Nucleophile-nucleofuge duality of azide and arylthiolate groups in the synthesis of quinazoline and tetrazoloquinazoline derivatives

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Nucleophile–nucleofuge duality of azide and

arylthiolate groups in the synthesis of quinazoline

Cite this: DOI: 10.1039/d1ob01315g

and tetrazoloquinazoline derivatives†

Andris Jeminejs, Irina Novosjolova, * Ērika Bizdēna and Māris Turks

*

5-Arylthio-tetrazolo[1,5-c]quinazolines (tautomers of 2-arylthio-4-azido-quinazolines) undergo facile

nucleophilic aromatic substitution reactions with amines, alcohols and alkylthiols. This, combined with

the recently reported arylsulfanyl group dance, provides straightforward access to 4-azido-2-N-, O-,

S-substituted quinazolines and/or their tetrazolo tautomers from commercially available 2,4-dichloroqui-

nazoline. The azidoazomethine-tetrazole tautomeric equilibrium and the electron-withdrawing character

of the fused tetrazolo system plays a central role in the developed transformations. 5-Amino-substituted

tetrazolo[1,5-c]quinazolines undergo media-controlled tautomeric equilibrium, which permits them to

demonstrate the reactivity traditionally associated with the azido substituent. Furthermore, a method for

5-O-substitited tetrazolo[1,5-a]quinazolines from 2,4-diazidoquinazoline was developed during the struc-

tural elucidation of the substitution products. The developed methodology will facilitate medicinal chem-

istry investigations into quinazoline derivatives and the discovered ﬂuorescent properties of some of the

products (e.g., 4-(4-phenyl-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)quinazoline: λ_em.= 461 nm,

Φ_DCM= 0.89) could serve as a starting point for their further applications in analytical and materials

science.

Received 6th July 2021,

Accepted 14th August 2021

DOI: 10.1039/d1ob01315g

rsc.li/obc

has not been thoroughly studied owing to the dominant pres-

ence of the tetrazole tautomeric form. On the other hand, the

Introduction

The quinazoline moiety represents a privileged class of addition of another condensed heterocycle to the quinazoline

scaﬀolds with a broad spectrum of biological activities. Several core has increased interest towards possible pharmacological

marketed anticancer drugs such as gefitinib, lapatinib, erloti- applications. Despite the fact that only a few substances with

nib and Afatinib are built around this heterocyclic core.^1–3suﬃcient evaluation of their biological properties are reported

These substances possess the ability to bind to the tyrosine in the literature, potential antiallergy,¹³antiulcer,¹³

kinase active site and inhibit its messenger activity, thus block- antimicrobial,^14,15antitumor,^14–16bronchodilator,¹⁷anticon-

ing the signaling process within cancer cells.^4,5Variation of vulsant¹⁸and antidepressant¹⁸activities have been found

the substituents also paved the way for potential apoptosis among the 5-substituted tetrazolo[1,5-a]quinazolines and sub-

inducers and inhibitors,⁶as well as alpha-adrenergic blocking stituted tetrazolo[1,5-c]quinazolines.

agents⁷in the case of the quinazoline based drug prazosin.

Quinazoline compounds also possess antibacterial,^8,9antima- razole ring at the C4 position of quinazoline (see Scheme 1)

larial¹⁰and anticonvulsant¹¹activities.

include: (1) S_NAr reactions with sodium azide, substituting

Strategies for the introduction of an azide group/fused tet-

The ability of the 2/4-azidoquinazolines to reach an azido- halogens (LG = Cl),^19,20heterocycles (LG = isoxazolone)²¹or

azomethine-tetrazole (azide-tetrazole) tautomeric equilibrium, oxygen-centered leaving groups (LG = O-benzotriazole, O–

and cyclize to the corresponding tetrazolo[1,5-a/c]quinazolines P⁺(NMe₂)₃);²²(2) diazotization of 4-hydrazinoquinazoline

has been known for several decades.¹²However, the impact derivatives with sodium nitrite and the subsequent azide-tetra-

and synthetic application of such tautomerism in quinazolines zole tautomerization;^11,23,24(3) the pyrimidine ring-closing

reaction of 2-tetrazolylaniline and potassium ethylxanthogen-

ate¹⁴or tert-butyl isocyanide with the addition of a cobalt²⁵or

palladium²⁶catalyst; and (4 the microwave assisted domino

Institute of Technology of Organic Chemistry, Faculty of Materials Science and

Applied Chemistry, Riga Technical University, Paula Valdena Str. 3, Riga, LV-1048,

cyclization-S_NAr procedure using anthranilic acid, formamide

Latvia. E-mail: irina.novosjolova@rtu.lv, maris.turks@rtu.lv

and TMSN₃.²⁷In the past few decades, a significant amount of

†Electronic supplementary information (ESI) available. See DOI: 10.1039/

d1ob01315g

attention has also been focused on the synthesis and bioactiv-

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In this paper, we report an array of synthetic applications

for modifying the quinazoline core that utilize the arylthiolate

leaving group and the intrinsic properties of the azide group

to act as a regioselectivity switch, providing access to a “less

active” C2 position of quinazoline and facilitating S_NAr reac-

tions. The research led to the development of a novel synthetic

method for the preparation of the 5-substituted tetrazolo[1,5-c]

quinazolines and their further synthetic applications, as the

hidden azide group can be accessed via the azide-tetrazole

equilibrium and introduced into copper(^I) catalyzed azide–

alkyne cycloaddition (CuAAC), Staudinger and other azide

reactions.

Scheme 1 Diﬀerent approaches to the synthesis of the tetrazolo[1,5-c]

quinazolines.

Results and discussion

The recently reported arylsulfanyl group dance³³demonstrated

the ability of the arylsulfanyl group to act as both a nucleo-

phile and a leaving group (Scheme 2). When combined with

the azidoazomethine-tetrazole tautomeric equilibrium, this

led to the successful sequence of events 1 → 2 → 3. This raised

further questions about whether the arylsulfanyl group at the

C2 position of quinazoline (C5 of tetrazolo[1,5-c]quinazoline)

can be further exchanged with other nucleophiles and how

resistant the products will be in the presence of the aryl thio-

late anion. Indeed, the S_NAr process 3 → 4 provides access to

the 4-azido-2-heteroatom-substituted quinazolines and/or their

tetrazole tautomers. It should be emphasized that the virtually

straightforward monosubstitution of 2,4-dichloroquinazoline

with an azide at C4 (compound 2), which would provide access

for another substitution at C2, is not synthetically practical

owing to the azide-tetrazole equilibrium.^32,33The latter pro-

vides the tetrazolo-form 2-T as an intermediate, which is extre-

mely susceptible towards the next nucleophile attack and 2,4-

diazidoquinazoline is formed in the presence of azide ions.

ity of the quinazoline derivatives, which contain azolyl substi-

tuents (imidazolyl, 1,2,4-triazolyl, 2-pyrazolyl groups) at the C4

position or azoles fused to the quinazoline core.^28–31To

acquire such structures, the prior construction of a substituted

quinazoline core and pyrimidine-ring closing reactions are

necessary.

Our group has developed several synthetic methodologies

that make use of azidoquinazoline,^32,33azidopurine,^34–37and

azido-7-deazapurine^38,39derivatives as versatile starting

materials. We have extended various S_NAr approaches that use

an azido group as a leaving group. Moreover, we have recently

developed a sulfanyl group dance around a quinazoline core

and a sulfonyl group dance around a purine cycle, which

demonstrates the synthetic application of the innate ability of

the azido substituent to reach the azidoazomethine-tetrazole

tautomeric equilibrium.^33,40

Scheme 2 Arylthioquinazoline rearrangement reaction sequence.

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Therefore, the synthetic sequence 2,4-dichloroquinazoline the initial dance substrate 1, the sulfanyl group goes full circle

→1 → 3 → 4 has the potential to provide an easy functionali- around the quinazoline core.

zation at the C5 position of the tetrazolo[1,5-c]quinazoline

Synthesis of the 5-N-/S-/O-substituted tetrazolo[1,5-c]qui-

nazolines

core.

Hence, we tested the susceptibility of compound 3 towards

piperidine as a model nucleophile. Indeed, the substitution of

the aryl thiolate moiety at C2 was observed (product 4a), and

at room temperature this was accompanied by the nucleophilic

attack of the expelled thiolate at C4 (product 5a). This

rearrangement is similar to the arylsulfanyl group dance pre-

viously reported by our group,³³although it moves in the oppo-

site direction, going from the C2 position to C4. Starting from

After the initial trials with piperidine, we investigated the

scope of the S_NAr reactions with other nucleophiles (Table 1).

Out of all previously synthesized 5-(arylthio)-tetrazolo-[1,5-c]

quinazoline derivatives,³³the 4-chlorophenyl-sulfanyl group

bearing derivative 3 was chosen as a starting material for all

further modifications owing to its excellent leaving group pro-

perties and synthetic availability.

