Two Approaches for the Synthesis of Fused Dihydropyridines via a 1,6-Electrocyclic Reaction: Fluorescent Properties and Prospects for Application

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Two Approaches for the Synthesis of Fused Dihydropyridines via a

1,6-Electrocyclic Reaction: Fluorescent Properties and Prospects for

Application

Aleksey A. Gagarin, Polina O. Suntsova, Artem S. Minin, Varvara A. Pozdina, Pavel A. Slepukhin,

Enrico Benassi,* and Nataliya P. Belskaya *

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ABSTRACT: Reactions of penta-2,4-dienethioamides with acetylenedi-

carboxylic acid, methyl and ethyl esters, and methyl propiolate were

systematically studied, and a number of new 2,3-dihydro-5H-thiazolo-

[3,2-a]pyridines (DTPs) and 4H,6H-pyrido[2,1-b][1,3]thiazines (PTZs)

were prepared. A possible mechanism for a multistep domino

transformation is suggested, and the key step is the 1,6-electrocyclic

reaction. An additional alternative method for the synthesis of new

heterocyclic systems was achieved. Evidence of the electrocyclic

mechanism of a key step was collected from the analysis of the spatial

structure of the synthesized bicyclic nonaromatic pyridines by X-ray diﬀraction and quantum chemical calculations, as well as from

the thermodynamic quantities. DTPs exhibited yellow ﬂuorescence in solution and yellow to red emissions in the solid state.

Biological investigations demonstrated the ability of DTPs to penetrate living and ﬁxed cells and presumably accumulate in

lysosomes.

cyclization (Scheme 1, reactions I and IIb).²⁹Finally, the

INTRODUCTION

■

introduction of an additional CC bond into a thioamide

Thioamides are building blocks widely used for the synthesis of

nitrogen- and sulfur-containing heterocyclic compounds.¹⁻⁸

molecule forms the conjugative 1-thiabuta-1,3-diene fragment,

which may be involved in the Diels−Alder reaction as a diene

Thioamides can react with various monoelectrophilic, dielec-

trophilic, and ambient agents, such as α-halocarbonyl

(Scheme 1, reactions IIa and III).^3,5,29−31Moreover, the

compounds and alkyl and alkenyl dihalides.⁹⁻¹⁶The CS

electronic eﬀects of substituents, both proximate to and remote

from the thioamide fragment, and the use of appropriate

catalysts and solvents represent important factors for the control

of the reaction progress (Scheme 1, reaction IIa and IIb).

Sometimes these factors may make these reactions unpredict-

able, leading to unexpected products and requiring the

veriﬁcation of diﬀerent conditions for their realization. Note

that the most commonly used acetylenic derivatives are dimethyl

acetylenedicarboxylate (DMAD) and methyl propiolate (MP),

which are the most active in this series of reagents.

bond of a thioamide group may react as a dienophile component

in [4 + 2] cycloaddition reactions¹⁷⁻¹⁹and as a dipolarophile in

the thermal and catalytic variants of 1,3-dipolar cycloaddition

reactions.^3,20,21Moreover, α-diazothioacetamides easily trans-

form into 1,2,3-thiadiazoles by a 1,5-electrocyclic reac-

tion.^3,22−25

A speciﬁc and signiﬁcant group of thioamide transformations

consists of reactions with acetylenedicarboxylic and propiolic

acids and their esters.^{5−8,26−34}These reactions are rather

complicated due to the diversity of alternative directions caused

by the multifunctionality of the reagents involved. Additional

functionalities in the thioamide structure increase the number of

active centers and expand their synthetic potential to obtain a

variety of monoheterocyclic compounds, ensembles, and fused

systems. Thus, thioamides bearing hydrazones, enamines, and

multiple CC lateral linear fragments have demonstrated new

prospects for the construction of heterocycles with diﬀerent ring

sizes and various numbers and types of heteroatoms (Scheme

1).^5,29−31These functionalities could aﬀect the molecular

electronic structure and thus could change the reaction direction

or expand its scope. On the other hand, NH-hydrazone or

enamine groups provide hydrogen atoms to facilitate hetero-

Herein, the results of our recent ﬁndings from ongoing

research of these reactions are presented. The usage of new

thioamide-bearing reagents (namely, penta-2,4-dienethioa-

mide) in the interaction with acetylenic acids and their esters

causes a series of subsequent transformations to aﬀord new

Received: August 10, 2020

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Scheme 1. Previous Examples of the Reactions of Thioamides Bearing Linear Lateral Functional Groups with DMAD and

MP²⁹⁻³¹

Table 1. Yields and Conversion Times for the Synthesis of 2-Cyano-5-phenylpenta-2,4-dienethioamide 3a by the Reaction of

a

Aldehydes 1a and Cyanoethanethioamide 2

b

c

entry

n equiv

base

T (°C)

time (h)

yield (%)

1

2

3

4

5

6

7

8

9

0.05

0.10

0.05

0.10

0.05

0.10

0.05

0.10

NMM

TEA

rt

40

60

24.0

5.0

4.0

3.0

4.0

6.0

2.0

3.0

0.5

30

65

60

65

71

50

46

48

95

a

b

Reactions were performed 3−5 times, and the yield and conversion time used for the best experiments are presented. Base: NMM, N-

c

methylmorfoline; TEA, triethylamine. Yield after separation and puriﬁcation.

heterocyclic systems. Furthermore, the investigated reactions

were performed by two synthetic procedures. On the one hand,

one-pot conversion of thioamides and acetylene derivatives

occurs through a series of sequential stages to yield bicyclic

products. An alternative approach, which involves another

sequence of stages, has important advantages as it prevents the

formation of undesirable byproducts (thiopyrans), expands the

scope of the reagents, and widens the library of new

heterocycles.

RESULTS AND DISCUSSION

■

The synthesis of the starting reagents penta-2,4-dienethioamide

3a and 3b is described in the literature as the Knoevenagel

condensation of cinnamaldehydes with cyanothioaceta-

mide.³⁵⁻³⁷Unfortunately, the conditions suggested in these

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Scheme 2. Condensation of Aldehydes 1b−e with Cyanothioacetamide 2

a

b

With 0.1 equiv of TEA. The best yield was obtained with 0.1 equiv of NMM.

Table 2. Multistep Domino Cyclization of 2-Cyanopenta-2,4-dienethioamide 3a with DMAD 5a

a

entry

solvent

T (°C)

time (h)

yield of 8a (%)

1

2

3

4

5

6

7

8

AcOH

CHCl₃

MeOH

rt

7.0

1.0

5.0

33

40

60

78

87

b

60

rt

7.0

10.0

2.0

60

40

c

57

a

b

c

Isolated yield. Product not formed (TLC). A mixture of compounds was formed (TLC).

publications did not reproduce the yield and transformation

time described by the authors, which encouraged us to carry out

a short study of the condition inﬂuence on the yield of penta-2,4-

dienethioamide 3a and the conversion time of starting reagents

1a and 2 (Table 1). This reaction is very sensitive to the

temperature, amount, and type of base used.

The heating of cinnamaldehyde 1a with cyanothioacetamide

2 in ethanol at 60 °C in the presence of TEA gives penta-2,4-

dienethioamide 3a with an excellent yield at a fast rate. Although

this condensation reaction also shows good results at room

temperature, it takes a longer time to complete the trans-

formation and leads to the formation and accumulation of

byproduct. Subsequent experiments showed that this undesir-

able product presumably has a thiopyran structure, 4a. It was

identiﬁed (by thin-layer chromatography, TLC) at higher

temperatures and required a careful procedure for puriﬁcation.

This procedure was successfully used to obtain thioamides

3b,c. In contrast, the yield of compound 3d was below average

(Scheme 2). Moreover, the condensation of α-methylcinnamic

aldehyde (1e) with cyanothioacetamide (2) led to the formation

of 2H-thiopyran-5-carbonitrile 4e as the single product. This

compound may be obtained as the result of the 1,6-

electrocyclization of the initially formed 5-phenylpenta-2,4-

dienethioamide 3e (Scheme 2).

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Table 3. Synthesis of 2,3-Dihydro-5H-thiazolo[3,2-a]pyridines 8b−j

structure

a

entry

compound

R¹

R³

time (h)

yield (%)

1

2

3

4

5

6

7

8

9

8b

8c

8d

8e

8f

8g

8h

8i

4-MeOC₆H₄

4-Me₂NC₆H₄

2-MeOC₆H₄

Ph

4-MeOC₆H₄

Me₂NC₆H₄

2-MeOC₆H₄

Ph

Me

Et

H

1.0

5.0

10.0

5.0

48.0

3.0

1.0

66

50

38

45

78

30

48

59

68

8j

4-MeOC₆H₄

a

Yield after separation and puriﬁcation.

Table 4. Synthesis of the 2,3-Dihydro-5H-thiazolo[3,2-a]pyridines along with the Second Procedure via the Initial Reaction of

Aldehyde 1 by Condensation with Thiazolidinones 9a−c

structure

a

entry

compound

R¹

R²

R³

time (h)

yield (%)

1

2

3

4

5

6

7

8a

8k

8l

8m

8e

8n

8o

Ph

Me

Ph

Me

H

Me

Et

15.0

18.0

14.0

18.0

16.0

39

59

22

15

34

26

Me

H

Me

Et

a

Yield after separation and puriﬁcation.

There are only a few known examples of thiopyran ring

ray diﬀraction (XRD) data. The experimental procedures and

spectral data of cinnamothioamides 3a−d and thiopyran 4 are

presented in the Supporting Information (Figures S1−S5).

The thioamide and acetylenic acid derivative interactions

were studied in diﬀerent solvents (AcOH, CHCl₃, MeOH,

xylene, and benzene) and at diﬀerent temperatures (from room

temperature to a reﬂuxing temperature).^{4−6,26−34}We performed

a series of preliminary experiments for the reaction of 2-cyano-5-

phenylpenta-2,4-dienethioamide 3a with DMAD 5a in acetic

acid, chloroform, and methanol, both at room temperature and

by heating (Table 2).

