Application of Azide-Tetrazole Tautomerism and Arylsulfanyl Group Dance in the Synthesis of Thiosubstituted Tetrazoloquinazolines

SYNTHESIS

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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2020, 52, A–N

paper

A

en

A. Jeminejs et al.

Paper

Synthesis

Application of Azide-Tetrazole Tautomerism and Arylsulfanyl

Group Dance in the Synthesis of Thiosubstituted Tetrazolo-

quinazolines

Andris Jeminejs^a

sulfanyl group

dance

N

N₁

S-Aryl

4

Svetlana M. Goliškina^a

Irina Novosjolova*^a

Dmitrijs Stepanovs^b

Ērika Bizdēna^a

3

N

NaN₃

N

5

Aryl-SH

K₂CO₃

N

2

N

S-Aryl

N

Cl

4

SR¹

4

Māris Turks*^a

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0

1

-

5

2

7

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0

3

6

9

N

2

N

2

N

Cl

N

^aInstitute of Technology of Organic Chemistry, Faculty of

Materials Science and Applied Chemistry, Riga Technical

University, Paula Valdena Str. 3, Riga, 1048, Latvia

irina.novosjolova@rtu.lv

maris.turks@rtu.lv

^bLatvian Institute of Organic Synthesis, Aizkraukles Str. 21,

Riga, 1006, Latvia

N

N₃

5

SR¹

5

R¹SH

K₂CO₃

R²

NaN₃

N

Cu (I)

R²

R¹= Alkyl, Aryl

N

1

N

₃N

1

N

Corresponding Authors

Received: 14.07.2020

Accepted after revision: 06.10.2020

Published online: 12.11.2020

The importance of thioquinazoline derivatives has in-

creased lately. Potential antibacterial,^10,11antimicrobial,¹²

antiviral,¹³antitumor,^14–17bronchodilatory¹⁸activity, and

monoamine oxidase inhibitor activity,¹⁹which is important

for the treatment of Parkinson’s disease were found among

2-substituted 4(3H)-quinazoline-4-thiones, substituted

2-thioquinazolin-4-one analogues, and unsubstituted or

2-substituted 4-thioquinazolines. Compounds from the

4-thioquinazoline series are also known as agriculture anti-

microbials.^20,21

DOI: 10.1055/s-0040-1706568; Art ID: ss-2020-n0383-op

Abstract Nucleophilic aromatic substitution reaction between 4-aryl-

thio-2-chloroquinazolines and NaN₃takes place with an unusual sulfanyl

group dance and leads to the formation of 5-(arylthio)tetrazolo[1,5-c]-

quinazolines, which do not form the azide tautomer and do not under-

go CuAAC reactions with alkynes. On the other hand, 5-azidotetrazo-

lo[1,5-a]quinazoline (formally described as 2,4-diazidoquinazoline) un-

dergoes regioselective nucleophilic aromatic substitution with thiols at

C5 and forms 5-(alkyl/arylthio)tetrazolo[1,5-a]quinazolines, the struc-

ture of which has been proved by X-ray crystallography. The latter exist

in tautomeric equilibrium with their 2-azidoquinazoline form, which

provides possibility for copper-catalyzed azide–alkyne 1,3-dipolar cyclo-

addition reaction, leading to the 4-alkyl/arylthio-2-(1H-1,2,3-triazol-

1-yl)quinazolines.

IB. (R¹= H)

1. CS₂/Et₃N

IA. (R¹= NH₂) [ref. 22]

[ref. 23]

X

NH•HX''

R²

X

CN

H₂N

NH₃

S

2. Cu(OAc)₂/Et₃N

Key words quinazolines, nucleophilic aromatic substitution, azide-

tetrazole equilibrium, thiols, azides, triazoles

MW

F

R¹

N

X

N

R²

Heterocyclic core of quinazoline belongs to the privi-

leged molecular scaffolds in terms of medicinal chemistry.¹

For example, marketed anticancer drugs such as erlotinib,

gefitinib, lapatinib, and afatinib contain quinazoline core.

These substances block the signaling process within the

cancer cells by inhibiting the messenger activity of the ty-

rosine kinase and the quinazoline fragment is recognized as

the kinase hinge binder.²Other quinazoline based mole-

cules are known as apoptosis inducers and apoptosis inhib-

itors depending on the exocyclic decoration.^3,4Additionally,

among the approved sympatholytic drugs there is also

quinazoline derivative prazosin, which is an ₁-blocker.⁵On

the other hand, biological activities like antibacterial,⁶anti-

malarial,⁷anticonvulsant⁸and antiviral⁹are described for

quinazoline compounds.

S

II. (R¹= OH, N₃)

[ref. 19, 24, 25]

III. (R¹= H)

[ref. 26.]

R¹

X

R²-Hal

N

Ar-Hal

Pd cat

N

transition-

metal-free

N

SH

H

N

SH

IV. (R¹= Alkyl, Aryl, H) [ref. 27–31]

Cl

V. (R¹= H)

[ref. 32,33]

SH

R²

N

S

R²-SH

R²-Hal

base

N

S_NAr

N

R¹

N

R¹

Scheme 1 Different approaches for the synthesis of C4/C2 substituted

thioquinazolines

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

A. Jeminejs et al.

Paper

Synthesis

Various approaches are used for the synthesis of thio-

quinazoline derivatives. Strategies for introduction of al-

kyl/arylthio group at C2 position of quinazoline include: 1)

cyclization reactions of o-fluorobenzonitriles with S-substi-

tuted isothiouronium salts under microwave irradiation²²

or cyclization of 2-aminobenzylamines and carbon disul-

fide;²³2) transition-metal-free alkylation/arylation of 2-

thioquinazoline or its potassium salt with alkyl/aryl halides

under neutral or basic conditions;^19,24,25and 3) transition-

metal-catalyzed cross-coupling reactions of 2-thioquinazo-

lines and alkyl/aryl/heteroaryl halides²⁶(Scheme 1).

tautomerism and the formed fused tetrazole intermediate I

(Scheme 2) can activate the system for further S_NAr attack,

albeit at C2. Moreover, the nucleofugal ArylS^–group from

the first S_NAr process now becomes a nucleophile for the

second S_NAr reaction. Investigation of reaction mechanism

was encumbered by the fact that transformation 2 + NaN₃

→ 3 is very fast and NMR studies in DMSO-d₆did not reveal

the presence of any intermediate (see SI). To the best of our

knowledge, this is one of the very few sulfanyl group dances

in quinazolines, apart from some historic examples report-

ed in 1940s.⁴¹

Strategies for introduction of alkyl/arylthio group at C4

position of quinazoline include: 1) S_NAr reactions between

4-chloroquinazoline derivatives and alkyl/aryl/heteroaryl

thiols;^27–31and 2) alkylation of thio group at C4 position

with alkyl halides^32,33(Scheme 1).

In the past decades, great attention was focused also on

the synthesis and bioactivity of quinazoline derivatives,

which contain azolyl substituents (imidazolyl, 1,2,4-tri-

azolyl, 2-pyrazolyl groups) at C2 or C4 position or azoles

fused to quinazoline core.^34–36To the best of our knowledge,

there is no synthetic studies available on the preparative

methodologies towards 2-azido-4-alkyl/arylthioquinazo-

lines and 4-azido-2-alkyl/arylthioquinazolines and their

applications in the synthesis of the corresponding 1,2,3-tri-

azole derivatives.

Our group has developed several synthetic methodolo-

gies that make use of azidoquinazoline,³⁷azidopurine,³⁸

and azido-7-deazapurine³⁹derivatives as versatile starting

materials. We have extended various S_NAr approaches in-

volving azido group as a leaving group. Moreover, we have

recently developed a sulfonyl group dance around purine

cycle, which is a synthetic application of the intrinsic prop-

erty of the azido substituent to undergo azidoazomethine-

tetrazole tautomeric equilibrium.⁴⁰In this paper, we report

unusual sulfanyl group dance around the quinazoline core

that leads to novel synthetic developments for the prepara-

tion of 2/4-azido-4/2-alkyl/arylthioquinazolines and their

further synthetic applications, which are based on both

leaving group capability of azido group and azidoazo-

methine-tetrazole tautomeric equilibrium.

First, several 4-alkyl/arylthio-2-chloroquinazoline de-

rivatives 2 were obtained in 51–83% yields from commer-

cially available 2,4-dichloroquinazoline (1), using C4-selec-

tive S_NAr reaction with thiols. The azide group was then in-

troduced to the quinazoline core. In the case of alkylthiols

(e.g., n-C₁₀H₂₁SH, Scheme 2), the compound 2f underwent a

further S_NAr reaction at C2 leading to product 4f in excellent

yield. On the other hand, the azide reaction with 4-arylthio-

2-chloroquinazolines 2a–e resulted in an unusual sulfanyl

group dance around the quinazoline core and products 3a–

e were obtained in 73–85% yield (Scheme 2, Table 1).

Arylthio substituents are better leaving groups than their

aliphatic congeners, therefore, the S_NAr substitution with

the azide ion occurs at C4. This leads to the azide-tetrazole

N

sulfanyl group dance

with arylthio derivatives:

N

N₁

S-Aryl

N

Cl

3

Aryl-SH

N

NaN₃

DMF

K₂CO₃

4

N

2

N₃

5

MeOH

N

S-Aryl

N

Cl

4

N

2

3a–e, 73–85%

2a–e, 51–83%

N

Cl

intermediate I

4

N

2

ArylS

N

Cl

1

S_NAr reaction at C2 with alkylthio derivatives:

n-C₁₀H₂₁

S

n-C₁₀H₂₁

S

5

n-C₁₀H₂₁SH

K₂CO₃, DMF

4

NaN₃

DMF

N

2

N

Cl

N

₃N

1

2f, 77%

4f, 95%

N

Scheme 2 Synthesis of 5-(arylthio)tetrazolo[1,5-c]quinazolines 3 and

5-(decylthio)tetrazolo[1,5-a]quinazoline 4f

Table 1 Yields for Transformations 1 → 2 and 2 → 3 (Scheme 2)

Entry

Aryl

C₆H₅

Product 2

Yield (%)

Product 3 Yield (%)

1

2

3

4

5

2a

2b

2c

2d

2e

55

62

83

51

70

3a

3b

3c

3d

3e

73

85

81

77

84

4-BrC₆H₄

4-FC₆H₄

4-ClC₆H₄

4-CH₃C₆H₄

Additionally, the one-pot synthetic procedure was brief-

ly studied for compounds 3 (Scheme 3, Table 2). Upon com-

pletion, the crude reaction mixture was suspended in brine

and filtered, then easily recrystallized. To ensure the forma-

tion of product 3, kinetic rates of competing thiol and azide

substitution reactions must be taken into account. We have

found that the molar ratio between starting material 1,

NaN₃, and thiol should be kept close to 1:1:1. Any notable

excess of NaN₃(>1.1 equiv) lead to formation of significant

amounts of 2,4-diazidoquinazoline 5, and any excess of thiol

(>1.1 equiv) lead to formation of 2,4-bisthio derivative 6.

C

A. Jeminejs et al.

Paper

Synthesis

The initial combination of reagents in DMF (Table 2, entry

1) leads to predominant formation of undesired diazide 5,

although the subsequent addition gives target product 3d

in 58% yield (entry 2).

tive 3c, for which trace amounts of open chain tautomer

were observed at elevated temperatures in toluene (Figure

1). It appeared that the tetrazole tautomers are particularly

stable for compounds 3a–e and they were totally inactive in

CuAAC reactions with various alkynes.

Aryl

N

1. Aryl-SH

K₂CO₃

2. NaN₃

N

3

N

S

1

N

1

5

DMF

solvent

0–5 °C

1 h

Aryl

N

S

N

Cl

0–5 °C, 5 h

3a–e

2a–e

Aryl

N₃

S

Aryl-SH

K₂CO₃

NaN₃

N

Aryl

N

N₃

N

S

6

5

Scheme 3 One-pot synthesis of 5-(arylthio)tetrazolo[1,5-c]quinazo-

lines 3

If the reaction medium is switched to ethanol (Table 2,

entry 3), the formation of diazide 5 is suppressed. However,

due to low solubility of intermediate 2 in ethanol the next

reaction proceeded slowly and full conversion of 2 to 3

could not be reached. On the other hand, telescopic switch

of the solvents (entries 4–9) yielded the best result with

minimal interference among competing reactions. In the

case of 4-bromothiophenol (entry 5) azide must be added

only upon the full conversion of starting material 1 to ex-

clude formation of by-products. In all other cases, NaN₃was

added in the beginning. The sulfanyl group dance is not ob-

served for 4-alkylthioquinazolines (entries 10 and 11).

