethyl acetate (9:1), R_f= 0.8. Yield

1

OMe), 3.99 (s, 3H, ОМе), 6.96 (s, 1Н, Н-8 (isoquin.)), 7.12-7.22 159 mg (49%). M.p. 151-153 °C. Н NMR (400 MHz, CDCl₃): δ

(m, 3Н, Ph), 7.23-7.32 (m, 2Н, Ph), 7.32-7.44 (m, 6Н, Ph, Н-5 2.39 (s, 3H, Me), 6.66 (m, 1H), 7.06 (m, 1Н), 7.30 (m, 1H), 7.34-

(Py)), 7.88-7.95 (ddd, J = 7.7, 7.7, 2.0 Hz, 1Н, Н-4 (Py)), 8.21- 7.42 (m, 2H), 7.45 (m, 1H), 7.47-7.56 (m, 3H), 7.91 (2H), 7.97

8.25 (dd, J = 7.7, 1.0 Hz, 1H, Н-3 (Py)), 8.30 (s, 1Н, Н-5 (m, 1H), 8.43 (m, 1H); ¹³С NMR (100 MHz, CDCl₃): δ 9.8, 100.9,

(isoquin.)), 8.80 (dd, J = 4.8, 2.0 Hz, 1Н, Н-6 (Py)); ¹³C NMR (100 109.3, 110.7, 116.1, 117.4, 121.0, 124.3, 124.5, 124.8, 124.9,

MHz, CDCl₃): δ 50.4, 50.7, 99.0, 99.5, 100.7, 116.4, 117.8, 126.9, 127.6, 128.0, 128.8, 131.9, 132.1, 132.5, 143.9. Anal.

120.4, 121.6, 122.1, 122.3, 123.2, 125.0, 125.1, 125.9, 129.1, Calcd For С₂₁Н₁₆N₄: C, 77.76; H, 4.97; N, 17.27%; Found: C,

131.9, 132.7, 135.8, 142.9, 143.4, 144.7, 147.2, 148.3, 153.9. 77.71; H, 5.06; N, 17.39%.

Anal. Calcd For С₂₈Н₂₂N₂O₂: C, 80.36; H, 5.30; N, 6.69%; Found: 10-(5-(1H-indol-3-yl)-4-phenyl-1H-1,2,3-triazol-1-

C, 80.29; H, 5.35; N, 6.61%.

yl)pyrido[1,2-a]indole (15e). Eluent: DCM/ethyl acetate (5:1),

R_f= 0.8. Yield 77 mg (18%). M.p. 158-160 °C. ¹Н NMR (400

6,7-Dimethoxy-1-(pyridin-2-yl)-4-phenylisoquinoline-3-

carbonitrile (3f). Eluent: DCM/ethyl acetate (3:1), R_f= 0.3. MHz, CDCl₃): δ 6.55 (ddd, J = 6.5, 6.5, 1.2 Hz, 1H), 6.88-6.94 (m,

Yield 0.037 g (10%). M.p. 171-173 °C. ¹Н NMR (400 MHz, 2Н), 6.97 (d, J = 2.7 Hz, 1H, Н-2 (indole)), 7.08-7.15 (m, 2Н),

CDCl₃): δ 3.82 (s, 3H, OMe), 4.00 (s, 3H, ОМе), 7.00 (s, 1Н, Н-8 7.22 (m, 1Н), 7.25-7.32 (m, 6Н), 7.42 (m, 1Н), 7.79 (m, 2Н, Ph),

(isoquin.)), 7.42-7.47 (ddd, J = 7.7, 4.8, 1.0 Hz, 1Н, Н-5 (Py)), 7.85 (m, 1Н), 8.11 (brs, 1Н, NH), 8.31 (m, 1Н). Anal. Calcd For

7.50-7.70 (m, 5H, Ph), 7.95-8.03 (ddd, J = 7.7, 7.7, 2.0 Hz, 1Н, С₂₈Н₁₉N₅: C, 79.04; H, 4.50; N, 16.46%; Found: C, 78.82; H,

Н-4 (Py)), 8.20-8.23 (dd, J = 7.7, 1.0 Hz, 1H, Н-3 (Py)), 8.46 (s, 4.35; N, 16.29%.