The formation of a new compound occurred when the

reagents were heated at 60 °C in acetic acid (TLC). The

resulting product was isolated by column chromatography in a

solvent system. Unexpectedly, the spectral data showed that the

obtained compound 8a was 2,3-dihydro-5H-thiazolo[3,2-a]-

pyridine (DTP). We can therefore conclude that the reaction

proceeds via the addition/condensation mechanism, which was

constructions by the 1,6-electrocyclization reaction, and this

process usually requires very high temperatures.^38,39Note that

the cyclization of thioamide 3e also proceeded at room

temperature. Moreover, thiopyrans 4a−d were identiﬁed by

TLC during the reaction of aldehydes 1a−d, with cyanothioa-

cetamide 2 forming as a side product in a small amount. Because

these reactions are accelerated by introducing subsequent

electron-withdrawing and electron-donating substituents due

to their resulting captodative eﬀect,^40,41the presence of an

electron-donating substituent (Me) at the 5-position and CN

group at the C(2) atom of the 1-thia-1,3,5-hexatriene system

facilitates compound 1e cyclization. This ﬁnding is very

interesting for the theory of electrocyclic reactions and organic

synthesis practices and certainly will be studied in further detail

with the help of quantum mechanical calculations.

The structures of new compounds 3a−d and 4 were

characterized using spectroscopy, elemental analysis, and X-

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known previously (Scheme 1, I).^6,29,30However, the inves-

tigated transformation did not stop at the cyclization stage and

thiazolidinone 7 formation. As the active 1-aza-1,3,5-hexatriene

system was created in intermediate compound 7, the 1,6-

electrocyclic reaction was initiated, and the pyridine ring fused

to a thiazolidinone cycle and aﬀorded the new heterocyclic

dihydro-5H-thiazolo[3,2-a]pyridine system. Considering the

known fact that such reactions facilitate systems simultaneously

containing electron-donating and electron-withdrawing sub-

stituents, we can assume that acetic acid not only is a good

solvent but also is capable of accelerating electrocyclization by

enhancing the electron-withdrawing properties of triene system

termini by protonating the nitrogen atom of the thiazole ring.

With this encouraging result, we continued our investigations

to determine the scope of this reaction and all the synthesized

thioamides, 3b−d, and acetylenic acid and esters 5a−c involved

in the interaction (Table 3). All reactions aﬀorded DTPs in a

moderate or good yield (Table 4).

Unlike the conditions proposed in the literature, we carried

out this reaction by heating in acetic acid for electrophilic

reagent activation. This change increased the yields of

thiazolidinones 9a−c and simpliﬁed the isolation and

puriﬁcation procedure (Scheme 3).

Furthermore, we carried out the condensation reaction of

aldehydes 1a,e−g with the obtained thiazolidinones 9a,b in

acetic acid. Indeed, this procedure led to the formation of new

DTPs; however, it required a higher temperature (Table 4).

We also included crotonaldehyde and tiglic aldehyde in this

interaction. However, the reaction was accompanied by the

products of the degradation of the starting reagents. Never-

theless, DTPs 8l,m,o were isolated using liquid column

chromatography and identiﬁed by spectral methods (see Figures

S20, S21, and 23). Our attempts to use 1,4-dioxane, ethanol,

chloroform, and acetonitrile in combination with bases (NMM,

TEA, AcONa, DIPEA, DBU) or acetic acid anhydride and

conducting the reaction under reﬂuxing conditions in a

microwave reactor or in an argon atmosphere did not improve

the yield. The reactions of aldehydes 1a−h and acid 9c were

unsuccessful because acid 9c was insoluble in acetic acid and

some of the other organic solvents (CHCl₃, EtOH, MeCN,

acetone, benzene).

To expand the scope of the starting reagent, we included the

methyl ester of propiolic acid in this reaction (Scheme 4). The

ﬁrst synthetic procedure (I, Scheme 4), which started from the

interaction of thioamide and methyl propiolate, allowed us to

obtain only one new compound, 12a. According to an

alternative method (II, Scheme 4), we obtained thiazinone 10

and then used it in a reaction with other aldehydes. Indeed, this

pathway allowed us to broaden the scope of 4H,6H-pyrido[2,1-

b][1,3]thiazines (PTZs) 12b−e by involving four additional

aldehydes in the reaction.

Since their discovery, pericyclic reactions have attracted the

attention of chemists due to the following unusual mechanism:

new bonds are formed without the interaction of active

intermediates but with the rearrangement of π-bond conjugative

systems, thus leading to the construction of new σ-bonds and

ring closures or to reverse processes.⁴²⁻⁴⁸This transformation

proceeds in a stereoselective manner, forming well-organized

transition states with a low activation barrier and very

advantageous thermodynamic characteristics. Under thermal

activation, 1,6-electrocyclization reactions were possible with

hexatriene-conjugated systems of double bonds with 6π-

electrons. During the formation of a new σ-bond, the terminal

orbitals overlapped by disrotation, and depending on the

direction of this motion, two diastereomers, 8A and 8B, might

be formed (Scheme 5). Two rings of the heterocyclic core in the

molecule of the product should be nonplanar. However, the

presence of a nitrogen atom in the terminal position of the

intermediate 7 heterohexatriene system could donate a pair of

electrons to an orbital already located in the plane of the formed

ring. This orbital could take part in new bond formation (a

heteroelectrocyclic or pseudopericyclic mechanism).³In this

case, only one orbital should turn, allowing overlap, and a new

bond would form due to monorotatory cyclization. Thus,

because of this reaction, enantiomers 8C and 8D should be

formed, in which the DTP heterocyclic fragment was planar

(Figure 1).

The best results in terms of yield were observed for the

reaction of thioamide 3b (Table 3, entries 1, 5, and 9). This

ﬁnding agrees with the previously considered hypothesis that

captodative substituents promote the 1,6-electrocyclic reaction.

In addition, acetic acid may accelerate condensation with the

acetylene reagents by activating their electrophilic centers and

binding the eliminated methanol. The decrease in the yield of

the reaction of thioamide 3c with esters 5b,c and the

ineﬀectiveness of its interaction with acetylenic acid 5a may be

related to the partial protonation of this substituent nitrogen

atom, which led to a decrease in its electron-donating properties.

1

The H and ¹³C NMR spectra, EI-TOF-MS spectra, and

Fourier transform infrared (FT-IR) spectra were consistent with

those of the structures expected for compounds 8 (see the

Experimental Section and Figures S6 −S15). Signals correspond-

ing to the CH protons of the heterocyclic core were observed in

the ¹H NMR spectrum of compound 8a as a doublet of C(4)H

doublets in the region of 6.02 ppm, whereas a doublet of C(5)H

doublets of protons at 5.90 ppm and a doublet of doublets C(6)

H at 6.23 ppm were observed with the corresponding constant.

The correlation of the signals was based on 2D NMR

experiments (Figure S6).

Clearly, the key compounds of this transformation are

intermediates 7, which may be obtained by condensation of

the corresponding aldehydes with (5-ylidene-4-oxothiazolidin-

2-ylidene)acetonitriles 9 (Scheme 3). The synthesis of

Scheme 3. Synthesis of (4-Oxothiazolidin-2-

ylidene)acetonitriles 9a−c

compounds 9a,b from cyanoethanethioamide and esters 5a,b

(Scheme 4) is described in the literature.³¹Thus, with these

compounds in hand, we could change the sequence of the

transformation stages. Furthermore, with this type of reaction

arrangement, we could avoid the side conversion of thioamides 3

into thiopyrans 4, which was a fundamental obstacle for the

eﬀectivity and scope of this transformation.

X-ray diﬀraction data obtained for a crystal of thiopyran 4a,

DTP 8a, and PTZ 12a that were grown from a dilute DMSO

solution demonstrated that both rings of a heterocyclic core lie

on the same plane, whereas the phenyl fragment deviates from

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a

Scheme 4. Synthesis of PTZs 12a−e by Two Synthetic Approaches

a

Yield after separation and puriﬁcation.

Scheme 5. Types of Terminal Orbital Rotations Occurring during the Cyclization of 1-Azahexatriene System Compound 7 to

Form a DTP System

this plane by angles of 86.1 (for 8a) and 89.9° (for 12a) (Figure

1). Thus, the spatial arrangement of the cyclic fragments in

thiopyran 4a, DTP 8a, and 12a indicates a monorotatory variant

of the electrocyclization of compounds 7 and 11 and the

formation of R- and S-enantiomers, which are both present in

the crystal.

The bicyclic ﬂat structure of DTP 8a was stabilized by a series

of weak interactions between sulfur and oxygen atoms and

between oxygen and hydrogen atoms, which held the lateral

linear fragments in one plane (Figure 1) and, in fact, led to the

formation of quasi-polycyclic molecules. This weak interaction

nature was veriﬁed by the RDG plot (Figure 2),⁴⁹⁻⁵²which is a

state-of-the-art technique based on electron density and is

particularly reliable for investigating weak interactions.

RDG analysis clearly conﬁrmed the existence of several van

der Waals-type interactions (green-turquoise isosurface) and

stronger bonding, in which sulfur binds with the oxygen atom

(light-blue-colored isosurface) of the carbonyl group. These

spatial features create the special architecture of the molecules,

where most of the lateral fragments and substituents are held

together by intramolecular electrostatic interactions.

To highlight the thermodynamics of the 1,6-electrocyclization

stage compounds 3a, 7a, and 11a, we performed quantum

mechanical calculations at the density functional theory (DFT)

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Table 5. ΔG and ΔH Values of the 1,6-Electrocyclization

Stage Leading to Thiopyran 4a, DTP 8a, and PTZ 12a

entry 1,6-electrocyclization stage

ΔG (kJ/mol)

ΔH (kJ/mol)

1

2

3

3a → 4a

7a → 8a

11a → 12a

−11.7 to 8.5

−67.9 to −50.8

−49.3 to −35.7

−21.9 to 1.2

−76.9 to −30.7

−64.1 to −44.1

3 and Table S2). The DTPs showed characteristic absorption

bands at 301−325 and 419−437 nm in their electronic spectra

Figure 3. (a) Absorption and (b) ﬂuorescence spectra of DTPs 8a-d

and k-m in DMSO. For the absorption measurements, c = 2.5×10⁻⁵M,

and for the ﬂuorescence spectra, c = 5×10⁻⁶M.

Figure 1. ORTEP view of thiopyran 4e (a,b), DTPs 8a (c,d), and PTZ

12a (e,f) with thermal ellipsoids at the 50% probability level: (a,c,e)

front view and (b,d,f) side view.

and emission maxima at 552−559 nm. The unusually large

Stokes shift (SS, up to 6487 cm⁻¹) was rationalized. The low

intensity of emission may be caused by the remarkable loss of the

absorbed energy via nonradiative processes during geometric

relaxation due to the nonaromatic structure of the DTPs 8.⁵³

DTP 8c did not exhibit any ﬂuorescence in the DMSO,

DMSO−H₂O, or MeCN solutions. However, we observed the

emission of this compound in DMSO after the addition of

triﬂuoroacetic acid (TFA), which might be induced by the

protonation of the N(Me)₂substituent.