Products 3a–e exist in their tetrazole form. Equilibrium

towards azide form was not practically observed in this se-

ries, with only exception being 4-fluorophenylthio deriva-

Figure 1 Azide-tetrazole equilibrium of compound 3c in Tol-d₈

(

(%) = 98:2 at 25 °C; 97:3 at 40 °C; 94:6 at 60 °C; 92:8 at 80 °C.

¹⁹F NMR 470.5 MHz) depending on temperature. Tetrazole:azide

To investigate and prove the regioselectivity of the ac-

quired products, we have also explored a possibility to ob-

tain isomer compounds of type 4 by a reverse order of S_NAr

reactions. One of the key starting materials – 2,4-diazido-

quinazoline (5) – was obtained in S_NAr reaction between

commercially available 2,4-dichloroquinazoline (1) and so-

dium azide in 97% yield (Scheme 4). It should be pointed

out that the name ‘diazide’ is used as a simplification and

the compound in solutions exists in tetrazole tautomeric

forms 5AT and 5TT, respectively.^37,42

Table 2 One-Pot Transformation 1 → 3 (Scheme 3)

Entry

Aryl

Compound 3

Solvent

NMR yield of product Compound composition Yield of crystallized

3^a(%)

of crude product 2:3:5:6 product 3 (%)

1^b

2^c

4-ClC₆H₄

3d

DMF

33

73

51

86

22

69

74

71

70

0

0: 37:42:21

1:78:0:21

40:57:0:3

1:93:2:4

1:29:49:21

3:75:12:10

1:80:5:14

4:81:2:13

1:95:0:4

–

DMF

58

–

3^b

EtOH

4^b

EtOH → DMF

DMF

80

–

5^b

4-BrC₆H₄

3b

6^c

56

69

62

52

–

7^b

4-CH₃C₆H₄

4-FC₆H₄

C₆H₅

3e

3c

3a

–

8^b

9^b

10^c

11^b

CH₃(CH₂)₉

DMF

0

–

^aDetermined on crude reaction mixture with 1,2,3-trimethoxybenzene as an internal standard.

^bNaN₃(1.1 equiv) was added at the beginning together with the thiol (1.1 equiv).

^cNaN₃(1.1 equiv) was added upon full conversion of starting material 1.

D

A. Jeminejs et al.

Paper

Synthesis

N₃

S

N

S

N

N₃

N

NaN₃

DMF

N

5

N

1

N

4a, 72%

4b, 80%

4c, 99%

5

N

N₃

N

N₁

⁴N

N

3

N

S(CH₂)₃CH₃

N

S(CH₂)₉CH₃

N

S(CH₂)₁₁CH₃

N

5AT

5TT

S

N

SR¹

4

N

SR¹

5

N

R²

N

R¹SH, K₂CO₃

N

₄N

N

2

N

CuSO₄•5H₂O

sodium ascorbate

THF/H₂O or DMF

4d, 66%

4e, 80%

4f, 99%

4g, 99%

DMF(Alkyl-SH)

EtOH or iPrOH

(Aryl-SH)

N

1

N

3

N

R²

Cl

F

4a–m, 60–99%

7a–n, 50–90%

S

N

S

N

Scheme 4 Synthesis of 4-alkyl/arylthio-2-(1H-1,2,3-triazol-1-yl)-

quinazolines 7a–n. Reagents and conditions: a) 5 → 4 rt–50 °C, DMF,

EtOH or iPrOH, 1.5–48 h; b) 4 → 7 rt–70 °C, 3–24 h.

N

4h, 71%

4i, 60%

4j, 91%

Br

S

N

S

N

S

N

4k, 80%

4l, 86%

4m, 86%

Figure 3 Single crystal X-ray analysis of 5-(decylthio)tetrazolo[1,5-a]-

quinazoline (4f)⁴³

Figure 2 Substrate 4 scope for the synthesis of 4-alkyl/arylthio-

2-(1H-1,2,3-triazol-1-yl)quinazolines 7 according to Scheme 4

Tautomer 5AT explains the leaving group ability of the

azido group at C5 position of tetrazoloquinozaline (= C4 po-

sition of quinazoline) in the S_NAr reactions with thiols: 1) it

liberates position C5; 2) the formed tetrazole as electron-

withdrawing substituent activates the substrate for the nu-

cleophile attack. The substitution proceeds easily with alkyl

or aryl thiols in EtOH, iPrOH, or DMF, providing derivatives

4 in 60–99% yields (Scheme 4, Figure 2).

Structure of 5-(decylthio)tetrazolo[1,5-a]quinazoline

(4f) was unambiguously established by X-ray analysis (Fig-

ure 3), which showed that the product adopted tetrazo-

lo[1,5-a]quinazoline form in the solid state. In this context,

thioquinazoline derivatives exhibit a similar azide-tetrazole

tautomerism to their amino substituted congeners, as

shown by us earlier on the example of 5-(piperidin-1-

yl)tetrazolo[1,5-a]quinazoline.³⁷

Figure 4 ¹H NMR (500 MHz, DMSO-d₆) spectral comparison of com-

pounds 4i and 3d. Δ = 0.81 ppm between CH (d) signals: CH [4i (d)] =

8.58 ppm; CH [3i (d)] = 7.77 ppm.

E

A. Jeminejs et al.

Paper

Synthesis

Figure 5 Azide-tetrazole equilibrium of compound 4f in CDCl₃and toluene-d₈at different temperatures studied by ¹H NMR (500 MHz) spectroscopy

The inversed regioselectivity of products 3a–e was

proven chemically by comparison of NMR spectra from two

independent experiments. Thus, the NMR data of isomeric

compounds 4i and 3d showed distinct differences. It is in-

teresting to note that the difference between CH(d) protons

of compounds 4i and 3d is 0.81 ppm (Figure 4).

tion reactions⁴⁵with different aliphatic and aromatic

alkynes. Products 7a–n containing 1,4-disustituted tri-

azole⁴⁵moiety were obtained in good to excellent yields

(Table 4). In this context quinazolines 4a–m exhibit a similar

In the solution, products 4a–m exhibited azide-tetra-

zole equilibrium, which was studied in different solvents at

different temperatures by H NMR spectroscopy. Spectral

Table 3 Azide-Tetrazole Equilibrium of Compound 4f Depending on

Temperature in Toluene-d₈and CDCl₃

a

1

analysis was performed for compounds 4f, 4j, and 4l. For 5-

(decylthio)tetrazolo[1,5-a]quinazoline (4f) azide-tetrazole

equilibrium was studied in CDCl₃at 25–50 °C and in tolu-

ene-d₈at 25–100 °C (Table 3, Figure 5). At room tempera-

ture the azide form was weakly present in both solvents:

1.3% and 2.2% in CDCl₃and toluene-d₈, respectively. Heating

of the solutions somewhat increased the amount of azide

form: 3% (CDCl₃at 50 °C) and 11% (toluene-d₈at 100 °C).

The azide-tetrazole equilibrium of arylthio derivatives 4j

and 4l in CDCl₃, DMSO-d₆, and toluene-d₈exhibited a simi-

lar pattern (see SI). It goes in line with the general rule that

nonpolar solvents and higher temperatures shift the equi-

librium towards azide form.⁴⁴Substituent effect also shows

an influence and for (4-fluorophenyl)thioquinazoline 4j the

amount of azide tautomer is higher than for the congeners

with electron-donating substituents (e.g., 4l and 4m).

Equilibrium in toluene-d₈

Temp (°C)

Azide (%)

Tetrazole (%)

25

1.3

2.1

98.7

97.9

96.2

94.5

92.8

91.4

89.5

40

60

3.8

70

5.5

80

7.2

90

8.6

100

10.5

Equilibrium in CDCl₃

25

30

40

50

2.2

2.3

2.7

3.1

97.8

97.7

97.3

96.9

To our delight the presence of azido tautomer in the

solutions of compounds 4a–m was sufficient to perform

the copper-catalyzed azide–alkyne 1,3-dipolar cycloaddi-

^aAmount of both forms was determined using 1,2,3-trimethoxybenzene as

an internal standard.

F

A. Jeminejs et al.

Paper

Synthesis

Table 4 Synthesis of 4-Alkyl/arylthio-2-(1H-1,2,3-triazol-1-yl)quinazo-

lines 7 from 5-(Alkyl/arylthio)tetrazolo[1,5-a]quinazolines 4 (Scheme 4)

n-BuS

N

Entry

Starting material 4 R²

Product 7 Yield (%)

N

HN

+

1

2

4c

4e

4f

C₆H₅

7a

7b

7c

7d

7e

7f

70

90

65

74

71

70

79

87

80

50

73

74

82

90

DMF

N

4-CH₃(CH₂)₃C₆H₄

4-CH₃(CH₂)₅

CH₃(CH₂)₃

c-Pr

N

3

4d

8, 76%

4

further substitution with

RSH not possible

5

6

4-CH₃OC₆H₄

C₆H₅

H

7

4g

7g

7h

7i

n-BuS

N(CH₂)₅CH₃

8

4-CH₃C₆H₄

C₆H₅

CH₃(CH₂)₅NH₂

THF

N

9

4h

4i

N

10

11

12

13

14

C₆H₅

7j

N

4j

C₆H₅

7k

7l

4-F₃CC₆H₄

C₆H₅

7b

9, 30%

4k

7m

7n

4m

C₆H₅

n-Bu

Scheme 5 S_NAr reactions between 4-alkylthioquinazoline derivatives

4d and 7b with N-nucleophiles. Reagents and conditions: a) 4d → 8

90 °C, 3 h; b) 7b → 9 35 °C, 72 h.

reactivity to other fused 2-azidopyrimidines reported by us

earlier.^38,39

With several novel quinazoline derivatives in hand, we

have also briefly explored their chemical reactivity. It was

found that the alkylthio group at C5 position in 4d can be

substituted with secondary amines (e.g., piperidine) giving

product 8³⁷in 76% yield (Scheme 5). Due to the fact that

amine is not a good leaving group in the present constella-

tion, this reaction is irreversible and further substitution of

product 8 with thiols is not possible. Also compound 7b un-

derwent C4-selective S_NAr reaction with n-hexylamine and

alkylthio substituent acted as the leaving group. 1,2,3-Tri-

azolyl substituent, which on some occasions also have been

reported as a leaving group, remained intact in this particu-

lar transformation.

Cl

S

N

O

N

K₂CO₃

EtOH

N

4i

10, 61%

N

S

N

O

Cl

K₂CO₃

EtOH

N

On the other hand, arylthio substituents can be used as

good leaving groups in reactions with nucleophiles at both

C2 and C4 positions. For example, 5-(4-chlorophen-

ylthio)tetrazoloquinazoline regioisomers 4i and 3d each

undergoes selective substitution of sulfanyl group with

EtOH in the presence of K₂CO₃, leading to products 10⁴⁶and

11 in good yields (Scheme 6). Acquired regioisomers exhibit

the same pattern of quinazoline core NMR signals as previ-

ously described (Figure 4, see SI).

In conclusion, we have developed synthetic approaches

towards 5-(arylthio)tetrazolo[1,5-c]quinazolines 3a–e by

an unusual sulfanyl group dance around the quinazoline

core. The latter methodology demonstrates a synthetic ap-

plication of azide-tetrazole tautomerism in the quinazoline

activation towards a C2-selective S_NAr reaction. Due to the

fact that C2 position of quinazolines is traditionally less re-

active, here described C2-selective modification is particu-

larly interesting. We have also explored isomeric 4-alkyl/

3d

11, 77%

Scheme 6 S_NAr reactions between 5-(arylthio)tetrazoloquinazoline

isomers 4i and 3d with O-nucleophile. Reagents and conditions:

a) 4i → 10 40 °C, 5 h; b) 3d → 11 40 °C, 5 h.

arylthio-substituted tetrazoloquinazolines. The developed

methodology for the synthesis of 5-(alkyl/arylthio)tetrazolo-

[1,5-a]quinazolines 4a–m makes use of azido substituent as

a leaving group in the S_NAr reactions. Additionally, we have

disclosed the azide-tetrazole tautomerism of obtained new

compound classes. In those cases when the azido form is

present, we have shown a further application of these scaf-

folds in CuAAC reactions yielding 2-(1H-1,2,3-triazol-1-yl)-

4-(alkyl/arylthio)quinazolines 7a–n. Quinazoline deriva-

tives belong to the privileged structures in terms of medici-

nal chemistry, therefore the developed synthetic methods

will serve as an important addition to the synthetic tool-

box of medicinal chemists.