Table 1 Synthesis of the 5-substituted tetrazolo[1,5-c]quinazolines 4, 6 and 7

Entry

1

–XR

Solvent

DMF

Base

Temp., °C

Time, h

1

Yield, %

—

0–5

4a, 82

2

3

DMF

—

0–5

1.5

4b, 78

4c, 91

4

5

6

7

DMF

—

0–5

r.t.

1

4d, 62

4e, 45

4f, 42

4g, 73

DMF

—

3

DMF

—

5 days

6 h

THF/H₂O

NEt₃

8

9

THF

K₂CO₃

r.t.

1.5

6a, 82

6b, 76

DMF

10

11

DMF

K₂CO₃

NEt₃

0–5

1

5

6c, 96

6d, 52

DMSO

r.t.

12

THF

K₂CO₃

50

3

7a, 80

13

14

THF

abs. DMF

K₂CO₃

NaH

50

0–5

1.5

7b, 55

7b, 71

15

abs. DMF

NaH

0–5

3

7c, 55

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The nucleophilic aromatic substitution reaction between istry,⁴¹proved superior for bulkier alcohols, requiring sodium

the 5-(arylthio)tetrazolo[1,5-c]quinazoline derivative and hydride as a strong base in anhydrous DMF (entries 14 and 15,

various primary and secondary amines leads to a class of 5- Table 1). However, the hydride had to be fully consumed

(alkylamino)tetrazolo[1,5-c]quinazolines (entries 1–7, during alkoxide formation before the addition of starting

3

4

Table 1). In most cases the substitution proceeded readily, material 3, otherwise degradation of the azide/tetrazole moiety

even at a reduced temperature, while reactions with diethyl- was observed.

amine and morpholine required considerably longer reaction

With the developed methods in hand, we modified the qui-

times to reach full conversion. The use of solvents such as nazoline core with more complex biomolecular substituents,

dimethyl sulfoxide (DMSO), tetrahydrofuran (THF) and MeCN such as peptides and sugar moieties. The sulfanyl group con-

aﬀorded the desired products, however, the reactions in di- taining tripeptide glutathione underwent a regioselective S_NAr

methylformamide (DMF) proceeded at a slightly higher rate. reaction leading to the quinazoline–peptide conjugate 6d

The cooling of the reaction mixture to 0–5 °C was imperative (entry 11, Table 1). The triethylamine/DMSO system was

during the synthesis of compounds 4a and d (entries 1 and 4, proved to be suitable for glutathione and aﬀorded homo-

Table 1), otherwise formation of the rearrangement product 5 geneous media, while trials with potassium carbonate had a

was observed in isolated yields up to 19% (Scheme 2). Finally, considerably slower conversion rate.³⁶The introduction of the

the reaction with ^L-proline and NEt₃in the THF/H₂O system sugar moiety to the quinazoline core was also studied. The

aﬀorded the amino acid conjugate 4g in a 73% yield (entry 7, reaction with diacetone glucose yielded the quinazoline–carbo-

Table 1).

hydrate conjugate 7c with an acceptable yield (entry 15,

5-(Alkylthio)tetrazolo[1,5-c]quinazoline derivatives 6a–c can Table 1).

be obtained by further S_NAr reaction with the corresponding

thiols (entries 8–11, Table 1). Although 5-(alkylthio)tetrazolo

[1,5-c]quinazolines 6 are only rarely mentioned in the litera-

ture, they have already been found to possess a variety of bio-

logical activities, including antibacterial, antifungal and anti-

cancer properties.¹⁴However, previous synthetic approaches to

similar compounds required harsh pyrimidine ring-closing

reactions, while we propose a simple pathway with an overall

higher yield (entries 8–10, Table 1).^14,15Substitution to the

alkylsulfanyl group proceeded rather quickly, reaching full

conversion in 1.5 h at room temperature. Potassium carbonate

was found to be a suitable base for the reactions, aﬀording a

clean conversion with a simple purification protocol. The

change in solvents had little impact on the conversion rate,

therefore, the choice was based on the preferred product puri-

fication method. The synthesis of the decylthio derivative 6a

was carried out in THF (entry 8, Table 1), while reactions with

cyclohexane and 2-propanethiol aﬀorded the best yield by

product precipitation from the DMF/brine mixture (entries

9–11, Table 1).

Scarce information can be found in the literature about 5-

(alkoxy)tetrazoloquinazolines 7, and only the methoxy and

ethoxy quinazoline derivatives are known.²⁰Previously such

compounds required complex reaction sequences with sub-

sequent opening and closing of the pyrimidine ring.²⁰We

have already introduced a simple approach for the synthesis of

the ethoxy bearing derivative³³and now we have developed a

synthetic pathway leading to the alkoxy substituted tetrazolo

[1,5-c]quinazolines 7 with high yields (entries 12–15, Table 1).

Two methods were investigated, the first one required potass-

ium carbonate as the base and alcohol as a co-solvent with

THF (entries 12 and 13, Table 1). The addition of THF was

necessary owing to the poor solubility of starting material 3 in

alcohols. The use of potassium carbonate only aﬀorded the

desired products in the presence of excess amounts (>10 eq.)

of low molecular weight alcohols, such as ethanol and isopro-

panol. The second method, already applied in purine chem-

Proof of regioselectivity via synthesis of the isomer

The obtained 5-(alkylamino) and 5-(alkylthio)tetrazolo[1,5-c]

quinazoline derivatives 4 and 6 exhibit spectroscopic diﬀer-

ences in their tetrazolo[1,5-a] regioisomers, the structures of

which were proved using X-ray data.^32,33Both regioisomers can

be easily distinguished using NMR, the main diﬀerence is the

chemical shift of the proton at the C5 position of quinazoline

(the C10 position of tetrazolo[1,5-c]quinazoline) that owing to

the electron withdrawing eﬀect of tetrazole is shifted down-

field (see ESI†).

The distinct structures of the O-substituted tetrazoloquina-

zolines 7 and 9 have been investigated previously, using the

ethoxy group bearing derivative.³³The class of inverted

O-substituted tetrazolo[1,5-a]quinazolines 9 is already known

to possess antidepressant and anticonvulsant activities.¹⁸

However, the previously reported synthetic pathway with the

subsequent addition of alcohol and sodium azide requires a

long reaction time.¹⁸We propose an alternative approach

(Table 2), employing the azidoazomethine-tetrazole equili-

brium of 2,4-diazido-quinazoline 8 in the form of 8-AT that

Table 2 Synthesis of the 5-(alkyl/aryloxy)tetrazolo[1,5-a]quinazolines 9

Entry

R

9

Yield, %

1^a

2^b

3^c

Ph

Bn

n-Hex

9a

9b

9c

85

49

75

^aConditions: K₂CO₃, i-PrOH, 60 °C, 4 h. ^bConditions: NaH, abs. DMF,

room temperature (r.t.), 2.5 h. ^cConditions: NaH, abs. DMF, 0–5 °C, 6 h.

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Table 3 Solvent optimization for the synthesis of 4-arylthio-2-piperidi-

nylquinazoline 5a

stability of the arylsulfanyl group at the C4 position was

heavily aﬀected by the choice of solvent, the reaction in DMF

lead to dominant substitution at the C4 position (entry 1,

Table 3). On the other hand, the use of THF and i-PrOH as sol-

vents favored the substitution at the C2 position and product

5a was aﬀorded in a good yield (entries 2 and 3, Table 3). In

the case of i-PrOH, heating was necessary to achieve the con-

version owing to the low solubility of the starting material 1.

With the developed method in hand, 4-arylthio-2-piperidinyl-

quinazolines 5a–b were synthesized from commercially avail-

able 2,4-dichloroquinazoline (11) in a two-step one-pot pro-

cedure with good yields (Scheme 3). To prove the position of

the substituents, inverted regioisomers 13a–b were also syn-

thesized from the 2,4-disulfanyl quinazolines 12, carrying out

a regioselective substitution at the C4 positions. Two pairs of

regioisomers have distinguishable UV spectra and the diﬀer-

ence is also detectable using NMR data, while the exact posi-

tion of the substituents can be proved using nuclear

Overhauser eﬀect spectroscopy (NOESY) spectra.³⁶

Entry

Solvent

Temp.

Yield of 5a, %

Yield of 10, %

1

2

3

DMF

THF

i-PrOH

r.t.

50 °C

17

64

71

63

23

17

facilitates S_NAr reactions at the C4 position of quinazoline (C5

of tetrazolo[1,5-a]quinazoline), previously reported by our

group.³³The starting material 8 was obtained in the S_NAr reac-

tion between the commercially available 2,4-dichloroquinazo-

line (11) and sodium azide in DMF with a 97% yield.³³Further

reactions with alcohols were performed in a similar fashion to

methods developed for compounds 7, although providing pro-

ducts 9 in a higher overall yield, which can be advantageous

for medicinal chemistry applications. This is yet another

example of how the regioselectivity switch executed by the

azide-tetrazole tautomeric equilibrium can be combined with

the leaving group potential of the azido group.