Further investigation of the DTP 8a behavior in solvents with

diﬀerent properties showed that the dependence of the

adsorption and emission parameters on the chosen solvent

was negligible (Figure 4 and Table 6). Additionally, the

quantum yield increased gradually, up to 2.72%, with decreasing

solvent polarity.

level, including examining solvent eﬀects (AcOH) at 333 K (cf.

Computational Details in the Supporting Information). The ΔG

and ΔH values of the last stage of cyclization with the formation

of thiopyran 4a, DTP 8a, and PTZ 12a were calculated (Table 5

and Table S1) for the more stable rotamers.

A comparison of the thermodynamic quantities showed that

the most favorable stage was cyclization to form DTP 8a, in

which the Gibbs free energy values were more negative than

those of the other stages. ΔG₃was also remarkably negative.

Despite the cyclization to thiopyran being less probable, it was

still possible. These ﬁndings agreed with the experimental data

and the general rules of the 1,6-electrocyclization process.

Photophysical Properties of the DTPs. DTPs 8a−o

exhibited good solubility in DMSO, CHCl₃, CH₂Cl₂, and DMF,

moderate solubility in EtOH, and poor solubility in hexane.

Their solutions exhibited yellow emissions. The absorption and

emission properties of the DTPs were studied in DMSO (Figure

Fluorophores used for biological research require their optical

properties be characterized in water. As DTPs 8a−o did not

dissolve in water, we studied their optical properties in a 1:9

mixture of DMSO−H₂O (Table S2). The addition of water in

this ratio did not cause the formation of suspensions or

Figure 2. RDG plot of DTPs 8a, 8k, and 8l in DMSO solution. NCI isosurface colors: red (strongly repulsive), yellow-green (weakly repulsive), green-

turquoise (weakly attractive), and blue (strongly attractive). Atom color: white (H), gray (C), blue (N), red (O), and yellow (S).

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Figure 4. (a) Absorption and (b) ﬂuorescence spectra of DTP 8a in solvents with diﬀerent polarities. For the absorption measurements, c = 5 × 10⁻⁵

M, and for the ﬂuorescence spectra, c = 5 × 10⁻⁵M. Photographs of the solutions of DTP 8a exposed to daylight (c) and upon irradiation (d) with a

hand-held UV lamp at 365 nm (solvents: 1, DMSO; 2, MeCN; 3, DMF; 4, acetone; 5, AcOEt; 6, AcOⁿBu; 7, EtOH; 8, THF; 9, CH₂Cl₂; 10, CHCl₃; 11,

1,4-dioxane; 12, toluene; 13, hexane).

Table 6. Photophysical Properties of DTP 8a in Diﬀerent

Solvents

λ_abs

ab

λ_em

(nm)

Stokes shift

(nm/cm⁻¹

QY

d

c

,

entry solvent (nm)

ε (M⁻¹cm⁻¹

)

(%)

1

2

3

4

5

6

7

8

9

DMSO

MeCN

DMF

acetone

AcOEt

AcOBu

EtOH

THF

CH₂Cl₂

CHCl₃

423

420

421

416

418

420

422

418

11400

11900

10800

11100

11900

11400

12100

12200

11200

559

557

559

557

555

558

556

555

553

554

136/5752

141/6085

138/5864

141/6085

139/6020

137/5905

140/6002

138/5938

135/5792

131/5613

136/5872

0.96

1.46

1.19

1.64

1.80

1.75

1.18

1.51

1.92

1.86

1.90

10

11

1,4-

dioxane

Figure 5. (a) Emission spectra of DTPs 8a−d,k−m in the solid state.

Photographs of DTPs 8a−d,k−m under irradiation with (b) sunlight

and (c) hand-held UV lamp at an emission wavelength of 380 nm.

12

13

toluene

hexane

422

416

11300

12200

553

541

131/5614

125/5554

2.20

2.72

a

Absorption measured in a solution with a concentration of 5 × 10⁻⁵

b

c

M. Only the longest absorption maxima are reported. Emission

Table 7. Absorption and Emission Values of DTPs 8a,b,d,k−

m in the Solid State

d

measured at a concentration of 5 × 10⁻⁵M. Quantum yield (QY) is

measured relative to quinine sulfate (λ_exc= 366 nm; Φ = 0.53).

entry compound λ_exc(nm) λ_em(nm) QY (%) SS (nm/cm⁻¹

)

aggregates; moreover, deviations in the shape of the spectra are

not observed. In general, the maximum absorption and emission

showed a slight red shift. The QY decreased by ∼1.2−5.5-fold,

and a larger QY decrease was observed for 8b and 8f due to the

MeO substituent located at the C(5) aromatic ring.

The solid DTP samples exhibited dark yellow to brick red

colors and yellow and red emissions upon irradiation (Figure 5

and Table 7). Emissions from the solid samples were observed

between 556 and 598 nm. Thus, the potential of the novel

heterocyclic core in the solid-state emission (SEE) family and

multifunctional ﬂuorophore was demonstrated.⁵⁴

The mechanism of solid-state ﬂuorescence is usually

explained by the restriction of intramolecular rotation (RIR)

due to twisted propeller-like molecular conformations and

decreasing nonradiative energy loss.⁵³Thus, we can suggest that,

for investigated DTPs 8, solid-state emission may occur owing

to the speciﬁc spatial location of the aromatic cycle at the C(5)

atom of the heterocyclic score (Figure 1c,d).

To conclude, the newly synthesized heterocyclic compounds

exhibited absorption in the visible range of the spectra and weak

but yellow ﬂuorescence, despite their short-conjugated system.

Moreover, the C(5) aromatic ring was located perpendicular to

the plane of the central heterocycle (XRD data, Figure 1c,d).

1

2

3

4

5

6

8a

8b

8d

8k

8l

463

417

463

573

556

570

587

598

580

1.58

0.88

1.21

1.02

0.64

0.80

110/4146

139/5995

107/4054

124/4562

135/4876

117/4357

8m

Such absorption and emission characteristics may be explained

by the presence of numerous heteroatoms with additional lone

pairs, the planarity of the heterocycle, and the lateral CC

double bond.

Quantum Mechanical Calculations. To study the DTP

behavior upon excitation and emission, we analyzed the

geometry and electronic structure at the ground state (GS)

and excited state (ES), including the eﬀect of solvation (DMSO

and MeCN). (All details of the quantum mechanical

calculations are presented in the Supporting Information.)

The possible rotamers of 8a,k,l were investigated, and the most

stable rotamers were established and used for the subsequent

calculations. The geometry of the most stable rotamers in the

ground and excited states are presented in the Supporting

Information (Figure S33 and Tables S3−S6). The main

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Table 8. Computed Absorption Wavelength (λ_a), Oscillator Strength (f₀₁), Emission Wavelength (λ_e), Oscillator Strength (f₁₀),

Modulus of Electric Dipole Moments in the Ground State (μ₀), Vertical Franck−Condon Excited State (μ_1v), Relaxed Excited

State (μ_1r), and Angles Formed by the Dipole Moment Vectors (θ_0,1vand θ_0,1r) for the Most Stable Rotamer of DTPs 8a, 8k, and 8o

in DMSO and MeCN

entry compound (solvent) λ₀₁(nm)

f ₀₁

μ₀(D)

c_H−L

λ_em(nm)

f₁₀

c_L−H

μ_1v(D) μ_1r(D) θ_0,1v(deg) θ_0,1r(deg)

1

2

3

4

5

6

8a (DMSO)

8a (MeCN)

8k (DMSO)

8k (MeCN)

8o (DMSO)

8o (MeCN)

423

417

429

427

436

427

0.6828

0.6802

0.6971

0.6944

0.7081

0.7055

6.0

5.9

6.3

0.68485

0.68490

0.68610

0.68620

0.68693

0.68701

562

560

558

561

557

0.6012

0.5980

0.6210

0.6180

0.6257

0.6231

0.69288

0.69292

0.69483

0.69487

0.69573

0.69577

6.4

7.9

8.2

7.3

8.9

8.8

9.2

9.1

88.2

88.1

90.1

90.0

109.5

109.2

92.8

92.6

94.1

93.9

112.3

111.9

structural peculiarities of compounds 8a,k,l are the planarity of

the heterocycle core and double CC bond. The aromatic ring

and central heterocycle are almost perpendicular to each other.

The geometry of DTPs 8a,k,o changes insigniﬁcantly upon

excitation. The bond lengths in their molecules, as well as the S···

O noncovalent interaction, tend to decrease (by ∼1%), whereas

the intramolecular O···H hydrogen bond becomes weaker.

Furthermore, we analyzed the electronic features of the

ground and excited state DTPs 8a,k,l (Table 8). The electric

dipole moment increases insigniﬁcantly upon excitation and

emission, whereas the direction changes from 88.1 to 112.3°.

The wavelength values calculated for the absorption and

emission maxima, both in DMSO and in MeCN, were close to

the experimental ones, which conﬁrms the applicability of the

method used and its potential for investigating the electronic

structure of the studied compounds. The electronic transitions

are essentially HOMO−LUMO excitations.

Figure 7. Plot of the MEPs of ATAs 8a, 8k, and 8l, as calculated by

time-dependent DFT at the ω-B97X-D/6-311++G**//IEF-PCM

(UFF) level of theory, for the ground and excited states in DMSO.

Map colors: red (negative potential), blue (positive potential).

Elements: hydrogen (white), carbon (gray), nitrogen (blue), oxygen

(red), sulfur (yellow) (range, −0.05 to 0.05 au; density |isovalue| =

0.0004 au).

For these molecules, HOMOs were delocalized on the

bicyclic core and CC bond, whereas LUMOs were slightly

shifted to ethoxycarbonyl fragments (Figure 6), suggesting

potential of the DTPs was associated with the presence of the

oxygen atoms and nitrogen of the CN group, and the positive

potential was related to the hydrogens of the pyridine ring. All

centers became more active upon excitation.

Bioassay Studies in Living and Fixed Cells. The design

and preparation of new ﬂuorophores to exploit their applications

in life science provides new opportunities for biology and

biomedical research. For biomedical applications, ﬂuorophores

that can visualize the evolution of biological processes and image

interactions between ﬂuorophores and biomolecules are highly

desired. To determine the prospects of DTPs for their use in

biology and medicine, we investigated the ability of these

produced substances to stain cells for ﬂuorescence micros-

copy.⁶⁰⁻⁶³Compounds 8a−o exhibited maximum absorption in

the visible region. This was an advantage for their use in

biological experiments as exposure to visible radiation is safer for

living organisms and living cells than exposure to UV radiation.