G

A. Jeminejs et al.

Paper

Synthesis

¹H NMR (300 MHz, CDCl₃):  = 8.14 (d, ³J = 8.4 Hz, 1 H, HC5), 7.93–

7.83 (m, 2 H, HC8, HC7), 7.67–7.56 (m, 3 H, 2 H_arom, HC6), 7.48 (d, ³J =

8.5 Hz, 2 H_arom).

¹³C NMR (75 MHz, CDCl₃):  = 173.6, 156.3, 150.1, 137.1, 135.1, 132.8,

128.2, 127.9, 125.3, 124.9, 123.9, 121.5.

Commercial reagents (Acros, Alfa Aesar, Sigma Aldrich) were used as

received. Reactions and purity of the synthesized compounds were

monitored by TLC using silica gel 60 F254 aluminum plates precoated

with a 0.25 mm layer of silica gel (Merck). Visualization was accom-

plished by UV light. Column chromatography was performed using

silica gel 60 (0.040–0.063 mm) (Merck). Yields refer to chromato-

graphically and spectroscopically homogeneous materials (with puri-

ty ≥95%).

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉BrClN₂S: 350.9353; found:

350.9346.

NMR spectra were recorded on Bruker Avance 300 and Bruker Avance

500 spectrometers. ¹H NMR spectra were recorded at 500 and 300

MHz, respectively, with internal references from residual nondeuter-

ated solvents ( = 7.26 for CDCl₃,  = 2.50 for DMSO-d₆, and  = 2.09 for

Tol-d₈). ¹³C NMR spectra were recorded at 125.7 and 75.5 MHz with

internal references from solvent carbon signals ( = 77.1 for CDCl₃and

 = 39.5 for DMSO-d₆). ¹⁹F NMR spectra were recorded at 470.5 MHz

with no internal reference. Coupling constants are reported in Hz and

chemical shifts of signals are given in ppm and standard abbrevia-

tions were used for multiplicity assignments. IR spectra were record-

ed on a PerkinElmer Spectrum BX spectrophotometer and are report-

2-Chloro-4-[(4-fluorophenyl)thio]quinazoline (2c)

Product was washed with hot EtOH (2 × 6 mL); yield: 0.60 g (83%);

colorless solid; R_f= 0.27 (Tol); mp 139–141 °C.

IR (KBr): 3095, 3063, 1630, 1610, 1589, 1559, 1527, 1479, 1443 cm^–1

¹H NMR (500 MHz, CDCl₃):  = 8.14 (d, ³J = 8.2 Hz, 1 H, HC5), 7.91–

7.84 (m, 2 H, HC8, HC7), 7.63–7.55 (m, 3 H, 2 H_arom, HC6), 7.18 (t, ³J =

8.7 Hz, 2 H_arom).

¹³C NMR (125.7 MHz, CDCl₃):  = 174.3, 164.0 (d, ¹J_C,F= 251 Hz), 156.3,

150.1, 137.9 (d, ³J_C,F= 9 Hz), 135.0, 128.2, 127.9, 123.9, 121.5, 121.4 (d,

⁴J_C,F= 3 Hz), 116.9 (d, ²J_C,F= 22 Hz).

.

ed in cm^–1

.

¹⁹F NMR (470.5 MHz, CDCl₃):  = –109.9.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉FClN₂S: 291.0154; found:

For HPLC analyses Agilent Technologies 1200 Series system was used

(X Bridge C18 column, 4.6 × 150 mm, particle size 3.5 m). Eluent A:

0.1% aq TFA/CH₃CN (95:5, v/v), eluent B: CH₃CN. Gradient: 30–95% B 5

min, 95% B 5 min, 95–30% B 2 min. Flow rate: 1 mL/min. Wavelength

of detection was set to 260 nm.

291.0138.

2-Chloro-4-[(4-chlorophenyl)thio]quinazoline (2d)

Yield: 0.39 g (51%); colorless solid; R_f= 0.28 (Tol); mp 154–156 °C.

HRMS analysis was performed on an Agilent 1290 Infinity series

UPLC system, connected to Agilent 6230 TOF LC/MS mass spectrome-

ter; column Extend C18 RRHD 2.1 × 50 mm, 1.8 m. Eluents: formic

acid in CH₃CN (0.1%) and aq 0.1% formic acid.

IR (KBr): 3095, 3060, 1614, 1558, 1529, 1483, 1475, 1444 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.16 (d, ³J = 8.3 Hz, 1 H, HC5), 7.92–

7.87 (m, 2 H, HC8, HC7), 7.63 (ddd, ³J = 8.3, 7.0 Hz, ⁴J = 2.4 Hz, 1 H,

HC6), 7.56 (d, ³J = 8.5 Hz, 2 H_arom), 7.47 (d, ³J = 8.5 Hz, 2 H_arom).

4-Arylthio-2-chloroquinazolines 2a–e; General Procedure

¹³C NMR (125.7 MHz, CDCl₃):  = 173.8, 156.3, 150.2, 136.9, 136.6,

2,4-Dichloroquinazoline (1; 0.5 g, 2.5 mmol, 1.0 equiv) and anhyd

K₂CO₃(0.39 g, 2.8 mmol, 1.1 equiv) were added to cooled (5–10 °C)

MeOH (10–15 mL) and the mixture was stirred under argon for 10

min. The suspension was cooled to 0 °C and the corresponding thiol

(2.8 mmol, 1.1 equiv) was added in small portions over 10–15 min.

The mixture was stirred at 0–5 °C for 5 h, controlled by HPLC. For

completion, the reaction the mixture was allowed to stand at 8–10 °C

overnight. The suspension was filtered, the precipitate was washed

with H₂O (2 × 10 mL) and EtOH (3 × 8 mL), and recrystallized from

EtOH or purified by column chromatography.

135.1, 129.8, 128.3, 127.9, 124.7, 123.9, 121.6.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉Cl₂N₂S: 306.9858; found:

306.9864.

2-Chloro-4-(p-tolylthio)quinazoline (2e)

Product was washed with hot EtOH (2 × 6 mL); yield: 1.0 g (70% from

1.0 g, 5.0 mmol of 1); slightly yellow solid; R_f= 0.19 (Tol); mp 138–

140 °C.

IR (KBr): 2873, 1619, 1587, 1563, 1533, 1497, 1486, 1472, 1449 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.19 (d, ³J = 8.2 Hz, 1 H, HC5), 7.92–

7.84 (m, 2 H, HC8, HC7), 7.61 (ddd, ³J = 8.2, 6.4 Hz, ⁴J = 1.8 Hz, 1 H,

HC6), 7.51 (d, ³J = 8.0 Hz, 2 H_arom), 7.30 (d, ³J = 8.0 Hz, 2 H_arom), 2.44 (s,

3 H, CH₃).

2-Chloro-4-(phenylthio)quinazoline (2a)

Yield: 0.76 g (55% from 1.0 g, 5.0 mmol of 1); colorless solid; R_f= 0.45

(Tol); mp 140–142 °C.

¹³C NMR (125.7 MHz, CDCl₃):  = 174.9, 156.5, 150.1, 140.4, 135.6,

134.9, 130.4, 128.2, 127.7, 124.1, 122.7, 121.7, 21.6.

IR (KBr): 3075, 3060, 3037, 2995, 2924, 2849, 1612, 1558, 1525, 1480,

1471, 1443 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.20 (d, ³J = 8.2 Hz, 1 H, HC5), 7.92–

7.86 (m, 2 H, HC8, HC7), 7.65–7.61 (m, 3 H, C₆H₅, HC6), 7.52–7.49 (m,

3 H, C₆H₅).

HRMS-ESI: m/z [M + H]⁺calcd for C₁₅H₁₂ClN₂S: 287.0404; found:

287.0400.

¹³C NMR (125.7 MHz, CDCl₃):  = 174.5, 156.4, 150.2, 135.7, 135.0,

2-Chloro-4-(decylthio)quinazoline (2f)

130.2, 129.6, 128.2, 127.8, 126.3, 124.0, 121.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₁₀ClN₂S: 273.0248; found:

273.0241.

K₂CO₃(0.76 g, 5.5 mmol) was added to a solution of 1-decanethiol

(0.96 g, 5.5 mmol) in DMF (15 mL) and the mixture was stirred for

15–20 min at rt under argon. A solution of 2,4-dichloroquinazoline

(1; 1.0 g, 5.0 mmol) in DMF (10 mL) was added and the reaction mix-

ture was stirred at 40–50 °C for 5 h, controlled by HPLC. After comple-

tion of the reaction, H₂O (40–50 mL) was added, the suspension was

cooled, and filtered. The precipitate was washed with H₂O (2 × 8 mL),

EtOH (3 × 8 mL), recrystallized from EtOH (120 mL), and dried in vac-

uo; yield: 1.30 g (77%); colorless solid; R_f= 0.41 (Tol); mp 51–53 °C.

4-[(4-Bromophenyl)thio]-2-chloroquinazoline (2b)

Yield: 0.55 g (62%); colorless solid; R_f= 0.31 (Tol); mp 166–168 °C.

IR (KBr): 3066, 3042, 1611, 1558, 1530, 1478, 1473, 1443 cm^–1

.

H

A. Jeminejs et al.

Paper

Synthesis

IR (KBr) 3054, 3029, 2964, 2917, 2848, 1614, 1560, 1524, 1482, 1467,

1442 cm^–1

5-[(4-Fluorophenyl)thio]tetrazolo[1,5-c]quinazoline (3c)

.

Product was washed with hot EtOH (2 × 4 mL); Method A, yield: 0.35

g (81% from 0.29 g, 1.0 mmol of 2c); Method B, yield: 0.46 g (62%);

colorless solid; R_f= 0.16 (Tol); mp 174–176 °C.

¹H NMR (500 MHz, CDCl₃):  = 8.05 (dd, ³J = 8.3 Hz, ⁴J = 1.5 Hz, 1 H,

HC5), 7.86 (dd, ³J = 8.2 Hz, ⁴J = 1.5 Hz, 1 H, HC8), 7.82 (ddd, ³J = 8.2, 6.9

4

3

4

Hz, J = 1.4 Hz, 1 H, HC7), 7.54 (ddd, J = 8.3, 6.9 Hz, J = 1.5 Hz, 1 H,

HC6), 3.37 (t, ³J = 7.3 Hz, 2 H, H₂C1′, 1.79 (quint, ³J = 7.3 Hz, 2 H,

H₂C2′), 1.48 (quint, ³J = 7.3 Hz, 2 H, H₂C3′), 1.35 (quint, ³J = 7.3 Hz, 2 H,

H₂C4′), 1.32–1.21 [m, 10 H, (CH₂)₅], 0.87 (t, ³J = 6.9 Hz, 3 H, H₃C10′).

IR (KBr): 3099, 3074, 2954, 2924, 2853, 1618, 1591, 1489, 1463, 1378

cm^–1

.

¹H NMR (500 MHz, DMSO-d₆):  = 8.52 (dd, ³J = 8.1 Hz, ⁴J = 1.1 Hz, 1 H,

HC10), 7.92 (ddd, ³J = 8.3, 7.1 Hz, ⁴J = 1.1 Hz, 1 H, HC8), 7.86 (dd, J =

3

¹³C NMR (125.7 MHz, CDCl₃):  = 175.2, 156.1, 149.5, 134.5, 128.0,

127.3, 124.0, 122.3, 31.9, 30.1, 29.55, 29.49, 29.3, 29.1, 28.9, 28.6,

22.7, 14.1.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₈H₂₆ClN₂S: 337.1500; found:

337.1503.