1Н, Н-5 (isoquin.)), 8.80 (dd, J = 4.8, 2.0 Hz, 1Н, Н-6 (Py)); ¹³C (E)-10-(4-Рhenyl-4-styryl-1H-1,2,3-triazol-1-yl)pyrido[1,2-

NMR (100 MHz, CDCl₃): δ 50.7, 50.9, 99.3, 101.6, 112.8, 118.6, a]indole (15f). Yield 128 mg (31%). M.p. 139-141 °C. IR-spectra

118.8, 119.1, 120.4, 123.7, 124.1, 124.8, 127.6, 129.0, 132.2, (neat, υ/cm^-1): 1198, 1262, 1338, 1474, 1628, 1725, 2919,

133.6, 143.1, 146.9, 148.1, 149.7, 152.3. Anal. Calcd For 3058. ¹Н NMR (400 MHz, CDCl₃): δ 6.87 (td, J = 6.5, 6.5, 1.0 Hz,

С₂₃Н₁₇N₃O₂: C, 75.19; H, 4.66; N, 11.44%; Found: C, 75.18; H, 1H), 6.88 (s, 2H, PhCHCH), 7.04-7.12 (m, 3H), 7.18 (m, 3H),

4.57; N, 11.48%.

7.36-7.48 (m, 4H), 7.52 (m, 2H), 7.64 (m, 1H), 7.92 (m, 2H),

1

8.00 (m, 1H), 8.46 (m, 1H). H NMR (400 MHz, CD₃CN): 6.71-

10-(4-Phenyl-5-phenylethynyl-1H-1,2,3-triazol-1-

yl)pyrido[1,2-a]indole (15a). Eluent: DCM/ethyl acetate (5:2), 6.80 (m, 2H), 6.95 (d, J = 16.8 Hz, 1H, CHCH), 7.09 (m, 2H),

R_f= 0.7. Yield 115 mg (28%). M.p. 146-148 °C. ¹Н NMR (400 7.14-7.22 (m, 4H), 7.33-7.50 (m, 4H), 7.55 (m, 3H), 7.91 (m,

MHz, CDCl₃): δ 6.69 (td, J = 6.5, 6.5, 1.0 Hz, 1H), 7.08-7.16 (m, 2H), 8.19 (m, 1H), 8.70 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆):

3H), 7.20-7.33 (m, 3H), 7.38-7.57 (m, 5H), 7.61 (m, 1H), 7.89 δ 100.9, 110.0, 112.6, 113.2, 115.6, 117.3, 121.3, 124.4, 125.0,

(m, 1H), 7.99 (m, 1H), 8.37 (m, 2H), 8.46 (m, 1H); ¹³C NMR (100 126.5, 126.5, 127.0, 128.2, 128.3, 128.7, 129.2, 129.2, 129.4,

MHz, CDCl₃): δ 76.7 (C-sp), 102.4 (C-sp), 109.4, 110.5, 117.0, 131.8, 132.1, 133.3, 135.4, 136.0, 144.0. Anal. Calcd For

118.6, 119.1, 121.0, 121.6, 124.0, 124.2, 124.3, 124.7, 126.4, С₂₈Н₂₀N₄: C, 81.53; H, 4.89; N, 13.58%; Found: C, 81.33; H,

128.0, 128.4, 128.6, 128.8, 129.3, 130.5, 131.3, 131.5, 147.3. 4.90; N, 13.61%.

Anal. Calcd For С₂₈Н₁₈N₄: C, 81.93; H, 4.42; N, 13.65%; Found: 10-(5-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)pyrido[1,2-

C, 81.76; H, 4.23; N, 13.46%.

a]indole (15g). Eluent: DCM/ethyl acetate (2:3), R_f= 0.8. Yield

85 mg (25%). M.p. 141-143 °C. ¹Н NMR (400 MHz, CDCl₃): δ

10-(4-Phenyl-5-(pyrrolidin-1-yl)-1H-1,2,3-triazol-1-

yl)pyrido[1,2-a]indole (15b). Eluent: DCM/ethyl acetate (5:1), 3.71 (s, 3H, OMe), 6.62 (ddd, J = 6.8, 6.8, 1.2 Hz, 1H), 6.69 (m,