A green monkey epithelial cell culture (Vero) was used for the

biological experiments. After being stained and washed,

preparations of living cells were examined using an LSM-710

confocal laser scanning microscope (CLSM, Carl Zeiss) with a

multichannel QUASAR detector (34 channels). Lasers at

wavelengths of 405 and 488 nm were used. Images were

obtained using an immersion lens (40×, 1.3 oil) with a

resolution of 1024 × 1024 pixels and an image size of 212 ×

212 μm. To obtain an informative ﬂuorescent image using

special software ZEN (Carl Zeiss), a special lambda mode (λ-

Figure 6. Frontier molecular orbitals, HOMO and LUMO, in the

ground (left) and excited states (right) for DTPs 8a,k,l in DMSO (|

isovalue(MO)| = 0.02 au; |isovalue(ρ)| = 0.0004 au).

negligible intramolecular charge transfer^53,55−57from the donor

to the acceptor moieties upon photoexcitation and emission.

The HOMO and LUMO exhibited remarkable overlapping of

the interacting orbitals upon excitation and emission. This was

supported by the large oscillator strengths for both absorption

and emission. The phenyl ring is not involved in the HOMO or

LUMO in either the ground or excited states due to its spatial

location.

The map of the molecular electrostatic potential (MEP)^58,59

conﬁrms that DTPs have many sites for nucleophilic and

electrophilic attack, the formation of hydrogen bonds, and other

weak interactions (Figure 7). The negative electrostatic

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mode) was used, which allowed for the determination of the

emission range with the maximum contrast for this preparation.

The above-mentioned study showed that the 8a and 8k

substances penetrated into the cell and accumulated as separate

bright points, most likely in lysosomes (Figure 8). The

alternative procedure with another step sequence, along with the

speciﬁc three-dimensional structure studied by XRD data,

quantum mechanical calculations, and the thermodynamic

characteristics of the 1,6-electrocyclic reaction, supported the

transformation mechanism.

However, studying and proving the detailed and accurate

mechanism of a chemical reaction is a rather complex task and

requires dedicated experimental and theoretic investigations,

including a variety of diﬀerent methods and approaches, which

are currently underway. These results will allow us not only to

deﬁne the geometry and thermodynamics of the transition state

but also to prove the correct classiﬁcation of the new example of

the 1,6-electrocyclic reactions and their place in pericyclic

transformations. Furthermore, we hope to establish the

speciﬁcity of the reactivity of the active intermediates and

relationships between their structure and reactivity and to

expand the scope of the reagents and variation in the new

heterocyclic products for speciﬁc applications.

Despite the scarcity of π-electrons in their structure and the

high nonaromaticity of the obtained 2,3-dihydro-5H-thiazolo-

[3,2-a]pyridines absorbed in the visible region, they demon-

strated yellow emissions.

Figure 8. CLSM images of Vero cells incubated with DTPs 8a, 8c, and

8k (1.0 μM) in DMEM for 0.5 h at 37 °C. The CLSM images were

obtained with 405 and 488 nm excitations, and a 488−600 nm long-

pass collection ﬁlter was used to generate the overlaid images.

Biological assays showed that DTPs penetrated through the

cellular membrane and presumably accumulated in lysosomes

without any undesirable eﬀects on the cells and cellular

organelles. Therefore, DTPs could also realize ﬂuorescence

visualization in living systems, thereby providing live cell

imaging for the transport of biologically active compounds or

natural compounds and diagnostic molecules to biotargets. The

pathways in this study have real application prospects due to the

numerous functional groups in molecular DTPs. In-depth

studies on the ﬂuorescence properties of new DTP derivatives

and further applications of the synthesized ﬂuorophores are

currently ongoing.

ﬂuorescence intensity of 8c was somewhat lower than that of

the other compounds; therefore, no deﬁnite conclusion on its

accumulation could be drawn. None of the test substances

penetrated the cell nucleus. Substances 8a and 8k ﬂuoresced in

the yellow range (550−580 nm) when excited by both lasers

with wavelengths of 405 and 488 nm.

A very similar pattern was observed in cells stained with 8a,

except that the ﬂuorescence response was slightly shifted to the

blue region (510−550 nm). The ﬂuorescence intensity of the 8a

substance was less than that the other substances in the cells, and

the ﬂuorescence spectrum of 8a diﬀered when it was excited by a

laser with a wavelength of 405 nm, showing a ﬂuorescence shift

in the blue region (450−500 nm). When excited at 488 nm, the

ﬂuorescence response was yellow-green (500−550 nm).

Importantly, the DTPs did not cause any visible toxic eﬀect

on the cells and cellular organs.

In ﬁxed cells, the results were signiﬁcantly diﬀerent. The

ﬂuorescence intensity of the dyes signiﬁcantly decreased.

Substances 8a and 8c in ﬁxed cells ﬂuoresced so dimly that it

was impossible to obtain a high-quality image. All of the

substances stained the cells, whereas the accumulation of dye in

the nucleus was observed; thus, the nucleolus was clearly

distinguished. The ﬂuorescence spectrum of all three substances

was in the blue-green region. Note that DTP 8c was

nonﬂuorescent in DMSO and DMSO−H₂O (1/9), and only

the addition of TFA to the DMSO solution led to an emission

(Table S1, entries 8 and 10). Thus, the interaction of DTP 8c

with biological objects induced appreciable ﬂuorescence.

Conclusions and Outlook. The synthesis of 1-aryl-2-

cyanopenta-2,4-dienethioamides was carried out, and their

reaction with acetylenedicarboxylic acid, ester derivatives, and

methyl propiolate was rationalized. The reaction pathway led to

the formation of an active intermediate bearing a 1-

azahexatriene chain, which was involved in the 1,6-electrocyclic

reaction to construct two new heterocyclic systems, namely, 2,3-

dihydro-5H-thiazolo[3,2-a]pyridines and 4-oxo-4H,6H-pyrido-

[2,1-b][1,3]thiazines. The results obtained according to an

EXPERIMENTAL SECTION

■

1

Materials and Methods. H NMR and ¹³C NMR spectra were

recorded with a Bruker Avance II (Karlsruhe, Germany) (400 MHz for

¹H, 100 MHz for ¹³C) spectrometer. Chemical shifts are reported in

parts per million (ppm) relative to TMS in ¹H NMR and to the residual

solvent signals in ¹³C as an external reference. Coupling constant (J)

values are given in hertz (Hz). Signal splitting patterns are described as a

singlet (s), doublet (d), triplet (t), quartet (q), sextet (sext), quintet

(quin), multiplet (m), broad (br), doublet of doublets (dd), doublet of

triplets (dt) or AA′XX′, spin system of para-substituted benzene with

two diﬀerent substituents. The major isomer signal is highlighted with

an asterisk (*). The ¹³C NMR signal patterns for several compounds

were determined by APT (attached proton test) and are described as

follows: “+” for secondary or quaternary carbon atoms (positive signal)

and “−” for primary or tertiary carbon atoms (negative signal). Mass

spectra were recorded with a Shimadzu GCMS-QP 2010 “Ultra”

(Kyoto, Japan) mass spectrometer using the electron impact (EI)

ionization technique (70 eV). The abbreviation [M]⁺refers to the

molecular ion. High-resolution mass spectra were obtained using an

Agilent 6545-Q-TOF (Agilent Technologies Inc., Santa Clara, CA,

USA) mass spectrometer equipped with an ESI source operating in

positive ionization mode with a resolution of 15000 (fwhm). The FT-

IR spectra were obtained using a Bruker Alpha (NPVO, ZnSe)

spectrometer (Ettlingen, Germany). Elemental analyses were carried

out using a PerkinElmer 2400 Series II CHNS/O analyzer (Shelton,

CT, USA). Melting points were determined with a Stuart SMP3

apparatus (Staﬀordshire, ST15 OSA, UK).

UV−vis absorption spectra were recorded with a PerkinElmer

Lambda 35 UV−vis spectrophotometer (Shelton, CT, USA).

Fluorescence of the sample solutions was measured using a Hitachi

F-7000 spectrophotometer (Tokyo, Japan). The absorption and

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emission spectra were recorded in hexane, toluene, 1,4-dioxane, CHCl₃,

CH₂Cl₂, EtOH, AcOⁿBu, AcOEt, DMF, MeCN, and DMSO using

10.00 mm quartz cells. The excitation wavelength was determined at the

absorption maxima. Atmospheric oxygen contained in solutions was

not removed. The concentrations of the compounds in the solution

were 2.5 × 10⁻⁵and 5.0 × 10⁻⁵M for absorption measurements and 5.0

× 10⁻⁵and 5.0 × 10⁻⁶M for ﬂuorescence measurements. The relative

ﬂuorescence quantum yields (Φ_F) were determined using quinine

sulfate in 0.1 M H₂SO₄as a standard (Φ_F= 0.546). The absolute

quantum yield for the solid-state and time-resolution study was

recorded with a Horiba FluoroMax 4 spectroﬂuorometer (Kyoto,

Japan) with a Quanta-φ integrating sphere using FluorEssence 3.5

software.

The reactions were monitored by analytical TLC on aluminum-

backed silica gel plates (Sorbﬁl UV-254). Visualization of components

was accomplished by short wavelength UV light (254 nm). Solvents

were dried and distilled according to common procedures. All solvents

were of spectroscopic grade. Aldehydes 1a−e and acetylenes 5a−e were

obtained from Acros Organics and used without further puriﬁcation.

Cyanthioacetamide 2 is known compound and was obtained by the

literature procedure.⁶²

Preparation and Characterization of Compounds. General

Procedure A (GP-A): Synthesis of the Penta-2,4-dienethioamides

3a−3d and Thiopyrane 4. TEA (1.0 mmol, 0.140 mL) was added to a

ﬂask containing a solution of cyanothioacetamide 2 (10.0 mmol, 1.000

g) and aldehyde 1 (10.0 mmol) in EtOH (5.0 mL). The reaction

mixture was stirred at 60 °C under oil-bath heating for 0.5−6.0 h until

the TLC analysis indicated total consumption of the starting

cyanothioacetamide 2. The resulting mixture was cooled in an ice

bath for 0.5 h. The precipitate was collected by ﬁltration, washed with

small quantities of ethanol, and dried.

General Procedure B (GP-B): Synthesis of the DTPs 8a−j. To a

solution of thioamide 3 (1.0 mmol) in acetic acid (2.0 mL) were added

the derivatives of acetylene dicarboxylic acid 5 (1.0 mmol), and the

mixture was stirred at 60 °C under oil-bath heating for 3−48 h until the

TLC analysis indicated total consumption of the starting thioamide 3.