8.2 Hz, ⁴J_H,F= 5.3 Hz, 2 H_arom), 7.80 (dd, ³J = 8.1, 7.1 Hz, 1 H, HC9), 7.73

(d, ³J = 8.3 Hz, 1 H, HC7), 7.47 (dd, ³J_H,F= 8.9 Hz, ³J = 8.2 Hz, 2 H_arom).

¹³C NMR (125.7 MHz, CDCl₃):  = 164.4 (d, ¹J_C,F= 252 Hz), 149.0, 146.6,

143.7, 138.4 (d, ³J_C,F= 9 Hz), 133.7, 128.8, 128.0, 124.8, 120.3 (d, ⁴J_C,F

4 Hz), 117.1 (d, ²J_C,F= 22 Hz), 113.9.

=

¹⁹F NMR (470.5 MHz, DMSO-d₆):  = –109.82.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉FN₅S: 298.0557; found:

5-(Arylthio)tetrazolo[1,5-c]quinazolines 3a–e; General Procedure

Method A: NaN₃(195 mg, 3.0 mmol, 1.5 equiv) was added to a stirred

solution of the corresponding 4-arylthio-2-chloroquinazoline 2 (2.0

mmol, 1.0 equiv) in DMF (15 mL) at 0–5 °C under argon. The mixture

was stirred at 0–5 °C for 5 h, controlled by HPLC. Cold brine (30 mL)

was added and after 1–5 h at 8–10 °C, the suspension was filtered,

washed with H₂O (2 × 5 mL), EtOH (3 × 5 mL) and dried in vacuo.

298.0560.

5-[(4-Chlorophenyl)thio]tetrazolo[1,5-c]quinazoline (3d)

Product was washed with hot EtOH (2 × 4 mL); Method A, yield: 0.24

g (77% from 0.30 g, 1.0 mmol of 2d); Method B, yield: 119 mg (80%

from 100 mg, 0.5 mmol of 1); colorless solid; R_f= 0.11 (Tol); mp 185–

187 °C.

Method B: 2,4-Dichloroquinazoline (1; 50 mg, 0.25 mmol, 1.0 equiv)

was added to a suspension of anhyd K₂CO₃(38 mg, 0.28 mmol, 1.1

equiv) and the corresponding thiol (0.28 mmol, 1.1 equiv) in cold (0

°C) EtOH (4 mL). The mixture was stirred at 0–5 °C for 5 min, then

NaN₃(18 mg, 0.28 mmol, 1.1 equiv) was added and the suspension

was stirred at 0–5 °C for another hour. After full conversion to 2a–e,

the mixture was evaporated at rt under reduced pressure and cold (0

°C) abs DMF (4 mL) was added. The solution was stirred at 0–5 °C for 5

h, controlled with HPLC. Cold brine (30 mL) was added and after 1–5 h

at 8–10 °C the suspension was filtered, washed with H₂O (2 × 5 mL),

cold EtOH (3 × 5 mL), and recrystallized from EtOH.

IR (KBr): 2952, 2925, 2855, 1742, 1617, 1591, 1463, 1377 cm^–1

.

¹H NMR (500 MHz, DMSO-d₆):  = 8.53 (dd, ³J = 8.1 Hz, ⁴J = 1.2 Hz, 1 H,

HC10), 7.92 (ddd, ³J = 8.3, 7.1 Hz, ⁴J = 1.2 Hz, 1 H, HC8), 7.83 (d, ³J = 8.4

Hz, 2 H_arom), 7.81 (dd, ³J = 8.1, 7.1 Hz, 1 H, HC9), 7.77 (d, ³J = 8.3 Hz, 1

H, HC7), 7.69 (d, ³J = 8.4 Hz, 2 H_arom).

¹³C NMR (125.7 MHz, DMSO-d₆):  = 149.3, 146.1, 143.6, 137.7, 136.1,

134.2, 130.3, 129.3, 127.9, 124.7, 124.7, 114.3.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉ClN₅S: 314.0262; found:

314.0260.

5-(Phenylthio)tetrazolo[1,5-c]quinazoline (3a)

5-(p-Tolylthio)tetrazolo[1,5-c]quinazoline (3e)

Method A, yield: 95 mg (73% from 0.13 g, 0.48 mmol of 2a); Method

B, yield: 36 mg (52%); colorless solid; R_f= 0.30 (Tol); mp 179–181 °C.

IR (KBr): 1619, 1587, 1560, 1532, 1488, 1472, 1451, 1440, 1379 cm^–1

Method A, yield: 0.49 g (84%); Method B, yield: 102 mg (69% from 100

mg, 0.5 mmol of 1); colorless solid; R_f= 0.13 (Tol); mp 176–178 °C.

IR (KBr): 2873, 1619, 1587, 1563, 1533, 1497, 1486, 1472, 1449 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.58 (dd, ³J = 8.1 Hz, ⁴J = 1.3 Hz, 1 H,

3

¹H NMR (500 MHz, CDCl₃):  = 8.51 (d, J = 8.0 Hz, 1 H, HC10), 7.75–

HC10), 7.80 (ddd, ³J = 8.4, 7.0 Hz, ⁴J = 1.3 Hz, 1 H, HC8), 7.78–7.73 (m,

3

7.69 (m, 2 H, HC8, HC7), 7.61 (dd, J = 8.0, 7.1 Hz, 1 H, HC9), 7.55 (d,

3

4

3 H, 2 H C₆H₅, HC7), 7.69 (ddd, J = 8.1, 7.0 Hz, J = 1.1 Hz, 1 H, HC9),

³J = 7.9 Hz, 2 H_arom), 7.28 (d, ³J = 8.0 Hz, 2 H_arom), 2.41 (s, 3 H, CH₃).

7.61–7.52 (m, 3 H, C₆H₅).

¹³C NMR (125.7 MHz, CDCl₃):  = 149.0, 146.7, 143.7, 136.1, 133.6,

130.7, 129.8, 128.6, 128.1, 125.1, 124.7, 113.9.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₁₀N₅S: 280.0651; found:

¹³C NMR (125.7 MHz, CDCl₃):  = 149.0, 147.1, 143.8, 141.2, 136.0,

133.6, 130.6, 128.5, 128.1, 124.7, 121.4, 113.8, 21.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₅H₁₂N₅S: 294.0808; found:

294.0817.

280.0656.

5-(Alkyl/arylthio)tetrazolo[1,5-a]quinazolines 4a–m; General Pro-

cedure

5-[(4-Bromophenyl)thio]tetrazolo[1,5-c]quinazoline (3b)

Method A, yield: 90 mg (85% from 0.10 g, 0.3 mmol of 2b); Method B,

yield: 50 mg (56%); yellow solid; R_f= 0.19 (Tol); mp 186–188 °C.

IR (KBr): 2954, 2924, 2870, 2852, 1618, 1590, 1494, 1464, 1377 cm^–1

¹H NMR (500 MHz, CDCl₃):  = 8.59 (d, ³J = 7.8 Hz, 1 H, HC10), 7.83

(dd, ³J = 7.8, 6.9 Hz, 1 H, HC8), 7.79 (d, ³J = 7.8 Hz, 1 H, HC7), 7.74–7.66

(m, 3 H, 2 H_arom, HC9), 7.62 (d, ³J = 8.4 Hz, 2H_arom).

¹³C NMR (125.7 MHz, CDCl₃):  = 149.0, 146.0, 143.7, 137.6, 133.7,

133.0, 128.8, 128.1, 125.7, 124.8, 124.1, 113.9.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉BrN₅S: 357.9757; found:

Method A: The corresponding thiol (2.2 mmol, 1.1 equiv) was dis-

solved in EtOH or iPrOH (20 mL) under argon at rt. Then 2,4-diazido-

quinazoline (5; 0.42 g, 2.0 mmol, 1.0 equiv) was added. Finally, anhyd

K₂CO₃(0.30 g, 2.2 mmol, 1.1 equiv) was added and the reaction mix-

ture was stirred under argon at rt or 36–50 °C for 8–48 h, controlled

by HPLC. After completion of the reaction, the obtained suspension

was cooled and filtered, the precipitate was washed with H₂O (2 × 6

mL), EtOH or iPrOH (3 × 5 mL), recrystallized from EtOH (40–50 mL),

and dried in vacuo.

.

357.9748.

I

A. Jeminejs et al.

Paper

Synthesis

Method B: Anhyd K₂CO₃(0.75 g, 5.4 mmol, 2.3 equiv) was added to a

solution of the corresponding thiol (1.7 equiv) in DMF (10 mL). The

solution was stirred under argon at rt for 15 min. Then a solution of

2,4-diazidoquinazoline (5; 0.5 g, 2.36 mmol, 1.0 equiv) in DMF (5 mL)

was added. The reaction mixture was stirred at rt for 1.5–3 h, con-

trolled by HPLC. After completion of the reaction, brine (10 mL) was

added, the suspension was filtered (after 1–2 h), the precipitate was

washed with H₂O (2 × 6 mL) and EtOH (3 × 5 mL), and recrystallized

from EtOH (40–50 mL), and dried in vacuo.

IR (KBr): 3024, 2934, 1591, 1560, 1534, 1499, 1431, 1412, 1333 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 8.47 (d, ³J = 8.3 Hz, 1 H, HC9), 8.20 (d,

³J = 8.2 Hz, 1 H, HC6), 7.97 (dd, ³J = 8.3, 7.4 Hz, 1 H, HC8), 7.68 (dd, ³J =

8.2, 7.4 Hz, 1 H, HC7), 7.31–7.22 (m, 4 H, C₆H₅), 7.21–7.15 (m, 1 H,

C₆H₅), 3.69 (t, ³J = 7.5 Hz, 2 H, CH₂), 3.10 (t, ³J = 7.5 Hz, 2 H, CH₂).

¹³C NMR (75.5 MHz, CDCl₃):  = 171.9, 152.6, 139.5, 135.6, 131.4,

128.8, 128.7, 128.5, 126.9, 126.3, 118.5, 116.7, 34.9, 32.2.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₆H₁₄N₅S: 308.0964; found:

308.0969.

5-(Cyclopentylthio)tetrazolo[1,5-a]quinazoline (4a)

5-(Butylthio)tetrazolo[1,5-a]quinazoline (4e)

Method A: reaction time 48 h at 40 °C in EtOH; yield: 0.39 g (72%);

Method B: reaction time 1.5 h; yield: 0.29 g (80% from 0.30 g, 1.42

mmol of diazide 5); yellow solid; R_f= 0.12 (hexane/EtOAc 15:1); mp

99–101 °C.

colorless solid; R_f= 0.74 (Tol/EtOAc 1:1); mp 153–155 °C.

IR (KBr): 3056, 2963, 2866, 2361, 2344, 1609, 1589, 1537, 1412, 1333

cm^–1

.

IR (KBr): 2940, 2925, 1590, 1535, 1410 cm^–1

.

¹H NMR (300 MHz, CDCl₃):  = 8.52 (d, ³J = 8.2 Hz, 1 H, HC9), 8.25 (d,

³J = 8.2 Hz, 1 H, HC6), 8.02 (dd, ³J = 8.2, 7.5 Hz, 1 H, HC8), 7.73 (dd, ³J =

8.2, 7.5 Hz, 1 H, HC7), 4.45 (quint, ³J = 7.6 Hz, 1 H, HCS), 2.47–2.31 (m,

2 H, 2 H_a), 1.84–1.67 (m, 6 H, 2 H_b, 2 × CH₂).

¹³C NMR (125.7 MHz, CDCl₃):  = 173.0, 152.7, 135.4, 131.4, 128.4,

126.3, 118.5, 116.7, 44.2, 33.2, 25.0.

¹H NMR (500 MHz, DMSO-d₆):  = 8.51 (dd, ³J = 8.3 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.35 (dd, ³J = 8.2 Hz, ⁴J = 1.2 Hz, 1 H, HC6), 8.18 (ddd, ³J = 8.3, 7.4

4

Hz, J = 1.2 Hz, 1 H, HC8), 7.86 (ddd, ³J = 8.3, 7.4 Hz, J = 1.1 Hz, 1 H,

HC7), 3.45 (t, ³J = 7.3 Hz, 2 H, H₂C1′), 1.78 (quint, ³J = 7.2 Hz, 2 H,

H₂C2′), 1.50 (sext, ³J = 7.3 Hz, 2 H, H₂C3′), 0.96 (t, ³J = 7.3 Hz, 3 H,

H₃C4′).