R_f= 0.6. Yield 133 mg (35%). M.p. 139-141 °C. ¹Н NMR (400 2H, 4-methoxyphenyl), 6.98 (m, 1H), 7.19 (m, 2H, 4-

MHz, CDCl₃): δ 1.61 (m, 4H, pyrrolidine), 2.94 (m, 4H, methoxyphenyl), 7.30-7.40 (m, 4H), 7.93 (m, 1H), 7.98 (s, 1H,

pyrrolidine), 6.66 (td, J = 6.5, 6.5, 1.0 Hz, 1H), 7.07 (ddd, J = 9.3, H-4), 8.39 (m, 1H). Anal. Calcd For C₂₁H₁₆N₄О: С, 74.10; H, 4.74;

6.5, 1.0 Hz, 1H), 7.33-7.49 (m, 7H), 7.64 (m, 1H), 7.75 (m, 2H), N, 16.46%; Found: С, 73.78; H, 4.58; N, 16.21%.

7.96 (m, 1H), 8.42 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 20.3 10-(4-(4-Nitrophenyl)-1H-1,2,3-triazol-1-yl)pyrido[1,2-

(pyrrolidine), 44.4 (pyrrolidine), 99.9, 103.8, 105.2, 111.1, a]indole (15h). Eluent: DCM/ethyl acetate (10:1), R_f= 0.8. Yield

112.5, 115.6, 119.0, 119.0, 119.3, 120.1, 122.1, 122.6, 122.9, 142 mg (40%). M.p. >250 °C. ¹Н NMR (400 MHz, СDCl₃): δ 6.72

123.1, 127.1, 127.3, 129.0, 137.0. Anal. Calcd For С₂₄Н₂₁N₅: C, (ddd, J = 6.8, 6.8, 1.2 Hz, 1H), 7.16 (ddd, J = 9.6, 6.5, 1.2 Hz,

75.97, H, 5.58, N, 18.46%; Found: C, 75.79, H, 5.44, N, 18.31%.

1H), 7.44 (m, 1Н), 7.53 (m, 1Н), 7.73 (m, 1Н), 7.85 (m, 1Н), 8.00

(m, 1Н), 8.16 (m, 2Н, nitrophenyl), 8.37 (m, 2Н, nitrophenyl),

10-(5-Metoxy-4-phenyl-1H-1,2,3-triazol-1-yl)pyrido[1,2-

a]indole (15c). Eluent: DCM/ethyl acetate (15:1), R_f= 0.6. Yield 8.38 (s, 1Н, Н-5 (triazole)), 8.46 (m, 1Н). Anal. Calcd For

1

136 mg (40%). M.p. 164-166 °C. Н NMR (400 MHz, CDCl₃): δ

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C₂₀H₁₃N₅О₂: С, 67.60; H, 3.69; N, 19.71%; Found: С, 67.51; H, (15:1), R_f= 0.7. Yield 0.19 g (49%). M.p. 163-165 °C. Н NMR

3.56; N, 19.48%.

(400 MHz, CDCl₃): δ 2.42 (s, 3H, Me), 3.64 (s, 3H, OMe), 6.71

(td, J = 6.5, 6.5, 1.0 Hz, 1H), 7.10 (ddd, J = 9.3, 6.2, 0.8 Hz, 1H),

2,3-Difluoro-10-(5-cyano-4-phenyl-1H-1,2,3-triazol-1-

yl)pyrido[1,2-a]indole (15i). Eluent: DCM, R_f= 0.7. Yield 137 7.30 (m, 2H, Tol), 7.50-7.57 (m, 2H), 7.75 (dd, J = 9.7, 6.3 Hz,

1

mg (37%). M.p. 155-157 °C. Н NMR (400 MHz, CDCl₃): δ 6.82 1H), 7.91 (m, 2H, Tol), 8.26 (m, 1H); ¹⁹F NMR (376.5 MHz,