4-Arylthio-2-piperidinylquinazolines 5 are rarely mentioned

in the literature. To prove the exact structure of the rearrange-

ment product 5a (Scheme 2), we investigated several synthetic

methods. The main disadvantage of the previously reported

rearrangement reaction (Scheme 2) is the oxidation of the

cleaved arylthiolate to the inert disulfide in the presence of

oxygen and basic media. The addition of the disulfide redu-

cing agents, such as H₃PO₂, led to the reduction of the tetra-

zole moiety. The nucleophilic aromatic substitution of the

corresponding 4-arylthio-2-chloroquinazoline 1 with piper-

idine was proved to be more eﬃcient (Table 3). However, the

NMR study of the azidoazomethine-tetrazole equilibrium

The previously mentioned compounds 3, 6 and 7 exist in both

the solid form and in solution in the tautomeric tetrazolo[1,5-

c]quinazoline form. However, several 5-(alkylamino)tetrazolo

[1,5-c]quinazoline derivatives 4 in the solutions revealed the

presence of an open azido-tautomer that had the ability to

facilitate diﬀerent transformations, such as the previously

mentioned rearrangement reaction (Scheme 2).

To gain insights into this matter, we investigated the azide-

tetrazole equilibrium of compounds 4 using NMR (Fig. 1). It

was found that the amino substituent has a substantial impact

on the azide-tetrazole ratio, the monosubstituted amino-quina-

zoline 4b showed only the tetrazole form, but for the hetero-

atom containing cyclic structures the equilibrium had shifted

towards the azide form. Moreover, the acyclic diethylamino

derivative 4f had a considerably higher azide ratio than the

slightly strained pyrrolidinyl substituted product 4c.

Scheme 3 Synthesis of the arylthio-piperidinylquinazoline regioisomers 5 and 13.

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Fig. 1 Amount of the azide tautomer (%) in the CDCl₃solutions of tetrazoloquinazolines 4a–f (500 MHz, 22 °C).

In comparison with the general rules of azidoazomethine-

The N-methylpiperazinyl derivative 4d exhibited a wide

tetrazole tautomeric equilibrium this particular case is incon- range of tautomeric ratios, from 7 to 59% for the azide form,

sistent with the known correlations between the substituent depending on the media. The results of both the solvent

electronic eﬀects and the nucleophilicity parameters of the polarity and the temperature eﬀects can be used to form a con-

corresponding amines.^42–45In line with the S-, O- and tinuous surface plot that can be used to predict the ratio of

N-substituted tetrazoloquinazolines, the compounds of type 4 tautomeric forms at any given point (Fig. 2). The highest azide

should have the least amount of azide owing to the strong elec- ratio of compound 4d was observed in acetic acid at elevated

tron donating properties of the amino group, facilitating the temperatures (up to 59% at 70 °C, see ESI†), which implied the

formation of the electron withdrawing tetrazole ring.

possible eﬀect of the pH on the tautomeric equilibrium.

However, a similar exception was also observed in the 4-azi-

Further investigation revealed that the possible partial pro-

dopyrimidines, in which the bulkier amino substituents tonation of amine nitrogen leads to the formation of a strong

shifted the equilibrium towards the azide.⁴⁴To study this electron withdrawing eﬀect that significantly shifts the equili-

further, other equilibrium aﬀecting factors, such as tempera- brium towards the azide. This eﬀect was the most pronounced

ture and solvents were also investigated (Fig. 2). The eﬀect of in the case of compound 4c, that has completely diﬀerent tau-

the solvent polarity and temperature on the tautomeric equili- tomeric form ratios (A : T) in chloroform (3 : 97) and acetic acid

brium of the substituted tetrazolo[1,5-c]quinazolines has rarely (79 : 21) (Fig. 3).

been presented in the literature owing to the dominant pres-

ence of the tetrazole form.⁴⁷

This steep change in the equilibrium can be used for reac-

tions that require the presence of an azide, such as cyclo-

However, these experiments have been thoroughly studied addition reactions.

for azidopyrimidines and pyridines,^48,49establishing general

Exploring the reactivity and novel compound classes

patterns to help predict the ratio of the forms. The tempera-

ture was proved to exhibit a linear eﬀect, and the solvent per-

missibility had a logarithmic correlation with the tautomeric

equilibrium.^42,43Despite having the reverse substituent eﬀect,

compounds 4 are in line with the other accepted rules: a

higher temperature provides more of the azide and polar sol-

vents facilitate the formation of a tetrazole.

Despite having a hidden azido substituent, previously known

tetrazolo[1,5-c]quinazoline derivatives,³³as well as compounds

3, 6 and 7, were completely inactive towards azide–alkyne

cycloaddition reactions and heating the reaction mixture above

100 °C led to the slow degradation of the tetrazole/azide

moiety. Similar trials with 5,6,7,8-tetrahydroquinazoline were

Fig. 2 Azide form content (A, %) of compound 4d depending on the temperature and solvent dielectric constant ε.⁴⁶

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Fig. 3 Protonation eﬀect on the azide-tetrazole equilibrium of compound 4c.

only successful for transformation into the electron-withdraw-

The fused tetrazole ring can be easily transformed into the

ing N-oxide.⁵⁰However, the observed azide-tetrazole equili- corresponding 4-aminoquinazolines by classical azide

brium and the presence of the azide tautomer in compounds 4 reduction (Scheme 4). The use of the copper(^II) sulfate penta-

can be applied for the synthesis of novel 4-triazolylquinazo- hydrate/sodium ascorbate system aﬀorded product 15 in an

lines 14 via CuAAC (Table 4).

excellent 90% yield using an easy purification process.^51,52

At elevated temperatures and in non-polar media the degra- Despite the absence of a detectable open azido tautomer, com-

dation process was suﬃciently diminished for compounds 4a pound 3 also underwent the Staudinger reaction, however, the

and 4d to undergo transformation, introducing the previously intermediate imino-phosphorane 16 was proved to possess a

unknown class of quinazolines 14a–c, containing the 1,4-di- high hydrolytic stability. The method also required the

substituted triazole moiety at the C4 position. Despite the additional removal of phosphine oxide by recrystallization to

observed pH eﬀect on the tautomeric equilibrium, switching aﬀord product 15 in an 80% yield.

the solvent to acetic acid led to a considerably higher rate of

azide reduction, aﬀording products 14 in lower yields or ates 16 raised the opportunity to isolate them. The reaction of

leading to complete degradation of the tetrazole moiety. tetrazolo[1,5-c]quinazoline 3 with phosphines in anhydrous

The stability of the observed iminophosphorane intermedi-

The corresponding RuAAC reaction was also investigated, THF led to a quick conversion to the desired products 16a–b

however, instead of the expected 1,5-triazole derivatives, only with yields of up to 73% (Scheme 4).

the formation of the 1,4-substituted product 14a was observed,

The obtained quinazoline iminophosphorane derivatives 16

while the degradation rate was considerably higher than in showed characteristic carbon-phosphorus coupling through

CuAAC. The highest isolated yield of 14a of 24% was achieved the C4, C4a and C8a positions of the quinazoline core, as

by CpRuCl(PPh₃)₂and RuCl(PPh₃)₃OAc (see ESI†).

observed in their ¹³C NMR spectra (see ESI†).

The aforementioned compounds are also stable enough to

withstand mild aqueous conditions, including extraction and

analytical chromatographic conditions (reverse phase). Despite

Table 4 Synthesis of 2-amino-4-triazolylquinazolines 14 via CuAAC

Entry

–R

–X–

14

Yield, %

1

2

3

–Ph

–(CH₂)₃CN

–CH_2–

>N–Me

–CH₂–

14a

14b

14c

40

48

52

Scheme 4 Reduction of fused tetrazole ring to 4-aminoquinazoline

derivative 15.

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Scheme 5 Synthesis of the 4-(alkyl/aryloxy)-2-triazolylquinazolines 17.

the reactive nature of the conventional iminophosphoranes,

these particular compounds were proved to exhibit poor

nucleophilic properties and, to our surprise, they did not react

with electrophiles, including aldehydes, ketones, carbon disul-

phide or isocyanates. To the best of our knowledge, this is the

first example of a series of tetrazolo[1,5-c]quinazolines in

which the azide-tetrazole equilibrium can be successfully used

to explore the azide reactivity: CuAAC, RuAAC and Staudinger

reaction.

As previously reported by our group, 5-thiosubstituted tetra-

zolo[1,5-a]quinazolines have a higher tautomeric ratio in the

azide form, which can be applied in cycloaddition reactions.³³

In addition, the obtained 5-(alkyl/aryloxy)tetrazolo[1,5-a]

quinazolines 13 easily undergo CuAAC reactions, leading to

novel 4-(alkyl/aryl-oxy)-2-triazolylquinazolines 17 with excellent

yields (Scheme 5).

Fig. 4 Photophysical properties of the synthesized quinazoline

derivatives.