HRMS-ESI: m/z [M + H]⁺calcd for C₁₃H₁₄N₅S: 272.0964; found:

272.0961.

¹³C NMR (125.7 MHz, DMSO-d₆):  = 171.3, 152.2, 136.0, 131.0, 128.7,

125.8, 118.0, 116.2, 30.1, 29.5, 21.5, 13.5.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₂H₁₄N₅S: 260.0964; found:

260.0953.

5-(Cyclohexylthio)tetrazolo[1,5-a]quinazoline (4b)

Method A: reaction time 48 h at 40 °C in EtOH; yield: 0.40 g (80%);

colorless solid; R_f= 0.74 (Tol/EtOAc 1:1); mp 184–185 °C.

IR (KBr): 3057, 2931, 2851, 1613, 1589, 1535, 1447, 1411, 1332 cm^–1

5-(Decylthio)tetrazolo[1,5-a]quinazoline (4f)

.

Method A: Reaction time 2 days at rt; yield: 0.60 g [88% from 0.42 g,

2.0 mmol of 2,4-diazidoquinazoline (5) in EtOH (20 mL)].

¹H NMR (500 MHz, CDCl₃):  = 8.52 (dd, ³J = 8.4 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.28 (dd, ³J = 8.3 Hz, ⁴J = 1.2 Hz, 1 H, HC), 8.01 (ddd, ³J = 8.4, 7.4

Method B: Reaction time 3 h; yield: 0.87 g (99%).

4

3

4

Hz, J = 1.2 Hz, 1 H, HC8), 7.72 (ddd, J = 8.3, 7.4 Hz, J = 1.1 Hz, 1 H,

HC7), 4.42–4.31 (m, 1 H, H_A), 2.26–2.13 (m, 2 H_B), 1.86–1.76 (m, 2 H, 2

H_C), 1.72–1.53 (m, 5 H, H_D, 2 H_E, 2 H_F), 1.42–1.31 (m, 1 H, H_G) (see SI

for H_A, etc. assignments).

Method C: NaN₃(1.2 g, 18.5 mmol, 4.2 equiv) was added to a solution

of 4-decylthio-2-chloroquinazoline (2f; 1.49 g, 4.4 mmol, 1.0 equiv)

in DMF (6 mL) at rt. The reaction mixture was stirred for 10 min, then

TFA (10–20 L) was added and the mixture was stirred for 5 h at 30

°C, controlled by HPLC. After completion of the reaction, 2–3 volumes

of H₂O were added, the obtained suspension was cooled and filtered,

the precipitate washed with H₂O (2 × 10 mL) and EtOH (3 × 5 mL), re-

crystallized from EtOH (100 mL), and dried in vacuo; yield: 0.40 g

(95%); colorless solid; R_f= 0.74 (Tol/EtOAc 1:1); mp 98–100 °C.

¹³C NMR (125.7 MHz, CDCl₃):  = 172.1, 152.6, 135.4, 131.5, 128.4,

126.3, 118.6, 116.7, 44.2, 32.7, 26.0, 25.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₁₆N₅S: 286.1121; found:

286.1118.

5-(Benzylthio)tetrazolo[1,5-a]quinazoline (4c)

IR (KBr): 3080, 2920, 2850, 1590, 1535, 1460, 1405 cm^–1

.

Method A: reaction time 8 h at rt in EtOH; yield: 0.58 g (99%); color-

less solid; R_f= 0.71 (Tol/EtOAc 1:1); mp 146–148 °C.

IR (KBr): 3090, 3037, 1614, 1590, 1531, 1494, 1449, 1409 cm^–1

¹H NMR (300 MHz, DMSO-d₆):  = 8.52 (d, ³J = 8.3 Hz, 1 H, HC9), 8.33

(d, ³J = 8.2 Hz, 1 H, HC6), 8.17 (dd, ³J = 8.3, 7.8 Hz, 1 H, HC8), 7.84 (dd,

³J = 8.2, 7.8 Hz, 1 H, HC7), 7.55 (d, ³J = 7.2 Hz, 2 H, C₆H₅), 7.36 (t, ³J = 7.2

Hz, 2 H, C₆H₅), 7.29 (t, ³J = 7.2 Hz, 1 H, C₆H₅), 4.74 (s, 2 H, CH₂).

¹H NMR (300 MHz, DMSO-d₆):  = 8.51 (d, ³J = 8.3 Hz, 1 H, HC9), 8.34

(d, ³J = 8.2 Hz, 1 H, HC6), 8.18 (dd, ³J = 8.3,7.8 Hz, 1 H, HC8), 7.86 (dd,

³J = 8.2, 7.8 Hz, 1 H, HC7), 3.43 (t, ³J = 7.2 Hz, 2 H, H₂C1′), 1.79 (quint,

³J = 7.2 Hz, 2 H, H₂C2′), 1.47 (quint, ³J = 7.2 Hz, 2 H, H₂C3′), 1.38–1.18

(m, 12 H, 6 × CH₂), 0.83 (t, 3 H, ³J = 6.5 Hz, H₃C10′).

¹³C NMR (75.5 MHz, DMSO-d₆):  = 171.4, 152.2, 136.0, 131.0, 128.7,

125.8, 118.1, 116.2, 39.5, 31.2, 29.8, 28.9, 28.9, 28.6, 28.5, 28.3, 27.9,

13.9.

.

¹³C NMR (75.5 MHz, DMSO-d₆):  = 170.7, 152.1, 136.1, 136.1, 131.1,

HRMS-ESI: m/z [M + H]⁺calcd for C₁₈H₂₆N₅S: 344.1910; found:

344.1909.

129.3, 128.8, 128.6, 127.6, 125.8, 117.8, 116.2, 33.8.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₅H₁₂N₅S: 294.0808; found:

294.0809.

5-(Dodecylthio)tetrazolo[1,5-a]quinazoline (4g)

5-[(2-Phenyl)ethylthio]tetrazolo[1,5-a]quinazoline (4d)

Method B: reaction time 1.5 h; yield: 2.11 g (99% from 1.0 g, 1.42

mmol of diazide 5); colorless solid; R_f= 0.88 (Tol/EtOAc 1:1); mp 101–

103 °C.

Method A: reaction time 12 h at 40 °C in EtOH; yield: 0.20 g (66% from

0.21 g, 1.0 mmol of 5); colorless solid; R_f= 0.75 (Tol/EtOAc 1:1); mp

153–156 °C.

IR (KBr): 2925, 2845, 1615, 1590, 1530, 1465 cm^–1

.

J

A. Jeminejs et al.

Paper

Synthesis

¹H NMR (500 MHz, CDCl₃):  = 8.54 (dd, ³J = 8.4 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.30 (dd, ³J = 8.3 Hz, ⁴J = 1.2 Hz, 1 H, HC6), 8.03 (ddd, ³J = 8.4, 7.4

Hz, ⁴J = 1.2 Hz, 1 H, HC8), 7.74 (dd, ³J = 8.3, 7.4 Hz, ⁴J = 1.1 Hz, 1 H,

HC7), 3.49 (t, ³J = 7.4 Hz, 2 H, H₂C1′), 1.84 (quint, ³J = 7.4 Hz, 2 H,

H₂C2′), 1.51 (quint, ³J = 7.4 Hz, 2 H, H₂C3′), 1.35 (quint, ³J = 7.4 Hz, 2 H,

H₂C4′), 1.31–1.22 [m, 14 H, (CH₂)₇], 0.87 (t, ³J = 7.0 Hz, 3 H, H₃C12′).

¹³C NMR (125.7 MHz, CDCl₃):  = 172.4, 152.7, 135.5, 131.4, 128.5,

126.3, 118.6, 116.7, 32.0, 31.0, 29.8, 29.75, 29.70, 29.6, 29.5, 29.3,

29.1, 28.6, 22.8, 14.2.

5-[(4-Bromophenyl)thio]tetrazolo[1,5-a]quinazoline (4k)

Method A: reaction time 48 h at 40 °C in EtOH (30 mL); yield: 0.80 g

(80% from 0.63 g, 3.0 mmol of diazide 5); colorless solid; R_f= 0.74

(Tol/EtOAc 1:1); mp 249–253 °C.

IR (KBr): 3068, 3037, 2360, 2343, 1610, 1590, 1530, 1472, 1412 cm^–1

¹H NMR (300 MHz, DMSO-d₆):  = 8.58 (d, ³J = 8.2 Hz, 1 H, HC9), 8.51

(d, ³J = 8.2 Hz, 1 H, HC6), 8.25 (dd, ³J = 8.2, 7.8 Hz, 1 H, HC8), 7.95 (dd,

³J = 8.2, 7.8 Hz, 1 H, HC7), 7.82 (d, ³J = 8.4 Hz, 2 H_arom), 7.66 (d, ³J = 8.4

Hz, 2 H_arom).

.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₀H₃₀N₅S: 372.2216; found:

372.2222.

¹³C NMR (75.5 MHz, DMSO-d₆):  = 170.4, 152.1, 137.8, 136.5, 132.8,

131.4, 129.0, 125.9, 125.2, 124.5, 117.6, 116.4.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉BrN₅S: 359.9736; found:

359.9695.

5-(Phenylthio)tetrazolo[1,5-a]quinazoline (4h)

Method A: reaction time 16 h at 40 °C in EtOH (10 mL); yield: 0.20 g

(71% from 0.21 g, 1.0 mmol of diazide 5); colorless solid; R_f= 0.78

(Tol/EtOAc 1:1); mp 204–210 °C.

IR (KBr): 3049, 2376, 2346, 1615, 1590, 1533, 1477, 1407 cm^–1

¹H NMR (300 MHz, DMSO-d₆):  = 8.55 (d, ³J = 8.4 Hz, 1 H, HC9), 8.51

(d, ³J = 8.4 Hz, 1 H, HC6), 8.23 (dd, ³J = 8.4, 7.7 Hz, 1 H, HC8), 7.93 (dd,

³J = 8.4, 7.7 Hz, 1 H, HC7), 7.77–7.67 (m, 2 H, C₆H₅), 7.65–7.56 (m, 3 H,

C₆H₅).

¹³C NMR (75.5 MHz, DMSO-d₆):  = 170.9, 152.1, 136.4, 135.9, 131.3,

130.5, 129.9, 129.0, 125.9, 125.6, 117.6, 116.3.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₁₀N₅S: 280.0651; found:

280.0627.

5-(p-Tolylthio)tetrazolo[1,5-a]quinazoline (4l)

Method A: reaction time 5 h at rt in iPrOH; yield: 0.50 g (86%); color-

less solid; R_f= 0.86 (Tol/EtOAc 1:1); mp 226–228 °C.

.

IR (KBr): 3079, 3040, 2913, 1614, 1588, 1531, 1495, 1407 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.58 (dd, ³J = 8.3 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.44 (dd, ³J = 8.2 Hz, ⁴J = 1.2 Hz, 1 H, HC6), 8.08 (ddd, ³J = 8.3, 7.3

4

Hz, J = 1.2 Hz, 1 H, HC8), 7.81 (ddd, ³J = 8.2, 7.3 Hz, J = 1.1 Hz, 1 H,

HC7), 7.52 (d, ³J = 8.1 Hz, 2 H_arom), 7.32 (d, ³J = 8.1 Hz, 2 H_arom), 2.45 (s,

3 H, CH₃).

¹³C NMR (125.7 MHz, CDCl₃):  = 172.3, 152.6, 141.2, 136.0, 135.7,

131.7, 130.8, 128.6, 126.2, 121.6, 118.0, 116.8, 21.6.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₅H₁₂N₅S: 294.0808; found:

294.0803.

5-[(4-Chlorophenyl)thio]tetrazolo[1,5-a]quinazoline (4i)

Method A: reaction time 6 h at 50 °C in iPrOH; yield: 0.38 g (60%);

colorless solid; R_f= 0.81 (Tol/EtOAc 1:1); mp 199–202 °C.

IR (KBr): 3084, 2370, 2346, 1612, 1591, 1535, 1476, 1406 cm^–1

5-[(4-tert-Butylphenyl)thio]tetrazolo[1,5-a]quinazoline (4m)

.