(td, J = 6.6, 6.6, 1.0 Hz, 1H), 7.23 (ddd, J = 9.4, 6.5, 1.0 Hz, 1H), CDCl₃): δ -141.69 (d, J = 20.6 Hz, 1F), -138.79 (d, J = 20.6 Hz,

7.45-7.61 (m, 6H), 7.71 (dd, J = 5.8, 3.2 Hz, 1H), 7.80 (dd, J = 1F); ¹³C NMR (100 MHz, CDCl₃): δ 21.3, 61.4, 99.1 (d, J = 22.8

9.6, 6.2 Hz, 1H), 8.21 (m, 2H), 8.32 (m, 1H); ¹⁹F NMR (376.5 Hz), 100.0, 104.7 (d, J = 20.2 Hz), 110.1, 116.7, 119.7 (d, J = 8.8

MHz, CDCl₃): δ -142.83 (d, J = 21.9 Hz, 1F), -139.43 (d, J = 21.9 Hz), 122.7 (d, J = 10.3 Hz), 124.0, 124.7, 125.8, 127.4, 129.5,

Hz, 1F); ¹³C NMR (100 MHz, CDCl₃): δ 99.4 (d, J = 23.1 Hz), 131.4, 132.4 (d, J = 2.9 Hz), 137.7, 147.3 (dd, J = 245.2, 15.5

100.2 (d, J = 4.2 Hz), 104.2 (d, J = 20.5 Hz), 109.2, 109.9, 110.7, Hz), 148.8, 149.6 (dd, J = 245.2, 15.5 Hz). Anal. Calcd For

115.9, 119.6 (d, J = 7.7 Hz), 122.9 (d, J = 9.6 Hz), 124.2, 125.9, С₂₂Н₁₆F₂N₄O: C, 67.69; H, 4.13; N, 14.35%; Found: C, 67.50; H,

126.7, 129.3, 130.5, 132.5, 132.9 (d, J = 3.0 Hz), 147.6 (dd, J = 3.98; N, 14.15%.

245.6, 17.3 Hz), 149.8 (d, J = 247.0, 15.9 Hz), 151.9. Anal. Calcd (E)-2,3-Difluoro-10-(4-phenyl-4-styryl-1H-1,2,3-triazol-1-

For С₂₁Н₁₁F₂N₅: C, 67.92; H, 2.99; N, 18.86%; Found: C, 67.90; yl)pyrido[1,2-a]indole (15n). Yield 188 mg (42%). M.p. 155-

1

157 °C. Н NMR (400 MHz, CDCl₃): δ 6.72 (td, J = 6.6, 6.6, 1.0

H, 2.88; N, 18.71%.

2,3-Difluoro-10-(5-cyano-4-tolyl-1H-1,2,3-triazol-1-

Hz, 1H), 6.84 (s, 2H, PhCHCH), 7.06-7.13 (m, 3H), 7.18-7.24 (m,

yl)pyrido[1,2-a]indole (15j). Eluent: DCM/ethyl acetate (7:5), 3H), 7.34-7.48 (m, 3H), 7.53 (m, 2H), 7.79 (dd, 9.8, 6.2 Hz, 1H),

R_f= 0.7. Yield 180 mg (45%). M.p. 149-151 °C. ¹Н NMR (400 7.90 (m, 2H), 8.29 (m, 1H); ¹H NMR (400 MHz, CD₃CN): 6.73 (d,

MHz, CDCl₃): δ 2.46 (s, 3H, Me), 6.81 (td, J = 6.6, 6.6, 1.0 Hz, J = 16.6 Hz, 1H, CHCH), 6.80 (td, J = 6.6, 6.6, 1.0 Hz, 1H), 6.94

1H), 7.23 (ddd, J = 9.4, 6.5, 1.0 Hz, 1H), 7.37 (m, 2H, Tol), 7.49 (d, J = 16.6 Hz, 1H, CHCH), 7.10-7.23 (m, 6H), 7.35 (m, 1H),

(m, 2H), 7.79 (dd, 1H, 9.5, 6.3 Hz), 8.09 (m, 2H, Tol), 8.31 (m, 7.39-7.50 (m, 2H), 7.55 (m, 2H), 7.90 (m, 2H), 8.12 (dd, J = 9.8,