The resulting mixture was cooled in an ice bath for 1 h. The precipitate

was collected by ﬁltration, washed with water (5 mL), and dried or the

crude product was obtained by ﬂash column chromatography on silica

gel (eluting with methylene chloride and chloroform/ethanol = 10/1)

to aﬀord the resulting compound.

General Procedure C (GP-C): Synthesis of 5-Oxothiazolidin-4-

ylidenes 9a−d. Acetylene dicarboxylic acid or ester (10.0 mmol) was

added to a solution of cyanothioacetamide 2 (10.0 mmol, 1.00 g) in

acetic acid (10.0 mL). The mixture was stirred at 60 °C under oil-bath

heating for 2−4 h until the TLC analysis indicated total consumption of

the starting cyanothioacetamide 2. The resulting mixture was diluted

with water (15 mL) and cooled in an ice bath for 1 h. The precipitate

was ﬁltrated, washed with water (20 mL), and dried.

General Procedure D (GP-D): Synthesis of the DTPs 8k−o. A

mixture of thiazolidinone 9 (1.0 mmol), aldehyde 1 (1.0 mmol), and

AcONa (2.0 mmol, 0.164 g) in acetic acid (2.0 mL) was stirred at 118

°C under oil-bath heating for 14−18 h until the TLC analysis indicated

total consumption of the starting thiazolidinone 9 and aldehyde 1. The

reaction mixture was poured into crushed ice and allowed to stand for 1

h. The precipitate was collected by ﬁltration, washed with water (5 mL),

and dried. Then the crude product was puriﬁed by ﬂash column

chromatography on silica gel (eluting with hexane/ethyl acetate = 3/2)

to aﬀord the resulting compound.

General Procedure E (GP-E): Synthesis of the 4H,6H-Pyrido[2,1-

b][1,3]thiazine 12a. To a solution of thioamide 3a (1.0 mmol, 0.214 g)

in acetic acid (2.0 mL) was added methyl propiolate (1.0 mmol, 0.088

mL), and the mixture was stirred at 60 °C under oil-bath heating until

the TLC analysis indicated total consumption of the starting thioamide

3. The resulting mixture was cooled in an ice bath for 1 h. The

precipitate was collected by ﬁltration and washed with water (5 mL).

General Procedure F (GP-F): Synthesis of the 4H,6H-Pyrido[2,1-

b][1,3]thiazines 12b−e. A mixture of thiazinone 10 (1.0 mmol, 0.152

g), aldehyde 1 (1.0 mmol), and AcONa (2.0 mmol, 0.164 g) in acetic

acid (2.0 mL) was stirred at 118 °C under oil-bath heating for 8−20 h

until the TLC analysis indicated total consumption of the starting

thiazinone 10 and aldehyde 1. The reaction mixture was poured into

crushed ice and allowed to stand for 1 h. The precipitate was collected

by ﬁltration, washed with water (5 mL), and dried. Then the crude

product was puriﬁed by ﬂash column chromatography on silica gel

(eluting with hexane/ethyl acetate = 3/2) to aﬀord the resulting

compound.

2-Cyano-5-phenylpenta-2,4-dienethioamide (3a): Prepared ac-

cording to GP-A; orange powder (2.033 g, 95% yield); mp = 166−167

°C; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.96 (br s, 1H), 9.45 (br s, 1H),

7.97 (d, 1H, J = 11.2 Hz), 7.71 (m, 2H), 7.47 (m, 4H), 7.17 (dd, 1H, J =

11.2, J = 15.4 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz, APT) δ (+)

191.6, (−) 148.3, (−) 148.1, (+) 135.5, (−) 131.2, (−) 129.7, (−)

128.7, (−) 123.9, (+) 115.6, (+) 113.9; FT-IR (neat) ν_max(cm⁻¹) 3342,

3266, 3154, 2221, 1605; MS-EI, m/z 214 (M⁺, 100%). Anal. Calcd for

C₁₂H₁₀N₂S: C, 67.26; H, 4.70; N, 13.07. Found: C, 67.17; H, 4.77; N,

13.18.

2-Cyano-5-(4-methoxyphenyl)penta-2,4-dienethioamide (3b):

Prepared according to GP-A; orange powder (1.830 g, 75% yield);

1

mp = 193−195 °C; H NMR (DMSO-d₆, 400 MHz) δ δ 9.86 (br s,

1H), 9.34 (br s), 7.97 (d, 1H, J = 11.3 Hz), 7.67 (d, 2H, J = 8.8 Hz), 7.43

(d, 1H, J = 15.2 Hz), 7.02 (m, 3H), 3.82 (s, 3H); ¹³C{¹H} NMR

(DMSO-d₆, 100 MHz, APT) δ (+) 191.2, (+) 161.5, (−) 148.8, (−)

147.9, (−) 130.3, (+) 127.7, (−) 121.1, (+) 115.4, (−) 114.7, (+)

111.7, (−) 55.4; FT-IR ν_max(cm⁻¹) 3388, 3320, 3222, 2214, 1644; MS-

EI, m/z 244 (M⁺, 100%). Anal. Calcd for C₁₃H₁₂N₂OS: C, 63.91; H,

4.95; N, 11.47. Found: C, 63.69; H, 4.97; N, 11.42.

2-Cyano-5-(4-(dimethylamino)phenyl)penta-2,4-dienethioa-

mide (3c): Prepared according to GP-A; dark red powder (2.107 g, 82%

yield); mp = 230−232 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.67 (br

s, 1H), 9.13 (br s, 1H), 7.98 (d, 1H, J = 11.5 Hz), 7.51 and 6.72

(AA′XX′, 4H, J = 8.9 Hz), 7.34 (d, 1H, J = 14.9 Hz), 6.88 (dd, 1H, J =

14.9, J = 11.6 Hz), 3.00 (s, 6H); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz)

δ 191.4, 152.2, 150.1, 149.7, 130.5, 122.4, 117.7, 116.0, 111.9, 108.5;

FT-IR (neat) ν_max(cm⁻¹) 3344, 3273, 3154, 2217, 1634; MS-EI, m/z

257 (M⁺, 100%). Anal. Calcd for C₁₄H₁₅N₃S: C, 65.34; H, 5.88; N,

16.33. Found: C, 65.51; H, 6.03; N, 16.46.

2-Cyano-5-(2-methoxyphenyl)penta-2,4-dienethioamide (3d):

Prepared according to GP-A; orange powder (0.586 g, 24% yield);

mp = 133−135 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.87 (br s, 1H),

9.34 (br s, 1H), 7.97 (d, 1H, J = 11.3 Hz), 7.66 (d, 1H, J = 7.1 Hz), 7.60

(d, 1H, J = 15.4 Hz), 7.42 (t, 1H, J = 7.3 Hz), 7.25 (dd, 1H, J = 15.4, J =

11.4 Hz), 7.09 (d, 1H, J = 8.3 Hz), 7.01 (t, 1H, J = 7.5 Hz), 3.87 (s, 3H);

¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 191.2, 158.0, 148.4, 142.9,

132.4, 128.9, 124.3, 123.4, 121.0, 115.3, 112.8, 111.9, 55.7; FT-IR

(neat) ν_max(cm⁻¹) 3413, 3273, 3167, 2200, 1629; MS-EI, m/z 244 (M⁺,

100%). Anal. Calcd for C₁₃H₁₂N₂OS: C, 63.91; H, 4.95; N, 11.47.

Found: C, 63.79; H, 4.96; N, 11.43.

6-Amino-3-methyl-2-phenyl-2H-thiopyran-5-carbonitrile (4):

Prepared according to GP-A; yellow powder (1.664 g, 73% yield);

mp = 130−132 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.31 (m, 5H),

6.95 (s, 2H), 5.98 (d, 1H, J = 1.4 Hz), 4.73 (s, 1H), 1.74 (d, 3H, J = 1.2

Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 154.3, 140.7, 128.6,

127.6, 127.1, 120.7, 119.4, 119.3, 72.4, 46.7, 21.5; FT-IR (neat) ν_max

(cm⁻¹) 3401, 3300, 3206, 3154, 2180, 1616; MS-EI, m/z 228 (M⁺,

100%). Anal. Calcd for C₁₃H₁₂N₂S: C, 68.39; H, 5.30; N, 12.27. Found:

C, 68.63; H, 5.38; N, 12.37.

Methyl-2-(8-cyano-3-oxo-5-phenyl-5H-thiazolo[3,2-a]pyridin-

2(3H)-ylidene)acetate (8a): Prepared according to GP-B; after column

chromatography (methylene chloride), an orange powder (0.253 mg,

78% yield) was obtained; mp = 178−180 °C; ¹H NMR (DMSO-d₆, 400

MHz) δ 7.35 (m, 5H), 6.78 (s, 1H), 6.23 (dd, 1H, J = 9.8, 1.5 Hz), 6.02

(dd, 1H, J = 4.5, 1.4 Hz), 5.90 (dd, 1H, J = 9.8, 4.6 Hz), 3.81 (s, 3H);

¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 166.2, 163.1, 147.4, 139.1,

138.4, 128.9, 128.4, 126.7, 123.3, 116.2, 116.1, 115.3, 84.1, 58.1, 52.8;

FT-IR (neat) ν_max(cm⁻¹) 3071, 2993, 2947, 2894, 2845, 2213, 1705,

1685 (CO); HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₇H₁₂N₂O₃SH 325.0641; found 325.0643; [M + Na]⁺calcd for

C₁₇H₁₂N₂O₃SNa 347.0461; found 347.0463; [M + K]⁺calcd for

C₁₇H₁₂N₂O₃SK 363.0200; found 363.0204.

K

https://dx.doi.org/10.1021/acs.joc.0c01934

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Methyl-2-(8-cyano-5-(4-methoxyphenyl)-3-oxo-5H-thiazolo[3,2-

a]pyridin-2(3H)-ylidene)acetate (8b): Prepared according to GP-B;

after column chromatography (methylene chloride), an orange powder

Na]⁺calcd for C₁₉H₁₆N₂O₄SNa 391.0723; found 391.0726; [M + K]⁺

calcd for C₁₉H₁₆N₂O₄SK 407.0462; found 407.0460.