Method A: reaction time 9 h at 40 °C in EtOH; yield: 0.57 g (86%); col-

orless solid; R_f= 0.88 (Tol/EtOAc 1:1); mp 183–185 °C.

¹H NMR (500 MHz, DMSO-d₆):  = 8.58 (dd, ³J = 8.3 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.52 (dd, ³J = 8.2 Hz, ⁴J = 1.2 Hz, 1 H, HC6), 8.25 (ddd, ³J = 8.3, 7.6

IR (KBr): 2959, 2867, 1611, 1589, 1530, 1459, 1434, 1409 cm^–1

.

4

3

4

Hz, J = 1.2 Hz, 1 H, HC8), 7.95 (ddd, J = 8.2, 7.6 Hz, J = 1.1 Hz, 1 H,

HC7), 7.74 (d, ³J = 8.6 Hz, 2 H_arom), 7.69 (d, ³J = 8.6 Hz, 2 H_arom).

¹H NMR (500 MHz, CDCl₃):  = 8.58 (dd, ³J = 8.4 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.45 (dd, ³J = 8.3 Hz, ⁴J = 1.2 Hz, 1 H, HC6), 8.08 (ddd, ³J = 8.4, 7.4

¹³C NMR (125.7 MHz, CDCl₃):  = 171.3, 152.5, 137.4, 137.3, 136.0,

131.8, 130.2, 128.8, 126.1, 123.6, 117.9, 116.9.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉ClN₅S: 314.0262; found:

314.0244.

4

Hz, J = 1.2 Hz, 1 H, HC8), 7.81 (ddd, ³J = 8.3, 7.4 Hz, J = 1.1 Hz, 1 H,

HC7), 7.57 (d, ³J = 8.6 Hz, 2 H_arom), 7.53 (d, ³J = 8.6 Hz, 2 H_arom), 1.39 (s,

9 H, t-C₄H₉).

¹³C NMR (125.7 MHz, CDCl₃):  = 172.2, 154.0, 152.6, 135.75, 135.67,

131.6, 128.6, 127.1, 126.2, 121.7, 118.0, 116.8, 35.1, 31.4.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₈H₁₈N₅S: 336.1277; found:

336.1273.

5-[(4-Fluorophenyl)thio]tetrazolo[1,5-a]quinazoline (4j)

Method A: reaction time 5 h at 40 °C in EtOH; yield: 0.54 g (91%);

slightly yellow solid; R_f= 0.81 (Tol/EtOAc 1:1); mp 204–206 °C.

IR (KBr): 3095, 3074, 1616, 1589, 1535, 1489, 1408 cm^–1

.

4-(Alkyl/arylthio)-2-(1H-1,2,3-triazol-1-yl)quinazolines 7a–n;

General Procedure

¹H NMR (500 MHz, CDCl₃):  = 8.58 (dd, ³J = 8.4 Hz, ⁴J = 1.1 Hz, 1 H,

HC9), 8.42 (dd, ³J = 8.3 Hz, ⁴J = 1.2 Hz, 1 H, HC6), 8.10 (ddd, ³J = 8.4, 7.4

Sodium ascorbate (0.08 mmol, 0.1 equiv), CuSO₄·5H₂O (0.04 mmol,

0.05 equiv), and substituted acetylene (1.6 mmol, 2.0 equiv) were

subsequently added to a stirred solution of 4 (0.80 mmol, 1.0 equiv)

in a mixture of THF (6 mL) and H₂O (1 mL). The reaction mixture was

stirred at 60 °C for 4–24 h, controlled by HPLC. The mixture was evap-

orated, dissolved in DCM or CHCl₃(20 mL), washed with aq NaHS (2 ×

5 mL) and H₂O (2 × 5 mL), dried (anhyd Na₂SO₄), and evaporated. The

remaining solid was suspended in CH₃CN or EtOH (10 mL), filtered,

washed several times with appropriate solvent, and purified by re-

crystallization or column chromatography.

4

3

4

Hz, J = 1.2 Hz, 1 H, HC8), 7.83 (ddd, J = 8.3, 7.4 Hz, J = 1.1 Hz, 1 H,

HC7), 7.62 (dddd, ³J = 8.9 Hz, J_H,F= 5.2 Hz, ⁴J = 3.0 Hz, ⁵J = 2.2 Hz, 2

H_arom), 7.22 (dddd, J = 8.9 Hz, J_H,F= 8.7 Hz, J = 3.0 Hz, J = 2.2 Hz, 2

4

3

4

5

H_arom).

¹³C NMR (125.7 MHz, CDCl₃):  = 171.7, 164.4 (d, ¹J_C,F= 252 Hz), 152.5,

138.3 (d, ³J_C,F= 9 Hz), 136.0, 131.7, 128.7, 126.1, 120.4 (d, ⁴J_C,F= 4 Hz),

117.9, 117.3 (d, ²J_C,F= 22 Hz), 116.9.

¹⁹F NMR (470.5 MHz, CDCl₃):  = –109.1.

HRMS-ESI: m/z [M + H]⁺calcd for C₁₄H₉FN₅S: 298.0557; found:

298.0554.

K

A. Jeminejs et al.

Paper

Synthesis

4-(Benzylthio)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)quinazoline (7a)

IR (KBr): 2920, 2855, 1575, 1550, 1465, 1470 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.38 [s, 1 H, HC(triazole)], 8.12 (d, ³J =

8.3 Hz, 1 H, HC5), 8.07 (d, ³J = 8.2 Hz, 1 H, HC8), 7.89 (dd, ³J = 8.2, 7.6

Hz, 1 H, HC7), 7.58 (dd, ³J = 8.3, 7.6 Hz, 1 H, HC6), 3.47 (t, ³J = 7.3 Hz, 2

H, H₂C1′), 2.86 (t, ³J = 7.6 Hz, 2 H, H₂C1′′), 1.87 (quint,³J = 7.3 Hz, 2 H,

H₂C2′), 1.76 (quint, ³J = 7.6 Hz, 2 H, H₂C2′′), 1.53 (quint, ³J = 7.3 Hz, 2 H,

H₂C3′), 1.44 (sext, ³J = 7.6 Hz, 2 H, H₂C3′′), 1.40–1.34 (m, 2 H, H₂C4′),

1.32–1.22 [m, 10 H, (CH₂)₅], 0.97 (t, ³J = 7.6 Hz, 3 H, H₃C4′′), 0.87 (t, ³J =

6.8 Hz, 3 H, H₃C10′).

¹³C NMR (125.7 MHz, CDCl₃):  = 175.6, 149.6, 148.84, 148.82, 135.0,

129.1, 127.5, 124.3, 123.2, 119.9, 32.0, 31.6, 30.5, 29.7 (2 C), 29.44,

29.40, 29.2, 28.9, 25.5, 22.8, 22.5, 14.2, 14.0.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₃₆N₅S: 426.2686; found:

426.2673.

Reaction time: 6 h at 56 °C; yield: 0.14 g (70%); yellow solid; R_f= 0.91

(Tol/EtOAc 1:1); mp 214–216 °C.

IR (KBr): 3161, 3061, 3028, 1611, 1569, 1547, 1496, 1462, 1416 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.82 [s, 1 H, HC(triazole)], 8.12 (d, ³J =

8.2 Hz, 1 H, HC5), 8.07 (d, ³J = 8.4 Hz, 1 H, HC8), 7.99 (d, ³J = 7.8 Hz,

2 H, C₆H₅), 7.91 (dd, ³J = 8.4, 7.1 Hz, 1 H, HC7), 7.62–7.57 (m, 3 H, HC6,

3

2 H, CH₂C₆H₅), 7.48 (t, J = 7.8 Hz, 2 H, C₆H₅), 7.40 (t, J = 7.8 Hz, 1 H,

C₆H₅), 7.36 (t, ³J = 7.5 Hz, 2 H, CH₂C₆H₅), 7.29 (t, ³J = 7.5 Hz, 1 H,

CH₂C₆H₅), 4.77 (s, 2 H, CH₂C₆H₅).

¹³C NMR (125.7 MHz, CDCl₃):  = 174.8, 149.5, 148.9, 148.0, 136.4,

135.2, 130.3, 129.4, 129.05, 129.00, 128.9, 128.7, 127.9, 127.7, 126.2,

124.3, 122.9, 118.7, 34.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₁₈N₅S: 396.1277; found:

396.1275.

4-(Decylthio)-2-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)quinazoline

(7e)

2-[4-(4-Butylphenyl)-1H-1,2,3-triazol-1-yl]-4-(butylthio)quinazo-

Reaction time: 7 h at 60 °C; yield: 0.14 g (71% from 0.16 g, 0.47 mmol

of 4f); yellow solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 76–78 °C.

line (7b)

Reaction time 24 h at rt; yield: 0.15 g (90% from 0.09 g, 0.35 mmol of

4e); yellow solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 89–91 °C.

IR (KBr): 2955, 2930, 1550, 1465, 1370 cm^–1

IR (KBr): 2930, 2850, 1570, 1550, 1465 cm^–1

.

¹H NMR (300 MHz, DMSO-d₆):  = 8.67 [s, 1 H, HC(triazole)], 8.18 (d,

.

³J = 8.2 Hz, 1 H, HC5), 8.09–7.97 (m, 2 H, HC8, HC7), 7.74 (dd, ³J = 8.2,

¹H NMR (300 MHz, DMSO-d₆):  = 9.34 [s, 1 H, HC(triazole)], 8.21 (d,

³J = 8.2 Hz, 1 H, HC5), 8.11–8.02 (m, 2 H, HC8, HC7), 7.96 (d, ³J = 8.0

Hz, 2 H_arom), 7.76 (ddd, ³J = 8.2, 6.0 Hz, ⁴J = 2.1 Hz, 1 H, HC6), 7.33 (d,

³J = 8.0 Hz, 2 H_arom), 3.57 (t, ³J = 7.3 Hz, 2 H H₂C1′), 2.63 (t, ³J = 7.6 Hz, 2

H, H₂C1′′), 1.82 (quint, ³J = 7.3 Hz, 2 H, H₂C2′), 1.60 (quint, ³J = 7.6 Hz, 2

H, H₂C2′′), 1.53 (sext, ³J = 7.3 Hz, 2 H, H₂C3′), 1.33 (sext, ³J = 7.6 Hz, 2

H, H₂C3′′), 0.96 (t, ³J = 7.3 Hz, 3 H, H₃C4′), 0.96 (t, ³J = 7.6 Hz, 3 H,

H₃C4′′).

3

6.7 Hz, 1 H, HC6), 3.49 (t, J = 7.2 Hz, 2 H, H₂C1′), 2.15–2.05 [m, 1 H,

HC(cyclopropyl)], 1.79 (quint, ³J = 7.2 Hz, 2 H, H₂C2′), 1.46 (quint, ³J =

7.2 Hz, 2 H, H₂C3′), 1.38–1.15 [m, 12 H, (CH₂)₆], 1.04–0.96 (m, 2 H_a),

0.92–0.85 (m, 2 H_b), 0.82 (t, ³J = 6.6 Hz, 3 H, H₃C10′).

¹³C NMR (75.5 MHz, DMSO-d₆):  = 174.5, 149.5, 148.8, 147.9, 135.3,

128.0, 127.8, 123.8, 122.1, 119.1, 31.0, 29.3, 28.65, 28.60, 28.4, 28.3,

28.2, 28.0, 21.8, 13.6, 7.4, 6.2.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₃₂N₅S: 410.2373; found:

410.2376.

¹³C NMR (75.5 MHz, DMSO-d₆):  = 174.9, 149.0, 148.0, 146.9, 142.8,

135.7, 128.9, 128.33, 128.30, 127.3, 125.6, 124.1, 122.4, 119.5, 34.6,

33.0, 30.4, 29.3, 21.8, 21.5, 13.8, 13.5.

4-(Decylthio)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-

yl]quinazoline (7f)

HRMS-ESI: m/z [M + H]⁺calcd for C₂₄H₂₈N₅S: 418.2060; found:

418.2058.

Reaction time: 15 h at 60 °C; yield: 0.21 g (70% from 0.22 g, 0.64

mmol of 4f); yellow solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 83–85

°C.

4-(Decylthio)-2-(4-hexyl-1H-1,2,3-triazol-1-yl)quinazoline (7c)

Reaction time: 24 h at rt; yield: 0.14 g (65% from 0.16 g, 0.47 mmol of

4f); colorless solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 78–79 °C.