1H); ¹⁹F NMR (376.5 MHz, CDCl₃): δ -140.55 (d, J = 19.4 Hz, 1F), 6.2 Hz, 1H), 8.56 (m, 1H); ¹⁹F NMR (376.5 MHz, CDCl₃): δ -

-137.42 (d, J = 19.4 Hz, 1F). ¹³C NMR (100 MHz, CDCl₃): δ 21.4, 141.47 (d, J = 20.8 Hz, 1F), -138.37 (d, J = 20.8 Hz, 1F). ¹³C NMR

99.3 (d, J = 20.9 Hz), 100.1 (d, J = 3.8 Hz), 104.1 (d, J = 21.2 Hz), (100 MHz, CDCl₃): δ 99.2 (d, J = 23.2 Hz), 99.3, 101.7, 104.4 (d,

108.7, 110.0, 110.6, 115.8, 119.5 (d, J = 8.2 Hz), 122.7 (d, J = J = 21.3 Hz), 110.1, 112.5, 116.4, 120.7 (d, J = 9.5 Hz), 122.8 (d,

9.5 Hz), 124.1, 124.7, 125.8, 126.5, 129.9, 132.8 (d, J = 3.0 Hz), J = 9.5 Hz), 124.0, 124.9, 126.6, 128.3, 128.4, 128.7, 128.7,

140.7, 147.5 (dd, J = 246.7, 16.3 Hz), 149.7 (dd, J = 247.6, 15.4 128.8, 131.6, 132.8, 133.5, 135.1, 136.0, 144.7, 147.4 (dd, J =

Hz), 152.0. Anal. Calcd For С₂₂Н₁₃F₂N₅: C, 68.57; H, 3.40; N, 245.6, 16.5 Hz), 149.6 (dd, J = 245.6, 14.8 Hz). Anal. Calcd For

18.17%; Found: C, 68.43; H, 3.23; N, 17.99%.

С₂₈Н₁₈F₂N₄: C, 74.99; H, 4.05; N, 12.49%; Found: C, 74.88; H,

2,3-Difluoro-10-(4-phenyl-5-phenylethynyl-1H-1,2,3-triazol-1- 3.93; N, 12.40%.

yl)pyrido[1,2-a]indole (15k). Eluent: DCM/ethyl acetate (5:1), 2,3-Dimetoxy-10-(4-phenyl-5-(pyrrolidin-1-yl)-1H-1,2,3-

R_f= 0.7. Yield 183 mg (41%). M.p. 144-146 °C. ¹Н NMR (400 triazol-1-yl)pyrido[1,2-a]indole (15o). Eluent: DCM/ethyl

MHz, CDCl₃): δ 6.74 (td, J = 6.9, 6.9, 1.0 Hz, 1H), 7.13 (ddd, J = acetate (10:3), R_f= 0.7. Yield 110 mg (25%). M.p. 127-129 °C.

9.2, 6.3, 0.8 Hz, 1H), 7.19-7.23 (m, 2H), 7.27-7.37 (m, 3H), 7.44 ¹Н NMR (400 MHz. CDCl₃): δ 1.63 (m, 4H, pyrrolidine), 2.94 (m,

(m, 1H), 7.54 (m, 2H), 7.58-7.67 (m, 2H), 7.78 (dd, J = 9.8, 6.5 4H, pyrrolidine), 3.93 (s, 3H, OMe), 4.03 (s, 3H, OMe), 6.61 (m,

Hz, 1H), 8.28 (m, 1H), 8.34 (m, 2H); ¹⁹F NMR (376.5 MHz, 1H), 6.94 (m, 1H), 6.99 (s, 1H), 7.28-7.39 (m, 3H), 7.42-7.49 (m,

CDCl₃): δ -141.68 (d, J 20.7 Hz, 1F), -139.05 (d, J = 20.7 Hz, 1F); 2H), 7.76 (m, 2H), 8.26 (m, 1H). Anal. Calcd For С₂₆Н₂₅N₅O₂: C,

¹³C NMR (100 MHz, CDCl₃): δ 76.2 (C-sp), 99.1 (d, J = 22.6 Hz), 71.05; H, 5.73; N, 15.93%; Found: C, 70.80; H, 5.55; N, 15.68%.