Ethyl-2-(8-cyano-5-(4-(dimethylamino)phenyl)-3-oxo-5H-

thiazolo[3,2-a]pyridin-2(3H)-ylidene)acetate (8g): Prepared accord-

ing to GP-B; after column chromatography (methylene chloride), an

orange powder (0.114 mg, 30% yield) was obtained; mp = 181−183

°C; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.14 and 6.67 (AA′XX′, 4H, J =

8.7 Hz), 6.72 (s, 1H), 6.23 (d, 1H, J = 9.7 Hz), 5.88 (d, 1H, J = 5.0 Hz),

5.84 (dd, 1H, J = 9.6 Hz, J = 4.7 Hz), 4.26 (q, 2H, J = 7.0 Hz), 2.87 (s,

6H), 1.26 (t, 3H, J = 7.1 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ

165.5, 163.1, 150.6, 146.8, 138.3, 128.0, 125.9, 123.4, 116.2, 115.9,

115.6, 112.3, 99.5, 84.3, 61.7, 57.7, 13.9; FT-IR (neat) ν_max(cm⁻¹)

3183, 3151, 3081, 3067, 3054, 3037, 2984, 2955, 2904, 2864, 2803,

2215, 1706, 1687; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₂₀H₁₉N₃O₃SH 382.1220; found 382.1232; [M + Na]⁺calcd for

C₂₀H₁₉N₃O₃SNa 404.1039; found 404.1038; [M + K]⁺calcd for

C₂₀H₁₉N₃O₃SK 420.0779; found 420.0775.

1

(0.234 mg, 66% yield) was obtained; mp = 169−171 °C; H NMR

(DMSO-d₆, 400 MHz) δ 7.28 and 6.92 (AA′XX′, 4H, J = 8.5 Hz), 6.76

(s, 1H), 6.24 (d, 1H, J = 9.8 Hz), 5.97 (d, 1H, J = 4.0 Hz), 5.86 (dd, 1H,

J = 9.8, 4.6 Hz), 3.80 (s, 3H), 3.74 (s, 3H); ¹³C{¹H} NMR (DMSO-d₆,

100 MHz) δ 165.8, 162.8, 159.3, 146.7, 138.1, 130.7, 128.2, 122.9,

116.1, 115.7, 115.1, 114.1, 84.0, 57.3, 54.9, 52.4; FT-IR (neat) ν_max

(cm⁻¹) 3070, 3043, 3014, 2960, 2839, 2218, 1713, 1683; HRMS (ESI-

TOF) m/z [M + H]⁺calcd for C₁₈H₁₄N₂O₄SH 355.0747; found

355.0744; [M + Na]⁺calcd for C₁₈H₁₄N₂O₄SNa 377.0566; found

377.0570; [M + K]⁺calcd for C₁₈H₁₄N₂O₄SK 393.0306; found

393.0301.

Methyl-2-(8-cyano-5-(4-(dimethylamino)phenyl)-3-oxo-5H-

thiazolo[3,2-a]pyridin-2(3H)-ylidene)acetate (8c): Prepared accord-

ing to GP-B; after column chromatography (methylene chloride), an

orange powder (0.184 mg, 50% yield) was obtained; mp = 210−212

°C; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.14 and 6.67 (AA′XX′, 4H, J =

7.6 Hz), 6.75 (s, 1H), 6.23 (d, 1H, J = 9.6 Hz), 5.88 (d, 1H, J = 4.1 Hz),

5.84 (dd, 1H, J = 9.6 Hz, J = 4.0 Hz), 3.80 (s, 3H), 2.88 (s, 6H);

¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 165.7, 162.8, 150.3, 146.5,

138.2, 127.8, 125.6, 123.1, 115.9, 115.7, 114.9, 112.0, 84.0, 57.5, 52.4,

39.6; FT-IR (neat) ν_max(cm⁻¹) 3066, 2954, 2888, 2803, 2217, 1707;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₉H₁₇N₃O₃SH 368.1063;

found 368.1069; [M + Na]⁺calcd for C₁₉H₁₇N₃O₃SNa 390.0883;

found 390.0874; [M + K]⁺calcd for C₁₉H₁₇N₃O₃SK 406.0622; found

406.0618.

Ethyl-2-(8-cyano-5-(2-methoxyphenyl)-3-oxo-5H-thiazolo[3,2-

a]pyridin-2(3H)-ylidene)acetate (8h): Prepared according to GP-B;

after column chromatography (methylene chloride), an orange powder

1

(0.177 mg, 48% yield) was obtained; mp = 188−190 °C; H NMR

(DMSO-d₆, 400 MHz) δ 7.30 (t, 1H, J = 7.9 Hz), 7.10 (dd, 1H, J = 7.6

Hz, J = 1.4 Hz), 7.06 (d, 1H, J = 8.2 Hz), 6.94 (t, 1H, J = 7.4 Hz), 6.73 (s,

1H), 6.17 (dd, 1H, J = 4.3 Hz, J = 1.4 Hz), 6.13 (dd, 1H, J = 9.8 Hz, J =

1.5 Hz), 5.79 (dd, 1H, J = 9.8, 4.5 Hz), 4.28 (q, 2H, J = 7.1 Hz), 3.82 (s,

3H), 1.27 (t, 3H, J = 7.1 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ

165.3, 162.6, 155.8, 147.5, 137.9, 129.3, 126.7, 121.6, 120.7, 116.2,

115.7, 115.2, 111.6, 83.8, 61.4, 55.6, 54.4; FT-IR (neat) ν_max(cm⁻¹)

3066, 2996, 2970, 2938, 2838, 2204, 1709, 1688; HRMS (ESI-TOF)

m/z [M + H]⁺calcd for C₁₉H₁₆N₂O₄SH 369.0904; found 369.0911;

[M + Na]⁺calcd for C₁₉H₁₆N₂O₄SNa 391.0723; found 391.0731; [M +

K]⁺calcd for C₁₉H₁₆N₂O₄SK 407.0462; found 407.0471.

Methyl-2-(8-cyano-5-(2-methoxyphenyl)-3-oxo-5H-thiazolo[3,2-

a]pyridin-2(3H)-ylidene)acetate (8d): Prepared according to GP-B;

after column chromatography (methylene chloride), an orange powder

1

(0.134 mg, 38% yield) was obtained; mp = 182−184 °C; H NMR

2-(8-Cyano-3-oxo-5-phenyl-5H-thiazolo[3,2-a]pyridin-2(3H)-

ylidene)acetic Acid (8i): Prepared according to GP-B; after column

chromatography (chloroform/ethanol = 10/1), an orange powder

(DMSO-d₆, 400 MHz) δ 7.30 (t, 1H, J = 7.8 Hz), 7.10 (dd, 1H, J = 7.5

Hz, J = 1.0 Hz), 7.06 (d, 1H, J = 8.2 Hz), 6.94 (t, 1H, J = 7.4 Hz), 6.75 (s,

1H), 6.17 (dd, 1H, J = 4.2 Hz, J = 0.9 Hz), 6.14 (dd, 1H, J = 9.9 Hz, J =

1.3 Hz), 5.79 (dd, 1H, J = 9.8, 4.5 Hz), 3.81 (s, 6H); ¹³C{¹H} NMR

(DMSO-d₆, 100 MHz) δ 166.7, 163.3, 156.4, 148.3, 138.9, 130.1, 127.4,

127.2, 122.4, 121.5, 116.8, 116.6, 115.5, 112.2, 84.5, 56.2, 55.1, 53.3;

FT-IR (neat) ν_max(cm⁻¹) 3064, 2995, 2947, 2837, 2207, 1710, 1689;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₄N₂O₄SH 355.0747;

found 355.0753; [M + Na]⁺calcd for C₁₈H₁₄N₂O₄SNa 377.0566;

found 377.0566; [M + K]⁺calcd for C₁₈H₁₄N₂O₄SK 393.0306; found

393.0315.

1

(0.183 mg, 59% yield) was obtained; mp = 219−221 °C; H NMR

(DMSO-d₆, 400 MHz) δ 7.34 (m, 5H), 6.71 (s, 1H), 6.21 (dd, 1H, J =

9.8, 1.2 Hz), 6.02 (d, 1H, J = 3.6 Hz), 5.88 (dd, 1H, J = 9.8, 4.6

Hz)_.¹³C{1H} NMR (DMSO-d₆, 100 MHz) δ 166.8, 163.3, 148.1,

139.2, 138.0, 128.9, 128.4, 126.7, 123.0, 116.6, 116.2, 116.1, 83.6, 58.0;

FT-IR (neat) ν_max(cm⁻¹) 3071, 3004, 2966, 2213, 1713, 1671; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₆H₁₀N₂O₃SH 311.0485; found

311.0484.

2-(8-Cyano-5-(4-methoxyphenyl)-3-oxo-5H-thiazolo[3,2-a]-

pyridin-2(3H)-ylidene)acetic Acid (8j): Prepared according to GP-B;

after column chromatography (chloroform/ethanol = 10/1), an orange

powder (0.231 mg, 68% yield) was obtained; mp = 204−206 °C; ¹H

NMR (DMSO-d₆, 400 MHz) δ 13.61 (br s, 1H), 7.27 and 6.92

(AA′XX′, 4H, J = 8.5 Hz), 6.69 (s, 1H), 6.21 (d, 1H, J = 9.8 Hz), 5.95

(d, 1H, J = 4.1 Hz), 5.84 (dd, 1H, J = 9.8, 4.6 Hz), 3.73 (s, 3H); ¹³C{¹H}

NMR (DMSO-d₆, 100 MHz) δ 166.9, 163.3, 159.3, 147.8, 137.9, 131.0,

128.5, 122.9, 116.8, 116.3, 116.2, 114.2, 83.6, 57.4, 55.1; FT-IR (neat)

ν_max(cm⁻¹) 3049, 3006, 2974, 2883, 2853, 2833, 2216, 1709, 1670;

HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₇H₁₂N₂O₄SH 341.0591;

found 341.0592; [M + Na]⁺calcd for C₁₇H₁₂N₂O₄SNa 363.0410;

found 363.0408; [M + K]⁺calcd for C₁₇H₁₂N₂O₄SK 379.0149; found

379.0149.