Some of the synthesized quinazoline derivatives demon-

strated promising photophysical properties, applicable in both

fluorescent sensing technologies and materials science

(Fig. 4). The triazolyl quinazolines 14 possess distinct fluo-

rescent properties with a blue emission and quantum yields of

up to 0.89 in DCM solution (see ESI†). These emission pro-

perties are presumably inherent owing to the prominent

“push–pull” system found in the molecule. The pair of regio-

isomers 5b and 13b have distinguishable UV emission spectra

with a quantum yield of up to 0.57 in DCM for compound 5b

and no emission for compounds 13b (see ESI†). Quinazoline

iminophosphoranes 16 were also found to possess a mediocre

fluorescence with a violet emission and a quantum yield up to

0.29 in DCM.

chlorobutadiene (4000–2000 cm⁻¹

)

and paraﬃn oil

(2000–450 cm⁻¹) with a FTIR Perkin–Elmer Spectrum 100

spectrometer. ¹H and ¹³C{¹H} NMR spectra were recorded

using a Bruker 300 MHz or Bruker 500 MHz spectrometer in

CDCl₃, DMSO-d₆or acetic acid-d₄. Chemical shifts (δ) are

reported in ppm and coupling constants (J) in Hz. Residual

solvent (¹H) or solvent (¹³C{¹H}) peaks were used as an

internal reference (CDCl₃δ = 7.26 ppm, DMSO-d₆δ =

1

2.50 ppm, acetic acid-d₄δ = 2.45 ppm for H NMR: CDCl₃δ =

77.2 ppm, DMSO-d₆δ = 39.5 ppm, acetic acid-d₄δ = 179.0 ppm

for ¹³C{¹H} NMR). High performance liquid chromatography

(HPLC) analyses were performed using an Agilent

Technologies 1200 Series system equipped with an X Bridge

C18 column, 4.6 × 150 mm, particle size 3.5 μm, with a flow

rate of 1 mL min⁻¹, using 0.1% TFA/H₂O and MeCN for the

mobile phase. The wavelength of detection was 260 nm. High

resolution mass spectrometry (HRMS) analyses were per-

formed on an Agilent 1290 Infinity series UPLC system

Experimental

Materials and methods

The solvents used in the reactions were dried using standard equipped with column Extend C₁₈RRHD 2.1 × 50 mm, 1.8 μm,

drying agents and freshly distilled prior to use. Commercially connected to an Agilent 6230 TOF LC/MS mass spectrometer.

available reagents were used as received. All reactions were fol- UV–vis absorption spectra were recorded with a PerkinElmer

lowed using thin layer chromatography (TLC) on E. Merck Lambda 35 UV/vis spectrometer in DCM using a 5 mm cell

Kieselgel 60 F254, with detection by UV light, HPLC, and NMR quartz cell. Emission spectra and Φ_PLwere measured using

analyses. Column chromatography was performed on silica gel QuantaMaster 40 steady state spectrofluorometer (Photon

(60 Å, 40–63 μm, ROCC). Melting points were recorded with a Technology International, Inc.) equipped with 6 inch integrat-

Fisher Digital Melting Point Analyzer Model 355 apparatus. ing sphere by LabSphere, using the software package provided

The infrared spectroscopy (IR) spectra were recorded in hexa- by the manufacturer.

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General procedures and characterization of products

3

Compounds 1,^{33 33}and 12¹²were prepared according to exist-

ing literature procedures. The spectroscopic data for com-

pounds 9a and 9c matched that previously reported in the

literature.¹⁸

124.79, 111.3, 41.7, 31.9, 29.4 (2C, assigned with HSQC spec-

trum), 29.3, 27.0, 22.8, 14.2. IR ν (cm⁻¹): 3255, 3054, 2922,

2853, 1647, 1564, 1541, 1481, 1466, 1456, 1438, 1389, 1378.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₆H₂₃N₆299.1979; found

299.1962 (5.68 ppm).

Synthesis of the 5-(alkylamino)tetrazolo[1,5-c]quinazoline

derivatives 4

Tautomeric mixture of 5-(piperidin-1-yl)tetrazolo[1,5-c]qui-

nazoline (4a-T) and 4-azido-2-(piperidin-1-yl)quinazoline (4a-

A). Piperidine (0.27 mL, ρ = 0.86 g mL⁻¹, 2.71 mmol, 3.0 eq.)

was added to a stirred solution of 3 (265 mg, 0.90 mmol, 1.0

eq.) in DMF (3 mL). The mixture was stirred at 0–5 °C for 1 h,

controlled using HPLC. Once the reaction was complete, brine

solution (30 mL) was added, and the mixture was left in the

freezer for 16 h. The water suspension was filtered and the

solid was purified using silica gel column chromatography

(Hex/EtOAc; 5 → 11%). Yield: 188 mg (82%); orange solid; R_f

(Tol/MeCN; 10 : 1) 0.60; m.p. 101–104 °C. Only the tetrazolo

5-(Pyrrolidin-1-yl)tetrazolo[1,5-c]quinazoline (4c). Pyrrolidine

(0.18 mL, ρ = 0.87 g mL⁻¹, 2.20 mmol, 3.0 eq.) was added to a

stirred solution of 3 (230 mg, 0.73 mmol, 1.0 eq.) in DMF

(3 mL). The mixture was stirred at 0–5 °C for 1.5 h, controlled

using HPLC. Once the reaction was complete, a brine solution

(30 mL) was added, and the mixture was left in the freezer

overnight. The water suspension was filtered and the solid was

washed with hexane (2 × 10 mL). Yield: 160 mg (91%); color-

less solid; R_f(Tol/MeCN; 10 : 1) 0.58; m.p. 154–156 °C. ¹H NMR

1

form was characterized from a 96 : 4 mixture of 4a-T/4a-A: H

3

(500 MHz, DMSO-d₆): δ 8.30 (d, 1H, J = 7.8 Hz, H–C(10)), 7.77

NMR (500 MHz, DMSO-d₆): δ 8.36 (d, 1H, ³J = 7.9 Hz, H–C(10)),

3

(dd, 1H, J = 8.3, 7.5 Hz, H–C(8)), 7.63 (d, 1H, J = 8.3 Hz, H–C

(7)), 7.43 (dd, 1H, ³J = 7.8, 7.5 Hz, H–C(9)), 4.12–3.95 (m, 4H, 2

× H₂–C(1′)), 2.05–1.99 (m, 4H, 2 × H₂–C(2′)). ¹³C{¹H} NMR

(125.7 MHz, DMSO-d₆): δ 150.9, 145.4, 141.1, 133.6, 125.0,

124.0, 123.8, 110.5, 50.0, 25.0. IR ν (cm⁻¹): 3147, 3055, 3028,

2976, 2957, 1616, 1561, 1528, 1478, 1451, 1408, 1366, 1340.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₂H₁₃N₆241.1196; found

241.1170 (10.8 ppm).

3

7.82 (dd, 1H, J = 8.3, 7.3 Hz, H–C(8)), 7.72 (d, 1H, J = 8.3 Hz,

3

H–C(7)), 7.53 (dd, 1H, J = 7.9, 7.3 Hz, H–C(9)), 4.03–3.98 (m,

4H, 2 × H₂–C(1′)), 1.77–1.71 (m, 6H, 2 × H₂–C(2′), H₂–C(3′)). ¹³

C

{¹H} NMR (125.7 MHz, DMSO-d₆): δ 151.2, 144.3, 142.4, 133.5,

125.6, 125.0, 123.9, 111.5, 48.7, 25.2, 23.9. IR ν (cm⁻¹): 3057,

3033, 2935, 2865, 2849, 1624, 1607, 1562, 1529, 1481, 1467,

1451, 1415, 1371. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₃H₁₅N₆

255.1353; found 255.1340 (5.10 ppm).