IR (KBr): 2920, 2850, 1565, 1550, 1465 cm^–1

.

¹H NMR (300 MHz, DMSO-d₆):  = 9.24 [s, 1 H, HC(triazole)], 8.15 (d,

³J = 8.2 Hz, 1 H, HC5), 8.08–7.99 (m, 2 H, HC8, HC7), 7.97 (d, ³J = 8.8

IR (KBr): 2925, 2855, 1575, 1550, 1465, 1355 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.37 [s, 1 H, HC(triazole)], 8.12 (dd, ³J =

8.2 Hz, ⁴J = 1.3 Hz, 1 H, HC5), 8.07 (dd, ³J = 8.3 Hz, ⁴J = 1.1 Hz, 1 H,

3

Hz, 2 H_arom), 7.72 (ddd, J = 8.2, 6.0 Hz, ⁴J = 2.1 Hz, 1 H, HC6), 7.04 (d,

³J = 8.8 Hz, 2 H_arom), 3.81 (s, 3 H, OCH₃), 3.51 (t, ³J = 7.2 Hz, 2 H, H₂C1′),

3

HC8), 7.89 (ddd, J = 8.3, 7.0 Hz, ⁴J = 1.3 Hz, 1 H, HC7), 7.58 (ddd, J =

8.2, 7.0 Hz, ⁴J = 1.1 Hz, 1 H, HC6), 3.47 (t, ³J = 7.3 Hz, 2 H, H₂C1′), 2.85

(t, ³J = 7.6 Hz, 2 H, H₂C1′′), 1.87 (quint, ³J = 7.3 Hz, 2 H, H₂C2′), 1.76

(quint, ³J = 7.6 Hz, 2 H, H₂C2′′), 1.53 (quint, ³J = 7.3 Hz, 2 H, H₂C3′),

1.78 (quint, ³J = 7.2 Hz, 2 H, H₂C2′), 1.45 (quint, ³J = 7.2 Hz, 2 H, H₂C3′),

3

1.29 (quint, J = 7.2 Hz, 2 H, H₂C4′), 1.22–1.09 [m, 10 H, (CH₂)₅], 0.78

(t, ³J = 6.7 Hz, 3 H, H₃C10′).

¹³C NMR (75.5 MHz, DMSO-d₆):  = 174.7, 159.4, 148.9, 147.9, 146.6,

135.4, 128.2, 128.0, 126.9, 123.9, 122.33, 122.27, 118.6, 114.2, 55.1,

31.1, 29.4, 28.8, 28.7, 28.5, 28.4, 28.3, 28.1, 21.8, 13.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₇H₃₄N₅OS: 476.2479; found:

476.2491.

3

1.44–1.23 [m, 18 H, (CH₂)₉], 0.89 (t, J = 6.2 Hz, 3 H, CH₃), 0.87 (t, ³J =

6.2 Hz, 3 H, CH₃).

¹³C NMR (125.7 MHz, CDCl₃):  = 175.6, 149.6, 148.9 (2 C), 135.0,

129.1, 127.5, 124.3, 123.1, 119.9, 32.0, 31.7, 30.5, 29.69 (2 C), 29.48,

29.45, 29.4, 29.2, 29.1, 28.9, 25.9, 22.8, 22.7, 14.24, 14.22

HRMS-ESI: m/z [M + H]⁺calcd for C₂₆H₄₀N₅S: 454.2999; found:

454.2998.

4-(Dodecylthio)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)quinazoline

(7g)

Reaction time: 24 h at 70 °C; yield: 0.23 g (79% from 0.20 g, 0.54

mmol of 4g); brown solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 74–76

°C.

4-(Decylthio)-2-(4-butyl-1H-1,2,3-triazol-1-yl)quinazoline (7d)

Reaction time: 24 h at rt; yield: 0.18 g (74% from 0.20 g, 0.58 mmol of

4f); brown solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 71–73 °C.

IR (KBr): 2920, 2850, 1570, 1545, 1465, 1370 cm^–1

.

L

A. Jeminejs et al.

Paper

Synthesis

¹H NMR (300 MHz, DMSO-d₆):  = 9.30 [s, 1 H, HC(triazole)], 8.16 (d,

³J = 8.2 Hz, 1 H, HC8), 8.08–7.99 (m, 4 H, HC5, HC6, C₆H₅), 7.73 (ddd,

³J = 8.2, 6.0 Hz, ⁴J = 2.3 Hz, 1 H, HC7), 7.49 (t, ³J = 7.5 Hz, 2 H, C₆H₅),

7.39 (t, ³J = 7.5 Hz, 1 H, C₆H₅), 3.53 (t, ³J = 7.2 Hz, 2 H, H₂C1′), 1.81

(quint, ³J = 7.2 Hz, 2 H, H₂C2′), 1.47 (quint, ³J = 7.2 Hz, 2 H, H₂C3′), 1.31

(quint, ³J = 7.2 Hz, 2 H, H₂C4′), 1.25–1.12 [m, 14 H, (CH₂)₇], 0.80 (t, ³J =

6.7 Hz, 3 H, H₃C12′).

¹³C NMR (75.5 MHz, DMSO-d₆):  = 174.8, 148.8, 147.8, 146.6, 135.4,

129.7, 128.7, 128.2, 128.1, 128.0, 125.5, 123.8, 122.3, 119.5, 31.0, 29.4,

28.70, 28.65, 28.64, 28.61, 28.4, 28.24, 28.19, 28.0, 21.7, 13.6

¹³C NMR (125.7 MHz, CDCl₃):  = 174.8, 149.5, 149.1, 147.7, 137.8,

137.0, 135.6, 130.0 (2 C) (the signal was assigned from HMBC spec-

trum), 129.4, 129.1, 128.7, 128.1, 125.9, 125.3, 124.0, 122.3, 118.7.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₅ClN₅S: 416.0731; found:

416.0721.

4-[(4-Fluorophenyl)thio]-2-(4-phenyl-1H-1,2,3-triazol-1-

yl)quinazoline (7k)

Reaction time: 3 h at 60 °C; yield: 0.14 g (73%); yellow solid; R_f= 0.74

(Tol/EtOAc 1:1); mp 194–196 °C.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₈H₃₆N₅S: 474.2686; found:

474.2694.

IR (KBr): 3161, 3061, 1611, 1569, 1547, 1496, 1462, 1416, 1367 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.20 (d, ³J = 8.2 Hz, 1 H, HC5), 8.15 (d,

³J = 8.4 Hz, 1 H, HC8), 8.13 [s, 1 H, HC(triazole)], 7.95 (dd, ³J = 8.4, 7.1

4-(Dodecylthio)-2-[4-(p-tolyl)-1H-1,2,3-triazol-1-yl]quinazoline

(7h)

3

Hz, 1 H, HC7), 7.80 (d, J = 7.6 Hz, 2 H_arom), 7.73–7.68 (m, 2 H, C₆H₅),

7.67 (dd, ³J = 8.2, 7.1 Hz, 1 H, HC6), 7.44 (dd, ³J = 7.6 Hz, ³J_H,F= 7.5 Hz, 2

Reaction time: 24 h at 70 °C; yield: 0.23 g (87% from 0.20 g, 0.54

mmol of 4g); brown solid; R_f= 0.14 (hexane/EtOAc 15:1); mp 83–84 °C.

H_arom), 7.37–7.28 (m, 3 H, C₆H₅).

¹³C NMR (125.7 MHz, CDCl₃):  = 175.0, 164.2 (d, ¹J_C,F= 252 Hz), 149.4,

IR (KBr): 2920, 2850, 1565, 1545, 1465, 1370 cm^–1

.

3

149.2, 147.7, 138.5 (d, J_C,F= 9 Hz), 135.5, 130.0, 129.3, 129.0, 128.6,

¹H NMR (300 MHz, DMSO-d₆):  = 9.27 ([s, 1 H, HC(triazole)], 8.21 (d,

³J = 8.3 Hz, 1 H, HC5), 8.11–8.02 (m, 2 H, HC8, HC7), 7.93 (d, ³J = 8.0

Hz, 2 H_arom), 7.76 (ddd, ³J = 8.3, 6.0 Hz, ⁴J = 1.9 Hz, 1 H, HC6), 7.31 (d,

³J = 8.0 Hz, 2 H_arom), 3.56 (t, ³J = 7.2 Hz, 2 H, H₂C1′), 2.37 (s, 3 H, CH₃),

1.84 (quint, ³J = 7.2 Hz, 2 H, H₂C2′), 1.50 (quint, ³J = 7.2 Hz, 2 H, H₂C3′),

1.41–1.30 (m, 2 H, H₂C4′), 1.30–1.11 [m, 14 H, (CH₂)₇], 0.83 (t, ³J = 6.7

Hz, 3 H, H₃C12′).

¹³C NMR (125.7 MHz, CDCl₃):  = 175.8, 149.5, 148.8, 148.0, 138.6,

135.0, 129.7, 129.1, 127.6, 127.5, 126.1, 124.3, 123.2, 118.2, 32.0, 30.5,

29.82, 29.77, 29.7 (2 C), 29.5, 29.4, 29.3, 28.9, 22.8, 21.5, 14.3.

128.0, 125.9, 124.0, 122.3, 122.0 (d, ⁴J_C,F= 3 Hz), 118.6, 117.0 (d, ²J_C,F

=

22 Hz).

¹⁹F NMR (470.5 MHz, CDCl₃):  = –109.6.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₅FN₅S: 400.1027; found:

400.1027.

2-{4-[4-(Trifluoromethyl)phenyl]-1H-1,2,3-triazol-1-yl}-4-

[(4-fluorophenyl)thio]quinazoline (7l)

Reaction time: 4 h at 55 °C; yield: 0.17 g (74%); colorless solid; R_f=

0.85 (Tol/EtOAc 1:1); mp 237–243 °C.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₉H₃₈N₅S: 488.2842; found:

488.2854.

IR (KBr): 3154, 3057, 1624, 1588, 1568, 1550, 1491, 1462, 1423, 1412

cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.21 (d, ³J = 8.3 Hz, 1 H, HC5), 8.19 [s, 1

2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-4-(phenylthio)quinazoline (7i)

H, HC(triazole)], 8.16 (d, ³J = 8.4 Hz, 1 H, HC8), 7.97 (dd, ³J = 8.4, 7.7

Reaction time: 5 h at 60 °C; yield: 0.15 g (80%); colorless solid; R_f=

0.73 (Tol/EtOAc 1:1); mp 196–198 °C.

3

Hz, 1 H, HC7), 7.90 (d, J = 8.1 Hz, 2 H_arom), 7.74–7.67 (m, 5 H, HC6, 2

H

_arom, 2 H, SAr), 7.33 (dd, ³J = 8.6 Hz, ³J_H,F= 8.4 Hz, 2 H, SAr).

IR (KBr): 3150, 3053, 1605, 1568, 1551, 1499, 1465, 1416, 1372, 1347

¹³C NMR (125.7 MHz, CDCl₃):  = 175.2, 164.3 (d, ¹J_C,F= 252 Hz), 149.3,

cm^–1

.

149.0, 146.3, 138.6 (d, ³J_C,F= 9 Hz), 135.6, 133.4, 130.4 (q, ²J_C,F= 33 Hz),

¹H NMR (500 MHz, CDCl₃):  = 8.24 (dd, ³J = 8.2 Hz, ⁴J = 1.3 Hz, 1 H,

3

1

129.3, 128.2, 126.00 (q, J_C,F= 4 Hz), 125.96, 124.2 (q, J_C,F= 272 Hz),

124.0, 122.3, 122.0 (d, ⁴J_C,F= 4 Hz), 119.4, 117.0 (d, ²J_C,F= 22 Hz).

3

HC5), 8.18 (dd, J = 8.4 Hz, ⁴J = 1.1 Hz, 1 H, HC8), 8.08 [s, 1 H, HC(tri-

azole)], 7.96 (ddd, ³J = 8.4, 7.1 Hz, ⁴J = 1.3 Hz, 1 H, HC7), 7.79 (d, ³J = 7.5

¹⁹F NMR (470.5 MHz, CDCl₃):  = –62.6, –109.5.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₃H₁₄F₄N₅S: 468.0901; found:

3

Hz, 2 H, C₆H₅), 7.72 (d, J = 8.0 Hz, 2 H, SC₆H₅), 7.67 (ddd, ³J = 8.2, 7.1

Hz, ⁴J = 1.1 Hz, 1 H, HC6), 7.65–7.58 (m, 3 H, SC₆H₅), 7.44 (t, ³J = 7.5 Hz,

2 H, C₆H₅), 7.35 (t, ³J = 7.5 Hz, 1 H, C₆H₅).

468.0904.