Methyl (2-(Cyanomethylene)-5-oxothiazolidin-4-ylidene)acetate

(9a): Prepared according to GP-C; white powder (1.428 g, 68% yield);

mp = 223−225 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 12.9 (br s, 1H),

6.72 and 6.66* (s, 1H); 5.44* and 5.39 (s, 1H), 3.81 and 3.78* (s, 3H);

5:1 mixture of isomers; ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 166.1*

and 166.0, 165.7* and 165.2, 154.8 and 153.5*, 142.6* and 141.8, 116.6

and 115.4*, 114.5 and 113.6*, 72.2 and 70.2*, 52.7 and 52.5*; FT-IR

(neat) ν_max(cm⁻¹) 3155, 2965, 2820, 2224, 1730, 1682; MS-EI, m/z

210 (M⁺, 83%). Anal. Calcd for C₈H₆N₂O₃S: C, 45.71; H, 2.88 2.86; N,

13.33. Found: C, 45.69; H, 2.80; N, 13.30.

Ethyl-2-(8-cyano-3-oxo-5-phenyl-5H-thiazolo[3,2-a]pyridin-

2(3H)-ylidene)acetate (8e): Prepared according to GP-B; after column

chromatography (methylene chloride), an orange powder (0.152 mg,

45% yield) was obtained; mp = 191−193 °C; ¹H NMR (DMSO-d₆, 400

MHz) δ 7.35 (m, 5H), 6.75 (s, 1H), 6.23 (d, 1H, J = 9.8 Hz), 6.03 (d,

1H, J = 4.3 Hz), 5.90 (dd, 1H, J = 9.8, 4.5 Hz), 4.27 (q, 2H, J = 7.0 Hz),

1.26 (t, 3H, J = 7.1 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 165.5,

163.1, 147.4, 139.1, 138.2, 128.9, 128.4, 126.7, 123.2, 116.4, 115.8,

115.7, 84.2, 61.7, 58.1, 13.9; FT-IR (neat) ν_max(cm⁻¹) 3066, 2983,

2962, 2887, 2213, 1707, 1683; HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₁₈H₁₄N₂O₃SH 339.0798; found 339.0798; [M + Na]⁺calcd for

C₁₈H₁₄N₂O₃SNa 361.0617; found 361.0617; [M + K]⁺calcd for

C₁₈H₁₄N₂O₃SK 377.0357; found 377.0367.

Ethyl-2-(8-cyano-5-(4-methoxyphenyl)-3-oxo-5H-thiazolo[3,2-

a]pyridin-2(3H)-ylidene)acetate (8f): Prepared according to GP-B;

after column chromatography (methylene chloride), an orange powder

1

(0.287 mg, 78% yield) was obtained; mp = 152−154 °C; H NMR

(DMSO-d₆, 400 MHz) δ 7.27 and 6.92 (AA′XX′, 4H, J = 8.6 Hz), 6.73

(s, 1H), 6.23 (d, 1H, J = 9.8 Hz), 5.96 (d, 1H, J = 4.4 Hz), 5.86 (dd, 1H,

J = 9.8, 4.6 Hz), 4.26 (q, 2H, J = 7.0 Hz), 3.73 (s, 3H), 1.26 (t, 3H, J =

7.1 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 165.6, 163.1, 159.3,

147.2, 138.4, 130.9, 128.5, 123.2, 116.2, 116.1, 115.5, 114.2, 84.0, 61.7,

57.5, 55.1, 13.9; FT-IR (neat) ν_max(cm⁻¹) 3063, 2992, 2960, 2904,

2838, 2211, 1705, 1683; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₉H₁₈N₂O₄SH 369.0904; found 369.0905; HRMS (ESI-TOF) m/z

[M + H]⁺calcd for C₁₉H₁₆N₂O₄SH 369.0904; found 369.0905; [M +

Ethyl (2-(Cyanomethylene)-5-oxothiazolidin-4-ylidene)acetate

(9b): Prepared according to GP-C; white powder (1.882 g, 84%

yield); mp = 201−203 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 12.9 (br

L

https://dx.doi.org/10.1021/acs.joc.0c01934

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

s, 1H), 6.70 and 6.64* (s, 1H), 5.44* and 5.39 (s, 1H), 4.27 (q, 2H, J =

7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz); 5:1 mixture of isomers; ¹³C{¹H} NMR

(DMSO-d₆, 100 MHz) δ 165.7* and 165.5, 165.6* and 165.2, 154.9

and 153.6*, 142.5* and 141.6, 116.6 and 115.4*, 114.8 and 114.0*, 72.1

and 70.1*, 61.6 and 61.4*, 13.9; FT-IR (neat) ν_max(cm⁻¹) 3156, 2981,

2931, 2828, 2208, 1729, 1683; MS-EI, m/z 224 (M⁺, 98%). Anal. Calcd

for C₉H₈N₂O₃S: C, 48.21; H, 3.60; N, 12.49. Found: C, 48.30; H, 3.50;

N, 12.48.

(2-(Cyanomethylene)-5-oxothiazolidin-4-ylidene)acetic Acid

(9c): Prepared according to GP-C; white powder (1.392 g, 71%

yield); mp = 276−278 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 13.19 (br

s, 2H), 6.65 and 6.60* (s, 1H), 5.37* and 5.34 (s, 1H); 5:1 mixture of

isomers; ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 167.4* and 167.3,

166.4* and 165.9, 156.0 and 154.6*, 142.4* and 141.6, 117.3 and

116.0*, 116.6 and 115.7*, 72.2 and 70.2*; FT-IR (neat) ν_max(cm⁻¹)

3244, 2225, 1726, 1676; MS-EI, m/z 196 (M⁺, 92%). Anal. Calcd for

C₇H₄N₂O₃S: C, 42.86; H, 2.06; N, 14.28. Found: C, 42.72; H, 2.04; N,

14.18.

Methyl-2-(8-cyano-6-methyl-3-oxo-5-phenyl-5H-thiazolo[3,2-a]-

pyridin-2(3H)-ylidene)acetate (8k): Prepared according to GP-D;

after column chromatography (hexane/ethyl acetate = 3/2), a red

powder (0.199 mg, 59% yield) was obtained; mp = 205−207 °C; ¹H

NMR (DMSO-d₆, 400 MHz) δ 7.37 (m, 5H), 6.74 (s, 1H), 6.09 (s,

1H), 5.83 (s, 1H), 3.79 (s, 3H), 1.65 (s, 3H); ¹³C{¹H} NMR (DMSO-

d₆, 100 MHz) δ 166.2, 162.9, 144.6, 138.7, 138.3, 131.9, 128.9, 128.7,

127.4, 116.2, 114.8, 113.1, 84.5, 61.5, 52.7, 19.2; FT-IR (neat) ν_max

(cm⁻¹) 3062, 3027, 2987, 2950, 2938, 2905, 2882, 2876, 2210, 1712,

1696; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₈H₁₄N₂O₃SH

339.0798; found 339.0802; [M + Na]⁺calcd for C₁₈H₁₄N₂O₃SNa

361.0617; found 361.0620; [M + K]⁺calcd for C₁₈H₁₄N₂O₃SK

377.0357; found 377.0363.

(DMSO-d₆, 400 MHz) δ 6.77 (s, 1H), 5.92 (s, 1H), 4.90 (q, 1H, J = 6.2

Hz), 4.28 (q, 2H, J = 7.1 Hz), 1.87 (s, 3H), 1.32 (d, 3H, J = 6.5 Hz), 1.28

(t, 3H, J = 7.1 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 168.8,

163.2, 144.6, 139.4, 133.2, 116.1, 114.4, 113.1, 84.8, 61.7, 54.0, 19.1,

17.6, 14.0; FT-IR (neat) ν_max(cm⁻¹) 3076, 2985, 2957, 2922, 2852,

2206, 1701, 1690; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₄H₁₄N₂O₃SH 291.0798; found 291.0803; [M + Na]⁺calcd for

C₁₄H₁₄N₂O₃SNa 313.0617; found 313.0622.

(4-Oxo-3,4-dihydro-2H-1,3-thiazin-2-ylidene)acetonitrile (10):

Methyl propiolate (10.0 mmol, 0.889 mL) was added to a solution of

cyanothioacetamide 2 (10.0 mmol, 1.000 g) in acetic acid (10.0 mL).

The mixture was stirred at 118 °C under oil-bath heating for 3 h until

the TLC analysis indicated total consumption of the starting

cyanothioacetamide 2. The resulting mixture was diluted with water

and cooled in an ice bath for 1 h. The precipitate was collected by

ﬁltration, washed with water (20 mL), and dried to obtain a brown

powder (0.866 g, 57% yield); mp = 187−189 °C; ¹H NMR (DMSO-d₆,

400 MHz) δ 11.63 (s, 1H), 7.69 and 6.22 (AX, 2H, J = 10.4 Hz), 4.89 (s,

1H); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 159.8, 154.2, 136.7,

117.1, 116.8, 68.7; FT-IR (neat) ν_max(cm⁻¹) 3516, 2198, 1685; MS-EI,

m/z 152 (M⁺, 65%). Anal. Calcd for C₆H₄N₂OS: C, 47.36; H, 2.65; N,

18.41. Found: C, 47.41; H, 2.67; N, 18.20.

4-Oxo-6-phenyl-4H,6H-pyrido[2,1-b][1,3]thiazine-9-carbonitrile

(12a): Prepared according to GP-E; yellow powder (0.162 mg, 62%

yield); mp = 165−166 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.75 and

6.39 (AX, 2H, J = 10.4 Hz), 7.35 (m, 5H), 6.52 (d, 1H, J = 6.0 Hz), 6.19

(d, 1H, J = 9.6 Hz), 5.30 (dd, 1H, J = 9.6 Hz, J = 5.9 Hz); ¹³C{¹H} NMR

(DMSO-d₆, 100 MHz) δ 159.2, 146.1, 140.1, 135.8, 128.9, 128.3, 126.2,

121.1, 118.4, 118.1, 116.7, 53.0; FT-IR (neat) ν_max(cm⁻¹) 3056, 2926,

2200, 1675; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₅H₁₀N₂OSH

267.0587; found 267.0590; [M + Na]⁺calcd for C₁₅H₁₀N₂OSNa

289.0406; found 289.0408; [M + K]⁺calcd for C₁₅H₁₀N₂OSK

305.0145; found 305.0147.

6-(4-Methoxyphenyl)-4-oxo-4H,6H-pyrido[2,1-b][1,3]thiazine-9-

carbonitrile (12b): Prepared according to GP-F; after column

chromatography (hexane/ethyl acetate = 3/2), a yellow powder (44

mg, 15% yield) was obtained; mp = 173−175 °C; ¹H NMR (DMSO-d₆,

400 MHz) δ 7.72 and 6.38 (AX, 2H, J = 10.4 Hz), 7.28 and 6.94

(AA′XX′, 4H, J = 8.7 Hz), 6.47 (d, 1H, J = 5.9 Hz), 6.22 (d, 1H, J = 9.6

Hz), 5.77 (dd, 1H, J = 9.6, 6.0 Hz), 3.74 (s, 3H); ¹³C{¹H} NMR

(DMSO-d₆, 100 MHz) δ 159.3, 159.2, 145.7, 135.6, 131.9, 128.1, 121.1,

118.3, 118.1, 116.8, 114.2, 86.8, 55.1, 52.3; FT-IR (neat) ν_max(cm⁻¹)

3066, 3008, 2963, 2944, 2931, 2907, 2891, 2871, 2856, 2804, 2199,

1668; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₆H₁₂N₂O₂SH

297.0692; found 297.0698; [M + Na]⁺calcd for C₁₆H₁₂N₂O₂SNa

319.0512; found 319.0514; [M + K]⁺calcd for C₁₆H₁₂N₂O₂SK

335.0251; found 335.0248.