5-(Octylamino)tetrazolo[1,5-c]quinazoline (4b). Octylamine

Tautomeric mixture of 5-(4-methylpiperazin-1-yl)tetrazolo

(0.47 mL, ρ = 0.78 g mL⁻¹, 2.85 mmol, 3.0 eq.) was added to a [1,5-c]quinazoline (4d-T) and 4-azido-2-(4-methylpiperazin-1-

stirred solution of 3 (298 mg, 0.95 mmol, 1.0 eq.) in DMF yl)quinazoline (4d-A). N-Methylpiperazine (0.23 mL, ρ =

(5 mL). The mixture was stirred at 0–5 °C for 1.5 h, controlled 0.90 g mL⁻¹, 2.10 mmol, 3.0 eq.) was added to a stirred solu-

using HPLC. Once the reaction was complete, brine solution tion of 3 (220 mg, 0.70 mmol, 1.0 eq.) in DMF (3 mL). The

(30 mL) was added, and the mixture was neutralized with mixture was stirred at 0–5 °C for 1 h, controlled using HPLC.

acetic acid to pH ≈7. The water suspension was extracted with Once the reaction was complete, a brine solution (30 mL)

a mixture of hexane and ethylacetate (40 and 20 mL, respect- was added, and the mixture was left in the freezer overnight.

ively). The organic phase was washed with brine (5 × 10 mL) The water suspension was filtered and the solid was washed

and water (3 × 5 mL), and dried over anhydrous Na₂SO₄, fil- with hexane (2 × 10 mL). Yield: 117 mg (62%); yellow solid;

tered and the solvent was evaporated. Yield: 222 mg (78%); R_f(Tol/EtOAc; 1 : 4) 0.67; m.p. 119–121 °C. Only the tetrazolo

1

colorless solid; R_f(Tol/MeCN; 10 : 1) 0.55; m.p. 150–152 °C. H form was characterized from a 95 : 5 mixture of 4d-T/4d-A: ¹H

3

NMR (500 MHz, CDCl₃): δ 8.46 (d, 1H, J = 7.9 Hz, H–C(10)), NMR (500 MHz, DMSO-d₆): δ 8.40 (d, 1H, ³J = 7.9 Hz, H–C

3

7.81–7.73 (m, 2H, H–C(7), H–C(8)), 7.47 (ddd, 1H, J = 7.9, 6.4 (10)), 7.85 (dd, 1H, J = 7.9, 7.4 Hz, H–C(8)), 7.76 (d, 1H, J =

Hz, J = 2.0 Hz, H–C(9)), 6.21 (t, 1H, J = 5.8 Hz, (–NH–)), 3.76 7.9 Hz, H–C(7)), 7.57 (dd, 1H, ³J = 7.9, 7.4 Hz, H–C(9)),

4

3

(td, 2H, J = 7.4, 5.8 Hz, H₂–C(1′)), 1.80 (quintet, 2H, J = 7.4 4.06–3.99 (m, 4H, 2 × H₂–C(1′)), 2.59–2.55 (m, 4H, 2 × H₂–C

Hz, H₂–C(2′)), 1.48 (quintet, 2H, ³J = 7.4 Hz, H₂–C(3′)), 1.39 (2′)), 2.27 (s, 3H, (–CH₃)). ¹³C{¹H} NMR (125.7 MHz, DMSO-

(quintet, 2H, ³J = 7.4 Hz, H₂–C(4′)), 1.34–1.26 (m, 6H, 3 × d₆): δ 151.1, 144.1, 142.5, 133.6, 125.8, 125.3, 124.0, 111.8,

(–CH₂–)), 0.88 (t, 3H, ³J = 6.7 Hz, H₃–C(8′)). ¹³C{¹H} NMR 54.0, 47.5, 45.6. IR ν (cm⁻¹): 2973, 2942, 2830, 2792, 2759,

(125.7 MHz, CDCl₃): δ 145.0, 145.4, 140.6, 133.7, 126.1, 124.82, 1625, 1606, 1562, 1531, 1480, 1452, 1409, 1382, 1365. HRMS

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(ESI) m/z: [M + H]⁺calcd for C₁₃H₁₆N₇270.1462; found 110.9, 44.6, 13.4. IR ν (cm⁻¹): 2975, 2933, 2923, 2874, 2855,

270.1443 (7.03 ppm).

1624, 1614, 1561, 1534, 1484, 1465, 1533. HRMS (ESI) m/z:

[M + H]⁺calcd for C₁₂H₁₅N₆243.1353; found 243.1376

(9.46 ppm).

Tautomeric mixture of 5-(morpholin-4-yl)tetrazolo[1,5-c]qui-

nazoline (4e-T) and 4-azido-2-(morpholin-4-yl)quinazoline (4e-

A). Morpholine (0.14 mL, ρ = 1.01 g mL⁻¹, 1.59 mmol, 3.0 eq.)

was added to a stirred solution of 3 (165 mg, 0.53 mmol, 1.0

eq.) in DMF (3 mL). The mixture was stirred at r.t. for 3 h, con-

trolled using HPLC. Once the reaction was complete, brine

solution (30 mL) was added, and the mixture was left in the

freezer overnight. The water suspension was filtered and the

solid was washed with hexane (2 × 10 mL), then purified using

silica gel column chromatography (DCM). Yield: 61 mg (45%);

orange solid; R_f(Tol/EtOAc; 1 : 4) 0.70; m.p. 185–190 °C. Only

the tetrazolo form was characterized from a 92 : 8 mixture of

Tautomeric mixture of tetrazolo[1,5-c]quinazolin-5-yl-L-

proline (4g-T) and (4-azidoquinazolin-2-yl)-^L-proline (4g-A).

Triethylamine (0.23 mL, ρ = 0.73 g mL⁻¹, 1.68 mmol, 2.5 eq.)

was added to a stirred suspension of 3 (210 mg, 0.67 mmol,

1.0 eq.) and ^L-proline (92 mg, 0.80 mmol, 1.2 eq.) in a mixture

of THF (10 mL) and water (5 mL). The mixture was stirred at r.

t. for 6 h, controlled using HPLC. Once the reaction was com-

plete, acetic acid was added until the solution was pH 5. The

resulting mixture was evaporated and purified using silica gel

column chromatography (DCM/MeOH; 0 → 10%). Yield:

139 mg (73%); yellow solid; R_f(DCM/MeOH; 9 : 1) 0.42; decom-

poses at 142 °C. Only the tetrazolo form was characterized

1

3

4e-T/4e-A: H NMR (500 MHz, DMSO-d₆): δ 8.41 (dd, 1H, J =

4

3

4

7.9 Hz, J = 0.9 Hz, H–C(10)), 7.86 (ddd, 1H, J = 8.2, 7.4 Hz, J

1

from a 97 : 3 mixture of 4g-T/4g-A: H NMR (500 MHz, DMSO-

3

= 0.9 Hz, H–C(8)), 7.77 (d, 1H, J = 8.2 Hz, H–C(7)), 7.58 (ddd,

1H, J = 7.9, 7.4 Hz, J = 0.8 Hz, H–C(9)), 4.03 (dd, 4H, J = 4.9,

4.6 Hz, 2 × H₂–C(1′)), 3.85 (dd, 4H, J = 4.9, 4.6 Hz, 2 × H₂–C

3

d₆, 50 °C): δ 8.34 (d, 1H, J = 7.9 Hz, H–C(10)), 7.80 (dd, 1H, J

3

4

3

= 8.2, 7.5 Hz, H–C(8)), 7.66 (d, 1H, J = 8.2 Hz, H–C(7)), 7.49

3

(dd, 1H, ³J = 7.9, 7.5 Hz, H–C(9)), 5.26 (br.s., 1H, H–C(2′)), 4.14

(br.s., 2H, H₂–C(5′)), 2.49–2.39 (m, 1H, H_a–C(3′)), 2.22–2.15 (m,

1H, H_b–C(3′)), 2.11–2.01 (m, 2H, H₂–C(4′)). ¹³C{¹H} NMR

(125.7 MHz, DMSO-d₆, 50 °C): δ 173.0, 150.6, 144.8, 140.6,

133.6, 125.1, 124.2, 123.8, 110.4, 61.9, 50.4, 29.9, 23.1. IR ν

(cm⁻¹): 3150, 3039, 3021, 2971, 2954, 1715, 1578, 1528, 1478,

1451, 1412, 1367, 1353. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₃H₁₃N₆O₂283.0943; found 283.0952 (3.18 ppm).

(2′)). ¹³C{¹H} NMR (125.7 MHz, DMSO-d₆): δ 151.1, 144.0,

142.5, 133.7, 125.8, 125.5, 124.0, 111.8, 65.7, 48.0. IR ν (cm⁻¹):

3054, 2974, 2916, 2866, 1625, 1608, 1562, 1526, 1478, 1466,

1455, 1446, 1392. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₂H₁₃N₆O 257.1145; found 257.1145 (<0.01 ppm).

Tautomeric mixture of 5-(diethylamino)tetrazolo[1,5-c]qui-

nazoline (4f-T) and 4-azido-2-(diethylamino)quinazoline (4f-A).