102.1 (d, J = 3.6 Hz), 102.7 (C-sp), 105.2 (d, J = 21.9 Hz), 110.1, 2,3-Dimethoxy-10-(3-methyl-4-phenyl-1H-1,2,3-triazol-1-

117.1, 119.0, 119.7 (d, J = 8.4 Hz), 121.3, 122.7 (d, J = 9.8 Hz), yl)pyrido[1,2-a]indole (15p). Eluent: DCM/ethyl acetate (9:1),

123.9, 124.6, 126.4, 128.5, 128.8, 128.8, 129.6, 130.3, 131.3, R_f= 0.7. Yield 108 mg (28%). M.p. 140-142 °C. ¹Н NMR (400

132.5 (d, J = 3.1 Hz), 147.3 (dd, J = 244.1, 16.3 Hz), 147.6, 149.3 MHz, CDCl₃): δ 2.40 (s, 3H, Me), 3.93 (s, 3H, OMe), 4.04 (s, 3H,

(dd, J = 244.8, 14.3 Hz). Anal. Calcd For С₂₈Н₁₆F₂N₄: C, 75.33; H, OMe), 6.65 (td, J = 6.9, 6.9, 1.0 Hz, 1H), 6.89 (s, 1H), 6.98 (ddd,

3.61; N, 12.55%; Found: C, 75.19; H, 3.50; N, 12.39%.

J = 9.2, 6.5, 0.8 Hz, 1H), 7.23 (m, 1Н), 7.37 (s, 1H), 7.52 (m, 3H,

Ph), 7.92 (m, 2H, Ph), 8.29 (m, 1H). ¹³С NMR (100 MHz, CDCl₃):

2,3-Difluoro-10-(4-phenyl-5-(pyrrolidin-1-yl)-1H-1,2,3-triazol-

1-yl)pyrido[1,2-a]indole (15l). Eluent: DCM/ethyl acetate δ 9.8, 56.3, 56.5, 93.3, 97.6, 100.6, 109.2, 115.8, 119.0, 122.6,

(10:3), R_f= 0.7. Yield 153 g (40%). M.p. 131-133 °C. ¹Н NMR 123.4, 126.9, 127.6, 128.8, 131.2, 131.9, 132.0, 143.8, 146.8,

(400 MHz, CDCl₃): δ 1.65 (m, 4H, pyrrolidin), 2.93 (m, 4H, 149.1, 160.5. Anal. Calcd For С₂₃Н₂₀N₄O₂: C, 71.86; H, 5.24; N,

pyrrolidin), 6.69 (td, J = 6.5, 6.5, 1.0 Hz, 1H), 7.07 (ddd, J = 9.3, 14.57%; Found: C, 71.98; H, 5.09; N, 14.76%.

6.5, 1.0 Hz, 1H), 7.34-7.42 (m, 3H), 7.43-7.50 (m, 2H), 7.67-7.78 (E)-2,3-Dimethoxy-10-(4-phenyl-4-styryl-1H-1,2,3-triazol-1-

(m, 3H), 8.25 (m, 1H); ¹⁹F NMR (376.5 MHz, CDCl₃): δ -142.02 yl)pyrido[1,2-a]indole (15q). Yield 142 mg (30%). M.p. 137-

(d, J = 20.7 Hz, 1F), -139.03 (d, J = 20.7 Hz, 1F). Anal. Calcd For 139 °C. ¹Н NMR (400 MHz, CDCl₃): δ 3.85 (s, 3H, OMe), 4.05 (s,

С₂₄Н₁₉F₂N₅: C, 69.39; H, 4.61; N, 16.86%; Found: C, 69.22; H, 3H, OMe), 6.65 (td, J = 6.6, 6.6, 1.0 Hz, 1H), 6.90 (s, 2H,

4.51; N, 16.72%.