7-Methyl-4-oxo-6-phenyl-4H,6H-pyrido[2,1-b][1,3]thiazine-9-

carbonitrile (12c): Prepared according to GP-F; after column

chromatography (hexane/ethyl acetate = 3/2), a yellow powder (129

mg, 46% yield) was obtained; mp = 174−176 °C; ¹H NMR (DMSO-d₆,

400 MHz) δ 7.68 and 6.33 (AX, 2H, J = 10.3 Hz), 7.39 (m, 5H), 6.27 (s,

1H), 6.04 (s, 1H), 1.71 (s, 3H); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz)

δ 159.2, 142.7, 138.8, 135.7, 130.3, 128.9, 128.8, 127.1, 117.9, 116.8,

114.4, 87.4, 57.2, 19.8; FT-IR (neat) ν_max(cm⁻¹) 3086, 3055, 3028,

3007, 2983, 2911, 2194, 1667; HRMS (ESI-TOF) m/z [M + H]⁺calcd

for C₁₆H₁₂N₂OSH 281.0743; found 281.0742.

6,7-Dimethyl-4-oxo-4H,6H-pyrido[2,1-b][1,3]thiazine-9-carboni-

trile (12d): Prepared according to GP-F; after column chromatography

(hexane/ethyl acetate = 3/2), a yellow powder (72 mg, 33% yield) was

obtained; mp = 161−163 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ 7.70

and 6.36 (AX, 2H, J = 10.4 Hz), 5.79 (d, 1H, J = 1.3 Hz), 5.26 (q, 1H, J =

6.5 Hz), 1.81 (s, 3H), 1.14 (d, 3H, J = 6.5 Hz); ¹³C{¹H} NMR (DMSO-

d₆, 100 MHz) δ 158.9, 142.2, 135.4, 131.8, 118.2, 116.9, 113.7, 87.4,

50.1, 19.4, 16.9; FT-IR (neat) ν_max(cm⁻¹) 3061, 2970, 2959, 2940,

2927, 2914, 2889, 2872, 2197, 1694; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₁₁H₁₀N₂OSH 219.0587; found 219.0584.

Methyl-2-(8-cyano-5,6-dimethyl-3-oxo-5H-thiazolo[3,2-a]-

pyridin-2(3H)-ylidene)acetate (8l): Prepared according to GP-D; after

column chromatography (hexane/ethyl acetate = 3/2), a red powder

1

(0.061 mg, 22% yield) was obtained; mp = 194−196 °C; H NMR

(DMSO-d₆, 400 MHz) δ 6.82 (s, 1H), 5.93 (s, 1H), 4.91 (q, 1H, J = 6.3

Hz), 3.82 (s, 3H), 1.87 (s, 3H), 1.32 (d, 3H, J = 6.4 Hz); ¹³C{¹H} NMR

(DMSO-d₆, 100 MHz) δ 166.3, 163.2, 144.6, 139.5, 133.2, 116.1, 114.2,

113.0, 84.8, 54.0, 52.7, 19.1, 17.6; FT-IR (neat) ν_max(cm⁻¹) 3056,

3006, 2987, 2951, 2918, 2200, 1704; HRMS (ESI-TOF) m/z [M + H]⁺

calcd for C₁₃H₁₂N₂O₃SH 277.0641; found 277.0642; [M + Na]⁺calcd

for C₁₃H₁₂N₂O₃SNa 299.0461; found 299.0460.

Methyl-2-(8-cyano-5-methyl-3-oxo-5H-thiazolo[3,2-a]pyridin-

2(3H)-ylidene)acetate (8m): Prepared according to GP-D; after

column chromatography (hexane/ethyl acetate = 3/2), an orange

powder (39 mg, 15% yield) was obtained; mp = 182−184 °C; ¹H NMR

(DMSO-d₆, 400 MHz) δ 6.83 (s, 1H), 6.12 (dd, 1H, J = 9.9 Hz, J = 1.3

Hz), 5.84 (dd, 1H, J = 9.9 Hz, J = 4.5 Hz), 5.03 (m, 1H), 3.82 (s, 3H),

1.32 (d, 3H, J = 6.5 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ

166.7, 163.9, 148.1, 139.7, 124.9, 117.2, 116.6, 115.1, 84.5, 53.3, 51.6,

20.2; FT-IR (neat) ν_max(cm⁻¹) 3049, 2928, 2851, 2206, 1711; HRMS

(ESI-TOF) m/z [M + H]⁺calcd for C₁₂H₁₀N₂O₃SH 263.0485; found

263.0487.

Ethyl-2-(8-cyano-6-methyl-3-oxo-5-phenyl-5H-thiazolo[3,2-a]-

pyridin-2(3H)-ylidene)acetate (8n): Prepared according to GP-D;

after column chromatography (hexane/ethyl acetate = 3/2), an orange

powder (0.120 mg, 34% yield) was obtained; mp = 189−191 °C; ¹H

NMR (DMSO-d₆, 400 MHz) δ 7.37 (m, 5H), 6.69 (s, 1H), 6.07 (s,

1H), 5.82 (s, 1H), 4.25 (q, 2H, J = 7.1 Hz), 1.66 (s, 3H), 1.25 (t, 3H, J =

7.1 Hz); ¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 165.6, 162.9, 144.6,

138.6, 138.2, 131.8, 128.8, 128.7, 127.4, 116.0, 115.2, 113.2, 84.6, 61.7,

61.5, 19.2, 13.9; FT-IR (neat) ν_max(cm⁻¹) 3079, 2983, 2208, 1703,

1686; HRMS (ESI-TOF) m/z [M + H]⁺calcd for C₁₉H₁₆N₂O₃SH

353.0954; found 353.0962; [M + Na]⁺calcd for C₁₉H₁₆N₂O₃SNa

375.0774; found 375.0773; [M + K]⁺calcd for C₁₉H₁₆N₂O₃SK

391.0513; found 391.0518.

Ethyl-2-(8-cyano-5,6-dimethyl-3-oxo-5H-thiazolo[3,2-a]pyridin-

2(3H)-ylidene)acetate (8o): Prepared according to GP-D; after column

chromatography (hexane/ethyl acetate = 3/2), an orange powder

6-Methyl-4-oxo-4H,6H-pyrido[2,1-b][1,3]thiazine-9-carbonitrile

(12e). Prepared according to GP-F; after column chromatography

(hexane/ethyl acetate = 3/2), an orange powder (31 mg, 15% yield)

1

(0.075 mg, 26% yield) was obtained; mp = 141−143 °C; H NMR

M

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was obtained; mp = 111−113 °C; ¹H NMR (DMSO-d₆, 400 MHz) δ

7.73 and 6.39 (AX, 2H, J = 10.4 Hz), 6.02 (d, 1H, J = 9.6 Hz), 5.63 (dd,

1H, J = 9.6 Hz, J = 5.8 Hz), 5.44 (m, 1H), 1.13 (d, 3H, J = 6.5 Hz);

¹³C{¹H} NMR (DMSO-d₆, 100 MHz) δ 159.4, 146.2, 135.9, 122.7,

118.8, 118.7, 117.5, 86.8, 47.2, 19.9; FT-IR (neat) ν_max(cm⁻¹) 3062,

2923, 2861, 2197, 1666; HRMS (ESI-TOF) m/z [M + H]⁺calcd for

C₁₀H₈N₂OSH 205.0430; found 205.0434.

Equipment SRC IIP UrB RAS. We also gratefully acknowledge

the Siberian Branch of the Russian Academy of Sciences (SB

RAS) Siberian Supercomputer Centre for providing super-

computer facilities.

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ASSOCIATED CONTENT

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■

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AUTHOR INFORMATION

Corresponding Authors

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(8) Jagodzinski, T. S. Thioamides as Useful Synthons in the Synthesis

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Nataliya P. Belskaya − Ural Federal University, Yekaterinburg

620002, Russian Federation; Postovsky Institute of Organic

Synthesis, Ural Branch of Russian Academy of Science,

Yekaterinburg 620219, Russian Federation; orcid.org/0000-

0002-2509-7916; Email: n.p.belskaya@urfu.ru

Enrico Benassi − Shihezi University, Shihezi, Xinjiang 832000,

China; orcid.org/0000-0002-4614-1568;

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ethoxycarbonylpyrene- and perylene thioamides as building blocks in

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Email: ebenassi3@gmail.com

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Authors

Aleksey A. Gagarin − Ural Federal University, Yekaterinburg

620002, Russian Federation

Polina O. Suntsova − Ural Federal University, Yekaterinburg

620002, Russian Federation

Artem S. Minin − Ural Federal University, Yekaterinburg

620002, Russian Federation; M. N. Mikheev Institute of Metal

Physics, Ural Branch of Russian Academy of Science,

Yekaterinburg 620219, Russian Federation; orcid.org/0000-

0003-3305-3195

Varvara A. Pozdina − Institute of Immunology and Physiology,

Ekaterinburg 620049, Russian Federation

Pavel A. Slepukhin − Postovsky Institute of Organic Synthesis,

Ural Branch of Russian Academy of Science, Yekaterinburg

620219, Russian Federation

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Belskaya, N. P. Synthesis of Thiazoles Bearing Aryl Enamine/Aza-

enamine Side Chains: Effect of the π -Conjugated Spacer Structure and

Hydrogen Bonding on Photophysical Properties. Eur. J. Org. Chem.

2017, 2017, 4175−4187.

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.0c01934

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Organic Synthesis. J. Heterocycl. Chem. 2017, 54, 825−843.

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Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank Russian Science Foundation for ﬁnancially supporting

this work through Project 20-13-00089. E.B. thanks the

Bingtuan Oasis Foreign Expert fund. This work was performed

using the equipment of the Shared Research Center of Scientiﬁc

N

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https://dx.doi.org/10.1021/acs.joc.0c01934

J. Org. Chem. XXXX, XXX, XXX−XXX

Article Doi

Two Approaches for the Synthesis of Fused Dihydropyridines via a 1,6-Electrocyclic Reaction: Fluorescent Properties and Prospects for Application

DOI: 10.1021/acs.joc.0c01934

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Full text of DOI:10.1021/acs.joc.0c01934

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