Diethylamine (0.18 mL, ρ = 0.71 g mL⁻¹, 1.71 mmol, 3.0 eq.)

was added to a stirred solution of 3 (107 mg, 0.341 mmol, 1.0

eq.) in DMF (3 mL). The mixture was stirred at r.t. for 5 d, con-

trolled by HPLC. Once the reaction was complete, the brine

solution (30 mL) was added, and the mixture was extracted

Synthesis of 4-(arylthio)-2-(piperidinyl)quinazoline derivatives 5

4-[(4-Chlorophenyl)thio]-2-(piperidin-1-yl)quinazoline (5a).

with a solution of Hex and EtOAc (6 : 1) (3 × 10 mL). The Method A: To a solution of 2-chloro-4-[(4-chlorophenyl)thio]

organic phase was combined, washed with water (5 × 5 mL), quinazoline (1a) (182 mg, 0.59 mmol, 1.0 eq.) in i-PrOH

dried over anhydrous Na₂SO₄, evaporated and purified using (10 mL) piperidine (0.17 mL, ρ = 0.86 g mL⁻¹, 1.77 mmol, 3.0

silica gel column chromatography (Tol/MeCN; 0 → 15%). eq.) was added and the mixture was stirred at 50 °C for 5 h,

Yield: 35 mg (42%); oﬀ-white solid; R_f(Tol/MeCN; 10 : 1) 0.62; controlled using HPLC. After completion of the reaction the

m.p. 83–85 °C. Only the tetrazolo form was characterized from mixture was purified using silica gel column chromatography

a 94 : 6 mixture of 4f-T/4f-A: ¹H NMR (500 MHz, DMSO-d₆): (Tol). Yield: 128 mg (71%); slightly green solid; R_f(Tol/MeCN;

δ 8.33 (d, 1H, ³J = 7.8 Hz, H–C(10)), 7.79 (dd, 1H, ³J = 8.3, 10 : 1) 0.74; m.p. 148–151 °C.

7.3 Hz, H–C(8)), 7.66 (d, 1H, ³J = 8.2 Hz, H–C(7)), 7.47 (dd, 1H,

Method B: The suspension of 2,4-dichloroquinazoline (9)

3

³J = 7.8, 7.3 Hz, H–C(9)), 3.95 (q, 4H, J = 6.9 Hz, 2 × (–CH₂–)), (200 mg, 1.00 mmol, 1.0 eq.), K₂CO₃(166 mg, 1.20 mmol, 1.2

3

1.34 (t, 6H, J = 6.9 Hz, 2 × (–CH₃)). ¹³C{¹H} NMR (125.7 MHz, eq.) and 4-chlorothiophenol (158 mg, 1.10 mmol, 1.1 eq.) in

DMSO-d₆): δ 151.3, 144.8, 141.7, 133.6, 125.2, 124.2, 123.9, i-PrOH (10 mL) was stirred at 0–5 °C for 1 h, controlled using

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HPLC. Then piperidine (0.30 mL, ρ = 0.88 g mL⁻¹, 3.00 mmol, Synthesis of 5-(alkylthio)tetrazolo[1,5-c]quinazoline

3.0 eq.) was added and the mixture was stirred at 50 °C for 5 h, derivatives 6

controlled using HPLC. After the completion of the reaction

5-(Decylthio)tetrazolo[1,5-c]quinazoline (6a). Decanethiol

the mixture was purified using silica gel column chromato-

(0.07 mL, ρ = 0.84 g mL⁻¹, 0.32 mmol, 1.2 eq.) and K₂CO₃

1

graphy (Tol). Yield: 192 mg (54%). H NMR (500 MHz, DMSO-

(48 mg, 0.35 mmol, 1.3 eq.) were added to a stirred solution

3

d₆): δ 7.89 (d, 1H, J = 8.1 Hz, H–C(5)), 7.70 (dd, 1H, J = 8.3,

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

(85 mg, 0.27 mmol, 1.0 eq.) in THF (3 mL). The suspension

was stirred at r.t. for 1.5 h, controlled using HPLC. Then the

mixture was evaporated, suspended in toluene (10 mL) and

washed with water (3 × 2 mL). The organic phase was dried

over anhydrous Na₂SO₄, filtered, evaporated and purified

using silica gel column chromatography (Tol). Yield: 76 mg

(82%); oﬀ-white solid; R_f(Tol/MeCN; 10 : 1) 0.69;

3

7.1 Hz, H-(7)), 7.65 (d, 2H, J = 8.5 Hz, 2 × H–C(Ar)), 7.58 (d,

2H, J = 8.5 Hz, 2 × H–C(Ar)), 7.45 (d, 1H, J = 8.3 Hz, H–C(8)),

7.25 (dd, 1H, J = 8.1, 7.1 Hz, H-(6)), 3.51 (br.s., 4H, 2 × H₂–C

3

(1′)), 1.60–1.53 (m, 2H, H₂–C(3′)), 1.44–1.31 (m, 4H, 2 × H₂–C

(2′)). ¹³C{¹H} NMR (125.7 MHz, DMSO-d₆): δ 169.9, 156.6,

151.0, 137.7, 134.7, 134.4, 129.2, 126.3, 125.7, 123.5, 122.3,

116.8, 44.3, 25.2, 24.3. IR ν (cm⁻¹): 2998, 2927, 2851, 1610,

1563, 1541, 1507, 1476, 1451, 1425, 1389, 1347. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₉H₁₉ClN₃S 356.0983; found 356.0981

(0.56 ppm).

1

m.p. 94–96 °C. H NMR (500 MHz, CDCl₃) δ: 8.57 (d, 1H, ³J =

3

7.9 Hz, H–C(10)), 7.97 (d, 1H, J = 8.3 Hz, H–C(7)), 7.87 (dd,

1H, ³J = 8.3, 7.6 Hz, H–C(8)), 7.69 (dd, 1H, ³J = 7.9, 7.6 Hz,

3

H–C(9)), 3.48 (t, 2H, J = 7.4 Hz, H₂–C(1′)), 1.90 (quintet, 2H,

³J = 7.4 Hz, H₂–C(2′)), 1.54 (quintet, 2H, ³J = 7.4 Hz, H₂–C

(3′)), 1.42–1.35 (m, 2H, H₂–C(4′)), 1.33–1.24 (m, 10H, 5 ×

(–CH₂–)), 0.87 (t, 3H, ³J = 6.9 Hz, H₂–C(10′)). ¹³C{¹H} NMR

(125.7 MHz, CDCl₃) δ: 148.7, 147.3, 143.8, 133.7, 128.3,

127.5, 124.8, 113.5, 32.0, 31.0, 29.7, 29.6, 29.4, 29.2, 28.9,

28.8, 22.8, 14.2. IR ν (cm⁻¹): 2955, 2926, 2849, 1618, 1586,

1560, 1489, 1478, 1473, 1451, 1422, 1381. HRMS (ESI) m/z:

[M + H]⁺calcd for C₁₈H₂₆N₅S 344.1910; found 344.1909

(2.91 ppm).

4-[(4-Bromophenyl)thio]-2-(piperidin-1-yl)quinazoline (5b).

The suspension of 2,4-dichloroquinazoline (11) (100 mg,

0.50 mmol, 1.0 eq.), K₂CO₃(76 mg, 0.55 mmol, 1.1 eq.) and

4-bromothiophenol (104 mg, 0.55 mmol, 1.1 eq.) in i-PrOH

(10 mL) was stirred at 0–5 °C for 1 h, controlled using HPLC.

Then piperidine (0.15 mL, ρ = 0.86 g mL⁻¹, 1.50 mmol, 3.0 eq.)

was added and the mixture was stirred at 50 °C for 5 h, con-

trolled using HPLC. After the completion of the reaction the

mixture was purified using silica gel column chromatography

(Tol). Yield: 91 mg (46%); slightly green solid; R_f(Tol/MeCN;

10 : 1) 0.78; m.p. 142–145 °C. ¹H NMR (500 MHz, CDCl₃): δ

5-(Cyclohexylthio)tetrazolo[1,5-c]quinazoline(6b).

Cyclohexanethiol (0.06 mL, ρ = 0.95 g mL⁻¹, 0.49 mmol, 1.2

eq.) and K₂CO₃(73 mg, 0.53 mmol, 1.3 eq.) were added to a

stirred solution of 3 (139 mg, 0.44 mmol, 1.0 eq.) in THF

(3 mL). The suspension was stirred at r.t. for 1.5 h, controlled

using HPLC. Then, the NaClO/H₂O solution (10 mL) and

EtOH (3 mL) were added, and the mixture was stirred for

5 min. The organic solvents were evaporated, and the leftover

water suspension was extracted using DCM (3 × 15 mL). The

organic phase was washed with water (3 × 5 mL), dried over

anhydrous Na₂SO₄, filtered, the solvent was evaporated and

purified using silica gel column chromatography (Tol/MeCN;

10 : 1). Yield: 95 mg (76%); oﬀ-white solid; R_f(Tol/MeCN;

10 : 1) 0.66; m.p. 139–141 °C. ¹H NMR (500 MHz, CDCl₃): δ

3

7.87 (d, 1H, J = 8.1 Hz, H–C(5)), 7.60 (dd, 1H, J = 7.9, 7.4 Hz,

3

H–C(7)), 7.57 (d, 2H, J = 8.4 Hz, 2 × H–C(Ar)), 7.49 (d, 1H, J =

7.9 Hz, H–C(8)), 7.47 (d, 2H, ³J = 8.4 Hz, 2 × H–C(Ar)), 7.15 (dd,

3

1H, J = 8.1, 7.4 Hz, H–C(6)), 3.61–3.53 (m, 4H, 2 × H₂–C(1′)),

1.63–1.59 (m, 2H, H₂–C(3′)), 1.50–1.45 (m, 4H, 2 × H₂–C(2′)).

¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ 170.5, 157.4, 151.8, 137.8,

133.9, 132.1, 127.8, 126.1, 123.9 (2C, assigned using heteronuc-

lear single quantum coherence (HSQC) and heteronuclear

multiple bond correlation (HMBC) spectra), 121.8, 117.8, 45.0,

25.9, 25.0. IR ν (cm⁻¹): 2924, 2850, 1610, 1564, 1542, 1507,

1479, 1425, 1388, 1347. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₉H₁₉BrN₃S 400.0478; found 400.0456 (5.50 ppm).

3

8.57 (d, 1H, J = 7.9 Hz, H–C(10)), 7.98 (d, 1H, J = 8.3 Hz, H–

3

C(7)), 7.87 (dd, 1H, J = 8.3, 7.6 Hz, H–C(8)), 7.69 (dd, 1H, J =

7.9, 7.6 Hz, H–C(9)), 4.27 (tt, 1H, ³J = 10.1, 3.8 Hz, H_A),

2.31–2.22 (m, 2H, 2 × H_B), 1.90–1.83 (m, 2H, 2 × H_C),

1.78–1.67 (m, 3H, H_D, 2 × H_E), 1.63–1.54 (m, 2H, 2 × H_F),

1.48–1.38 (m, 1H, H_G). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ

148.8, 147.1, 143.8, 133.6, 128.2, 127.6, 124.8, 113.6, 44.9,

32.8, 25.9, 25.7. IR ν (cm⁻¹): 2937, 2909, 2872, 2862, 2844,

1618, 1584, 1560, 1487, 1474, 1447, 1378. HRMS (ESI) m/z:

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[M + H]⁺calcd for C₁₄H₁₆N₅S 286.1121; found 286.1109 {¹H} NMR (125.7 MHz, CD₃COOD): δ 176.4, 175.1, 174.8,

(4.19 ppm).

173.1, 150.6, 148.2, 145.4, 135.8, 130.4, 129.4, 126.5, 115.2,

55.6, 54.2, 42.6, 33.5, 33.2, 27.4. IR ν (cm⁻¹): 3348, 3317,

3293, 3291, 1740, 1640, 1619, 1591, 1575, 1542, 1494, 1476,

1451. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₈H₂₁N₈O₆S

477.1299; found 477.1275 (5.03 ppm).

5-(Isopropylthio)tetrazolo[1,5-c]quinazoline (6c). Propane-2-

thiol (0.05 mL, ρ = 0.81 g mL⁻¹, 0.53 mmol, 1.1 eq.) was

added to a stirred suspension of 5-(arylthio)tetrazolo[1,5-c]

quinazoline 3 (150 mg, 0.48 mmol, 1.0 eq.) and K₂CO₃

(79 mg, 0.58 mmol, 1.2 eq.) in DMF (3 mL). The suspension

was stirred at 0–5 °C for 1 h, controlled using HPLC. Once the

reaction was complete, NaClO/H₂O solution (10 mL) and

EtOH (3 mL) were added, and the mixture was stirred for

10 min. Then the organic solvents were evaporated, and the

leftover water suspension was extracted using DCM (3 ×

15 mL). The organic phase was washed with water (3 × 5 mL),

dried over anhydrous Na₂SO₄, filtered, and the solvent was

evaporated. Yield: 112 mg (96%); oﬀ-white solid R_f(Tol/

MeCN; 10 : 1) 0.61; m.p. 141–143 °C. ¹H NMR (500 MHz,

CDCl₃): δ 8.59 (d, 1H, J = 7.9 Hz, H–C(10)), 8.00 (d, 1H, J =

8.2 Hz, H–C(7)), 7.89 (dd, 1H, ³J = 8.2, 7.4 Hz, H–C(8)), 7.71

(dd, 1H, ³J = 7.9, 7.4 Hz, H–C(9)), 4.38 (heptet, 1H, ³J = 6.9 Hz,

H–C(1′)), 1.62 (d, 6H, ³J = 6.9 Hz, 2 × (H₃–C(2′))). ¹³C{¹H}

NMR (125.7 MHz, CDCl₃): δ 148.8, 147.1, 143.9, 133.7, 128.3,

127.6, 124.9, 113.6, 37.4, 22.9. IR ν (cm⁻¹): 3049, 2974, 2923,

2863, 1620, 1584, 1562, 1488, 1452, 1382, 1366. HRMS (ESI)

m/z: [M + H]⁺calcd for C₁₁H₁₂N₅S 246.0808; found 246.0807

(0.41 ppm).

Synthesis of 5-(alkyloxy)tetrazolo[1,5-a/c]quinazoline derivatives

7 and 9

5-(Isopropoxy)tetrazolo[1,5-c]quinazoline

(7a).

5-[(4-

Chlorophenyl)thio]tetrazolo[1,5-c]quinazoline (3) (336 mg,

1.07 mmol, 1.0 eq.) and K₂CO₃(177 mg, 1.28 mmol, 1.2 eq.)

were suspended in i-PrOH (15 mL) and THF (5 mL). The

mixture was stirred at 50 °C for 3 h, controlled using HPLC.

After the completion of the reaction the mixture was evaporated

and purified using silica gel column chromatography (Tol/

MeCN; 6 → 9%). Yield: 190 mg (80%); colorless solid; R_f(Tol/

MeCN; 10 : 1) 0.54; m.p. 210–213 °C. ¹H NMR (500 MHz,

CDCl₃): δ 8.54 (d, 1H, ³J = 7.9 Hz, H–C(10)), 7.86 (d, 1H, ³J = 8.2

Hz, H–C(7)), 7.82 (dd, 1H, ³J = 8.2, 7.3 Hz, H–C(8)), 7.62 (dd, 1H,

3

³J = 7.9, 7.3 Hz, H–C(9)), 5.78 (septet, 1H, J = 6.3 Hz, H–C(1′)),

1.62 (d, 6H, ³J = 6.3 Hz, 2 × H₃–C(2′)). ¹³C{¹H} NMR (125.7 MHz,

CDCl₃): δ 151.4, 143.7, 143.4, 133.8, 127.0, 126.9, 125.0, 113.1,

75.4, 21.8. IR ν (cm⁻¹): 2973, 2926, 1630, 1562, 1524, 1483, 1454,

1418, 1405, 1399, 1367. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₁H₁₂N₅O 230.1036; found 230.1012 (10.43 ppm).

Glutathione–tetrazolo[1,5-c]quinazoline conjugate 6d. To a

stirred solution of 3 (153 mg, 0.49 mmol, 1.0 eq.) and gluta-

thione (165 mg, 0.54 mmol, 1.1 eq.) in DMSO (10 mL) tri-

methylamine (0.17 mL, ρ = 0.73 g mL⁻¹, 1.23 mmol, 2.5 eq.)

was added and the mixture was stirred at r.t. for 5 h, con-

trolled using HPLC. Then methyl tertiary-butyl ether (MTBE)

(40 mL) was added, and the suspension was filtered and

5-(Cyclopentyloxy)tetrazolo[1,5-c]quinazoline (7b). Sodium

washed with MTBE (3 × 3 mL). The solids were suspended in hydride (60% dispersion in mineral oil corresponding to 11 mg,

a mixture of MeCN (25 mL) and water (10 mL), and 0.5 M 0.44 mmol, 1.5 eq. of pure sodium hydride) was added to a solu-

hydrochloric acid was added until the pH reached 6–7. tion of cyclopentanol (0.05 mL, ρ = 0.94 g mL⁻¹, 0.58 mmol, 2.0

Afterwards the suspension was recrystallized, filtered and eq.) in absolute DMF (4 mL). The mixture was stirred in an ice bath

washed with water (4 × 5 mL). Yield: 121 mg (52%); oﬀ-white for 45 min. Then a suspension of 3 (90 mg, 0.29 mmol, 1.0 eq.) in

solid; R_f(MeOH) 0.60; decomposes at 205 °C. ¹H NMR absolute DMF (1 mL) was added, and the mixture was stirred in an

(500 MHz, CD₃COOD): δ 9.08 (d, 1H, ³J = 7.9 Hz, H–C(10)), ice bath for 1.5 h, controlled using HPLC. After completion of the

8.57 (d, 1H, ³J = 8.3 Hz, H–C(7)), 8.41 (dd, 1H, ³J = 8.3, 7.3 Hz, reaction brine (25 mL) was added, and the mixture was placed in

3

H–C(8)), 8.23 (dd, 1H, J = 7.9, 7.3 Hz, H–C(9)), 5.69 (dd, 1H, the freezer for 2 h. Then the suspension was filtered and washed

3

³J = 8.1, 5.2 Hz, H–C(2′)), 4.66 (dd, 1H, ²J = 14.3 Hz, J = 5.2 with H₂O (5 × 5 mL) and hexane (5 × 5 mL). Yield: 52 mg (71%);

Hz, H_a–C(1′)), 4.54–4.46 (m, 3H, H₂–C(3′), H–C(6′)), 4.21 (dd, colorless solid; R_f(Tol/MeCN; 10 : 1) 0.57; m.p. 210–214 °C. ¹H