¹³C NMR (125.7 MHz, CDCl₃):  = 175.3, 149.4, 149.2, 147.6, 136.4,

135.4, 130.3, 130.2, 129.7, 129.3, 129.0, 128.5, 127.9, 126.8, 126.0,

124.1, 122.4, 118.8.

4-[(4-Bromophenyl)thio]-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-

quinazoline (7m)

Reaction time: 12 h at 60 °C; yield: 0.19 g (82%); colorless solid; R_f=

0.75 (Tol/EtOAc 1:1); mp 244–246 °C.

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₆N₅S: 382.1121; found:

382.1102.

IR (KBr): 3155, 3058, 3047, 1612, 1568, 1550, 1499, 1461, 1414 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.19 (dd, ³J = 8.1 Hz, ⁴J = 1.3 Hz, 1 H,

HC5), 8.17 (d, ³J = 8.4 Hz, 1 H, HC8), 8.08 [s, 1 H, HC(triazole)], 7.96

(ddd, ³J = 8.4, 7.1 Hz, ⁴J = 1.3 Hz, 1 H, HC7) 7.84 (d, ³J = 7.5 Hz, 2 H,

C₆H₅), 7.76 (d, ³J = 8.4 Hz, 2 H_arom), 7.68 (dd, ³J = 8.1, 7.1 Hz, 1 H, HC6),

7.58 (d, ³J = 8.4 Hz, 2 H_arom), 7.45 (t, ³J = 7.5 Hz, 2 H, C₆H₅), 7.35 (t, ³J =

7.5 Hz, 1 H, C₆H₅).

¹³C NMR (125.7 MHz, CDCl₃):  = 174.6, 149.5, 149.0, 147.7, 138.0,

135.6, 132.9, 129.9, 129.4, 129.1, 128.6, 128.1, 126.0, 125.9, 125.2,

124.0, 122.3, 118.7.

4-[(4-Chlorophenyl)thio]-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-

quinazoline (7j)

Reaction time: 6 h at 60 °C; yield: 0.10 g (50%); brown solid; R_f= 0.75

(Tol/EtOAc 1:1); mp 185–187 °C.

IR (KBr): 3153, 3052, 2924, 1609, 1568, 1549, 1499, 1463, 1415, 1371

cm^–1

.

¹H NMR (300 MHz, DMSO-d₆):  = 8.64 [s, 1 H, HC(triazole)], 8.33 (d,

³J = 8.3 Hz, 1 H, HC5), 8.18–8.08 (m, 2 H, HC8, HC7), 7.89 (d, ³J = 7.3

Hz, 2 H, C₆H₅), 7.87–7.78 (m, 3 H, HC6, 2 H_arom), 7.73 (d, ³J = 8.4 Hz, 2

H_arom), 7.51 (t, ³J = 7.3 Hz, 2 H, C₆H₅), 7.41 (t, ³J = 7.3 Hz, 1 H, C₆H₅).

M

A. Jeminejs et al.

Paper

Synthesis

HRMS-ESI: m/z [M + H]⁺calcd for C₂₂H₁₅BrN₅S: 460.0226; found:

460.0213.

¹H NMR (500 MHz, CDCl₃):  = 8.58 (d, ³J = 8.0 Hz, 1 H, HC10), 7.89 (d,

³J = 8.1 Hz, 1 H, HC7), 7.85 (dd, ³J = 8.1, 7.6 Hz, 1 H, HC8), 7.65 (dd, ³J =

8.0, 7.6 Hz, 1 H, HC9), 4.91 (q, ³J = 7.1 Hz, 2 H, CH₂), 1.66 (t, ³J = 7.1 Hz,

3 H, CH₃).

4-[(4-tert-Butylphenyl)thio]-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-

quinazoline (7n)

¹³C NMR (125.7 MHz, CDCl₃):  = 151.4, 143.9, 143.7, 133.9, 127.2,

127.0, 125.1, 113.3, 66.9, 14.3.

Reaction time: 6 h at 60 °C; yield: 0.20 g (90%); colorless solid; R_f=

HRMS-ESI: m/z [M + H]⁺calcd for C₁₀H₁₀N₅O: 216.0880; found:

0.74 (Tol/EtOAc 1:1); mp 234–236 °C.

216.0891.

IR (KBr): 3143, 2961, 2901, 2866, 1612, 1568, 1551, 1498, 1465, 1416

cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 8.24 (d, ³J = 8.2 Hz, 1 H, HC5), 8.19 (d,

³J = 8.4 Hz, 1 H, HC8), 8.12 [s, 1 H, HC(triazole)], 7.95 (dd, ³J = 8.4, 7.3

Hz, 1 H, HC7), 7.78 (d, ³J = 7.2 Hz, 2 H, C₆H₅), 7.67 (dd, ³J = 8.2, 7.3 Hz, 1

H, HC6), 7.65–7.60 (m, 4 H_arom), 7.39 (t, ³J = 7.2 Hz, 2 H, C₆H₅), 7.34 (t,

³J = 7.2 Hz, 1 H, C₆H₅), 1.45 (s, 9 H, t-C₄H₉).

¹³C NMR (125.7 MHz, CDCl₃):  = 175.6, 154.0, 149.4, 149.1, 147.5,

136.1, 135.3, 130.1, 129.3, 128.8, 128.5, 127.9, 126.7, 125.9, 124.1,

123.1, 122.3, 119.0, 35.1, 31.4.

Funding Information

This work is supported by the Central Finance and Contracting Agen-

cy of the Republic of Latvia (ERDF 1.1.1.1. activity project No.

1.1.1.1/16/A/131).()

Acknowledgment

HRMS-ESI: m/z [M + H]⁺calcd for C₂₆H₂₄N₅S: 438.1747; found:

438.1748.

The authors are grateful to high school students Mihails Šatlikovs and

Airita Skaldere for the assistance in acquiring experimental data.

2-[4-(4-Butylphenyl)-1H-1,2,3-triazol-1-yl]-4-(hexylamino)-

quinazoline (9)

Supporting Information

Hexylamine (0.18 mL,  = 0.77 g/mL, 1.38 mmol, 1.0 equiv) was added

to a solution of 2-[4-(4-butylphenyl)-1H-1,2,3-triazol-1-yl]-4-(butyl-

thio)quinazoline (7b; 115 mg, 0.28 mmol, 1.0 equiv) in THF (3 mL)

and H₂O (3 mL) and the mixture was stirred for 3 days at 35 °C, con-

trolled by HPLC. After completion of the reaction, the mixture was

evaporated and suspended in H₂O (3 mL). The suspension was filtered

and the solid product was dried in vacuo. The product was dissolved

in DCM (15 mL) and washed with brine (2 × 10 mL) and H₂O (2 × 10

mL). The organic phase was dried (anhyd Na₂SO₄), evaporated, and

suspended in CH₃CN (5 mL). The suspension was filtered and dried in

vacuo; yield: 35 mg (30%); slightly green solid; R_f= 0.67 (Tol/EtOAc

10:1); mp 194–196 °C.

Supporting information for this article is available online at

https://doi.org/10.1055/s-0040-1706568. Su

p

ortingInformatio

n

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p

ortingInformatio

n

References

(1) (a) Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.;

Saeed, A. Bioorg. Med. Chem. 2016, 24, 2361. (b) Ravez, S.;

Castillo-Aguilera, O.; Depreux, P.; Goossens, L. Expert Opin. Ther.

Patents 2015, 25, 789. (c) Ajani, O. O.; Aderohunmu, D. V.;

Umeokoro, E. N.; Olomieja, A. O. Bangladesh J. Pharmacol. 2016,

11, 716.

(2) (a) Cui, J. J. ACS Med. Chem. Lett. 2014, 5, 272. (b) Ismail, R. S. M.;

Ismail, N. S. M.; Abuserii, S.; El Ella, D. A. A. Future J. Pharm. Sci.

2016, 2, 9.

(3) Mehndiratta, S.; Sapra, S.; Singh, G.; Singh, M.; Nepali, K. Recent

Patents Anti-Cancer Drug Discov. 2016, 11, 2.

(4) Dumas, J.; Sibley, R.; Smith, R.; Su, N.; Chen, Y.; Wood, J.;

Guernon, L.; Dixon, J.; Brennan, C.; Boyer, S. PCT Int. Appl WO

2003055866 A1 20030710, 2003.

IR (KBr): 3270, 2925, 1595, 1560, 1380 cm^–1

.

¹H NMR (300 MHz, DMSO-d₆+ D₂O):  = 9.10 [s, 1 H, HC(triazole)],

8.30 (d, ³J = 8.2, 1 H, HC5), 7.88 (d, ³J = 8.1 Hz, 2 H_arom), 7.85–7.76 (m, 2

H, HC7, HC8), 7.55 (dd, ³J = 8.2, 6.7 Hz, 1 H, HC6), 7.30 (d, ³J = 8.1 Hz, 2

H

_arom), 3.69 (t, ³J = 7.1 Hz, 2 H, H₂C1′), 2.62 (t, ³J = 7.5 Hz, 2 H, H₂C1′′),

1.71 (quint, ³J = 7.1 Hz, 2 H, H₂C2′), 1.58 (quint, ³J = 7.4 Hz, 2 H, H₂C2′′),

1.45–1.22 [m, 8 H, (CH₂)₄], 0.90 (t, ³J = 7.3 Hz, 3 H, H₃C4′′), 0.83 (t, ³J =

7.0 Hz, 3 H, H₃C6′).

¹³C NMR (75.5 MHz, DMSO-d₆):  = 161.1, 150.9, 149.3, 142.2, 133.2,

128.4, 127.5, 127.1, 125.6, 125.5, 125.3, 122.9, 118.8, 114.1, 40.7, 34.3,

32.6, 30.7, 28.1, 25.8, 21.7, 21.3, 13.4, 13.3.

(5) da Silva, J. F. M.; Walters, M.; Al-Damluji, S.; Ganellin, C. R.

Bioorg. Med. Chem. 2008, 16, 7254.

(6) (a) Jafari, E.; Khajouei, M. R.; Hassanzadeh, F.; Hakimelahi, G. H.;

Khodarahmi, G. A. Res. Pharm. Sci. 2016, 11, 1. (b) Parhi, A. K.;

Zhang, Y.; Saionz, K. W.; Pradhan, P.; Kaul, M.; Trivedi, K.; Pilch,

D. S.; LaVoie, E. J. Bioorg. Med. Chem. Lett. 2013, 23, 4968.

(7) Michael, J. P. Nat. Prod. Rep. 2005, 22, 627.

HRMS-ESI: m/z [M + H]⁺calcd for C₈H₆N₆: 429.2761; found: 429.2757.

5-(Ethoxy)tetrazolo[1,5-c]quinazoline (11)

Quinazoline 3d (30 mg, 0.10 mmol, 1.0 equiv) was added to a suspen-

sion of K₂CO₃(15 mg, 0.11 mmol, 1.1 equiv) in EtOH (5 mL) and

stirred for 5 h at 40 °C, controlled by HPLC. After completion of the

reaction, the mixture was evaporated, suspended in DCM (30 mL),

and washed with H₂O (3 × 5 mL). Aqueous phases were back-extract-

ed with DCM (2 × 5 mL). The organic phase was dried (anhyd Na₂SO₄),

filtered, and evaporated. The product was then suspended in DCM (3

drops) and hexane (30 mL). The precipitate formed was filtered,

washed with hexane (5 mL), and dried in vacuo; yield: 17 mg (77%);

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Article Doi

Application of Azide-Tetrazole Tautomerism and Arylsulfanyl Group Dance in the Synthesis of Thiosubstituted Tetrazoloquinazolines

DOI: 10.1055/s-0040-1706568

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Article abstract of DOI:10.1055/s-0040-1706568

Full text of DOI:10.1055/s-0040-1706568

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