PhCHCH), 6.93-7.00 (m, 2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.34

2,3-Difluoro-10-(5-methoxy-4-tolyl-1H-1,2,3-triazol-1-

(m, 1H), 7.36-7.47 (m, 3H), 7.52 (m, 2H), 7.93 (m, 2H), 8.30 (m,

1

yl)pyrido[1,2-a]indole (15m). Eluent: DCM/ethyl acetate 1H); Н NMR (400 MHz, CD₃CN): δ 3.74 (s, 3H, OMe), 3.96 (s,

14 | J. Name., 2012, 00, 1-3

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2

(a) P. Gouthami, R. Chegondi and S. Chandrasekhar, Org.

Lett., 2016, 18, 2044; (b) N. Chandrasomaa, N. Browna, A.

Brassfielda, A. Nerurkara, S. Suareza and K. R. Buszeka,

Tetrahedron Lett., 2013, 54, 913; (c) A. E. Goetz, T. K. Shah

and N. K. Garg, Chem. Commun., 2015, 51, 34. For the

reviews see: (d) C. M. Gampe and E. M. Carreira, Angew.

Chem. Int. Ed., 2012, 51, 3766.

(a) P. Anzenbacher Jr, L. Mosca, M. A. Palacios, G. V.

Zyryanov and P. Koutnik, Chem.- Euro. J., 2012, 18, 12712; (b)

G. V. Zyryanov, M. A. Palacios and P. Anzenbacher Jr, Org.

Lett., 2008, 10, 3681; (c) A. F. Khasanov, D. S. Kopchuk, I. S.

Kovalev, O. S. Taniya, K. Giri, P. A. Slepukhin, S. Santra, M.

Rahman, A. Majee, V. N. Charushin and O. N. Chupakhin,

New J. Chem., 2017, 41, 2309; (d) S. Umezu, G. Dos Passos

Gomez, T. Yoshinaga, M. Sakae, K. Matsumoto, T. Iwata, I. V.

3H, OMe), 6.71 (td, J = 6.6, 6.6, 1.0 Hz, 1H), 6.76 (d, J = 16.7 Hz,

CHCH, 1H), 6.96 (m, 2H), 7.03 (m, 1H), 7.09-7.14 (m, 2H), 7.17-

7.24 (m, 3H), 7.30 (m, 2H), 7.46 (m, 1H), 7.55 (m, 2H), 7.65 (s,

1H), 7.92 (m, 2H), 8.56 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ

56.2, 56.5, 93.4, 98.2, 101.4, 109.3, 113.0, 116.2, 118.8, 122.0,

122.6, 123.3, 126.5, 128.2, 128.4, 128.6, 128.6, 128.8, 131.2,

131.8, 132.7, 134.6, 136.2, 144.4, 146.9, 149.2. Anal. Calcd For

С₃₀Н₂₄N₄O₂: C, 76.25; H, 5.12; N, 11.86%; Found: C, 76.09; H,

5.10; N, 11.90%.

4-Phenyl-5-phenylethynyl-1-(2-pyridyl)isoquinoline

(16a).

Eluent: DCM/ethyl acetate (5:2), R_f= 0.55. Yield 46 mg (12%).

M.p. 143-145 °C. ¹Н NMR (400 MHz, CDCl₃): δ 7.19-7.30 (m,

5H), 7.43 (m, 1H, H-5 (Py)), 7.50-7.65 (m, 6H), 7.70 (m, 1H,

isoquinoline), 7.94 (ddd, J = 7.8, 7.8, 1.8 Hz, 1H, H-4 (Py)), 8.09

(m, 1H, isoquinoline), 8.57 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)),

8.81 (dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)); ¹³C NMR (100 MHz,

CDCl₃): δ 89.6 (C-sp), 92.4 (C-sp), 122.9, 123.5, 126.5, 125.8,

125.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 130.5, 130.8,

131.8, 143.6, 136.3, 136.7, 137.0, 137.2, 148.6, 157.6, 157.8.

Anal. Calcd For С₂₈Н₁₈N₂: C, 87.93; H, 4.74; N, 7.32%; Found: C,

87.77; H, 4.60; N, 7.06%.

Alabugin and M. Shindo, Angew. Chem. Int. Ed., 2017, 56

1298.

,

3

4

(a) H. H. Wenk, M. Winkler and W. Sander, Angew. Chem.

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(E)-4-Phenyl-1-(2-pyridyl)-3-styrylisoquinoline (16b). Yield 12

mg (3%). M.p. 133-135 °C. ¹Н NMR (400 MHz, CDCl₃): δ 7.08 (d,

J = 15.6 Hz, CHCH, 1H), 7.19 (m, 1H), 7.22-7.30 (m, 2H), 7.37-

7.46 (m, 5H), 7.48-7.60 (m, 6H), 7.93-8.00 (m, 2H, CHCH, H-4

(Py)), 8.21 (dd, J = 7.8, 0.8 Hz, 1H, H-3 (Py)), 8.67 (m, 1H,

isoquinoline), 8.82 (dd, J = 4.8, 1.8 Hz, 1H, H-6 (Py)). Anal.

Calcd For С₂₈Н₂₀N₂: C, 87.47; H, 5.24; N, 7.29%; Found: C,

87.32; H, 5.11; N, 7.22%.

6

7

6,7-Dimethoxy-1-(pyridin-2-yl)-4-tolylisoquinoline-3-

carbonitrile (16c). Eluent: DCM/ethyl acetate (3:1), R_f= 0.55.

Yield 0.053 g (14%). M.p. 141-143 °C. ¹Н NMR (400 MHz,

CDCl₃): δ 2.49 (s, 3Н, Ме), 3.83 (s, 3Н, ОМе); 3.99 (s, 3Н, ОМе);

7.04 (s, 1Н, Н-5 (isoquin.)); 7.38-7.45 (brs, 5Н, Рh, Н-5 (Ру)),

7.95-7.96 (ddd, J = 7.7, 7.7, 2.0 Hz, 1H, Н-4 (Py)), 8.19-8.21

(dd, J = 7.7, 1.0 Hz, 1H, Н-3 (Py)), 8.44 (s, 1Н, Н-8 (isoquin.)),

8.78-8.79 (s, J = 4.8 Hz, 1H, Н-6 (Ру)). Anal. Calcd For

С₂₄Н₁₉N₃O₂: C, 75.59; H, 4.96; N, 11.00%; Found: C, 75.57; H,

5.02; N, 11.02%.

8

9

10 D. S. Kopchuk, I. L. Nikonov, G. V. Zyryanov, E. V. Nosova,

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O. S. Taniya, V. L. Rusinov and O. N. Chupakhin, Russ. J. Org.

Chem., 2015, 51, 1170.

Conflicts of interest

There are no conflicts to declare.

12 D. S. Kopchuk, I. L. Nikonov, G. V. Zyryanov, I. S. Kovalev,

V. L. Rusinov and O. N. Chupakhin, Chem. Heterocycl. Comp.,

2014, 50, 907.

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Acknowledgements

We are thankful to Prof. Vasily A. Bakulev (UrFU) for the

fruitful discussions on the aryne-mediated transformations.

This work was supported by the Russian Science Foundation

(Ref. # 18-13-00365) and for A. Majee by DST-RSF Major

Research Project (Ref. No. INT/RUS/RSF/P-08). K. Giri

acknowledges financial support from DST, Govt. of India (Ref. #

YSS/2014/000060).

16 See for example: (а) P. J. Burke, L. C. Wong, T. C. Jenkins,

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Notes and references

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DOI: 10.1039/C8OB00847G

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16 | J. Name., 2012, 00, 1-3

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DOI: 10.1039/C8OB00847G

Graphical Abstract

Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with

arynes: Inverse demand aza-Diels-Alder reaction versus aryne-

mediated domino process

X

R₂

R₁

N

R₂

R₁

R₂

R₁

N

X

N

R₂

R₁

+

N

X

N

X

F

X

X = H, OMe

Domino Products + ID aza-Diels-Alder Products

F

X = F

Only Domino Products

R₁= H, CN, Ar, Styryl, Phenyethynyl; R₂= H, Ar

Broad substrates scope DFT Studies

Article Doi

Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels-Alder reaction versus aryne-mediated domino process

DOI: 10.1039/c8ob00847g

Source and publish data:

Authors:

Article abstract of DOI:10.1039/c8ob00847g

Full text of DOI:10.1039/c8ob00847g

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