3

1H, ²J = 14.3 Hz, ³J = 8.1 Hz, H_b–C(1′)), 3.05 (t, 2H, ³J = 6.7 Hz, NMR (500 MHz, CDCl₃): δ 8.56 (d, 1H, J = 7.9 Hz, H–C(10)), 7.88

H₂–C(4′)), 2.70 (m, 1H, H_a–C(5′)), 2.60 (m, 1H, H_b–C(5′)). ¹³C (d, 1H, ³J = 8.1 Hz, H–C(7)), 7.84 (dd, 1H, ³J = 8.1, 7.4 Hz, H–C(8)),

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7.63 (dd, 1H, J = 7.9, 7.4 Hz, H–C(9)), 5.96–5.84 (m, 1H, H–C(1′)), 8 mL). The aqueous phases were combined and back-extracted

2.21–2.12 (m, 4H, 2 × H₂–C(2′)), 2.00–1.91 (m, 2H, 2 × H_a–C(3′)), with toluene (3 × 5 mL). Then the organic phases were com-

1.80–1.71 (m, 2H, 2 × H_b–C(3′)). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): bined, dried over anhydrous Na₂SO₄, filtered, evaporated and

δ 151.4, 143.8, 143.7, 133.8, 126.98, 126.96, 125.0, 113.1, 84.4, 32.9, recrystallized from EtOH (50 mL). Yield: 277 mg (49%); oﬀ-

24.0. IR ν (cm⁻¹): 3063, 2968, 2873, 1630, 1561, 1524, 1482, 1454, white solid; R_f(Tol/MeCN 10 : 1) 0.31; m.p. 171–173 °C. ¹H

1419, 1407, 1399. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₃H₁₄N₅O NMR (500 MHz, CDCl₃): δ 8.52 (d, 1H, ³J = 8.3 Hz, H–C(9)),

3

256.1193; found 256.1189 (1.56 ppm).

8.35 (d, 1H, J = 8.1 Hz, H–C(6)), 8.04 (dd, 1H, J = 8.3, 7.5 Hz,

3

HC(8)), 7.74 (dd, 1H, J = 8.1, 7.5 Hz, H–C(7)), 7.58 (d, 2H, J =

7.2 Hz, 2 × H–C(Ph)), 7.44 (t, 2H, ³J = 7.2 Hz, 2 × H–C(Ph)),

7.40 (t, 1H, ³J = 7.2 Hz, H–C(Ph)), 5.78 (s, 2H, (–CH₂–)). ¹³C{¹H}

NMR (125.7 MHz, CDCl₃): δ 164.4, 153.2, 135.7, 134.9, 134.0,

129.1, 128.99, 128.95, 128.5, 126.7, 116.3, 113.0, 70.8. IR ν

(cm⁻¹): 1618, 1603, 1548, 1478, 1455, 1421, 1394, 1343, 1305.

HRMS (ESI) m/z: [M + H]⁺calcd for C₁₅H₁₂N₅O 278.1036;

found 278.1060 (8.63 ppm).

Diacetone glucose–quinazoline conjugate 7c. Sodium

hydride (60% dispersion in mineral oil corresponding to

19 mg, 0.80 mmol, and 1.2 eq. of pure sodium hydride) was

added to a solution of diacetone glucose (226 mg, 0.869 mmol,

1.3 eq.) in absolute DMF (5 mL). The mixture was stirred in an

ice bath for 45 min. Then a suspension of 3 (210 mg,

0.67 mmol, 1.0 eq.) in absolute DMF (2 mL) was added, and

the mixture was stirred in an ice bath for 3 h, controlled using

HPLC. After completion of the reaction brine (25 mL) was

added, and the mixture was placed in the freezer for 2 h. Then

the suspension was filtered, washed with H₂O (5 × 5 mL) and

hexane (5 × 5 mL). The solids were purified using silica gel

column chromatography (Tol/MeCN; 0 → 15%). Yield: 149 mg

(52%); colorless solid; R_f(Tol/MeCN; 10 : 1) 0.38;

Synthesis of the 2,4-bis-(arylthio)quinazoline derivatives 12

This method was used to synthesize compounds 12a and 12b.

2,4-Bis-[(4-chlorophenyl)thio]quinazoline (12a). Anhydrous

K₂CO₃(1.52 g, 11.0 mmol, 2.2 equiv.) was added to a stirred

solution of arylthiol (11.0 mmol, 2.2 equiv.) and 2,4-dichloroqui-

nazoline (11) (1.0 g, 5.0 mmol, 1.0 equiv.) in EtOH (50 mL)

under argon. The reaction mixture was stirred at 40 °C for 18 h,

controlled using HPLC. Then the mixture was cooled to room

temperature and filtered. The precipitate was washed with water

(2 × 8 mL) and EtOH (3 × 6 ml) and dried in a vacuum. Yield

1

m.p. 175–177 °C. H NMR (500 MHz, DMSO-d₆): δ 8.52 (d, 1H,

³J = 7.9 Hz, H–C(10)), 8.01–7.96 (m, 2H, H–C(7), H–C(8)),

7.80–7.75 (m, 1H, H–C(9)), 6.06 (d, 1H, ³J = 3.8 Hz, H–C(1′)),

3

5.76 (d, 1H, J = 2.2 Hz, H–C(3′)), 5.00 (d, 1H, J = 3.8 Hz, H–C

(2′)), 4.52–4.46 (m, 2H, H–C(4′), H–C(5′)), 4.24–4.19 (m, 1H,

H_a–C(6′)), 4.10–4.05 (m, 1H, H_b–C(6′)), 1.52, 1.35, 1.28, 1.21

(4s, 12H, 4 × (–CH₃)). ¹³C{¹H} NMR (125.7 MHz, DMSO-d₆): δ

151.2, 142.8, 142.7, 134.0, 127.5, 126.7, 124.4, 113.3, 111.5,

108.2, 104.7, 81.8, 81.2, 78.6, 72.4, 65.4, 26.5, 26.4, 26.1, 25.1.

IR ν (cm⁻¹): 2990, 2937, 2894, 1634, 1565, 1525, 1484, 1457,

1412, 1373, 1348. HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₀H₂₄N₅O₆430.1721; found 430.1732 (2.56 ppm).

1

1.5 g (71%); colorless solid, R_f(Tol) 0.37, m.p. 135–137 °C. H

3

NMR (500 MHz, CDCl₃): δ 7.95 (dd, 1H, J = 8.3 Hz, ⁴J = 1.3 Hz,

3

H–C(5)), 7.72–7.66 (m, 2H, H–C(7), H–C(8)), 7.39 (ddd, 1H, J =

8.3, 6.5 Hz, ⁴J = 1.7 Hz, H–C(6)), 7.23 (d, 2H, ³J = 8.5 Hz, 2 × H–

C(Ar)), 7.20 (d, 2H, ³J = 8.7 Hz, 2 × H–C(Ar)), 7.17 (d, 2H, ³J = 8.7

3

Hz, 2 × H–C(Ar)), 7.12 (d, 2H, J = 8.5 Hz, 2 × H–C(Ar)). ¹³C{¹H}

NMR (125.7 MHz, CDCl₃): δ 171.3, 166.3, 149.3, 136.9, 136.3,

136.2, 135.2, 134.6, 129.4, 129.1, 128.3, 127.8, 126.6, 125.0,

123.9, 120.9. IR ν (cm⁻¹): 3089, 3047, 3010, 1697, 1613, 1571,

1556, 1519, 1474, 1434. HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₀H₁₃Cl₂N₂S₂414.9892; found 414.9896 (0.96 ppm).

5-(Benzyloxy)tetrazolo[1,5-a]quinazoline

(9b).

Sodium

hydride (60% dispersion in mineral oil corresponding to

68 mg, 2.83 mmol, and 1.2 eq. of pure sodium hydride) was

added to a solution of benzyl alcohol (0.29 mL, ρ = 1.04 g

2,4-Bis-[(4-bromophenyl)thio]quinazoline (12b). Yield (from

mL⁻¹, 2.83 mmol, 1.2 eq.) and 2,4-diazidoquinazoline (8) 0.5 g (2.5 mmol) of 11) 1.0 g (84%); colorless solid; R_f(Tol) 0.38;

(500 mg, 2.36 mmol, 1.0 eq.) in absolute DMF (7 mL). The m.p. 156–158 °C. ¹H NMR (500 MHz, CDCl₃): δ 8.07 (dd, 1H, ³J =

4

3

4

mixture was stirred at r.t. for 2.5 h, controlled using HPLC. 8.3 Hz, J = 1.3 Hz, H–C(5)), 7.81 (ddd, 1H, J = 7.9, 6.7 Hz, J =

After completion of the reaction toluene (60 mL) was added, 1.3 Hz, H–C(7)), 7.77 (dd, 1H, J = 7.9 Hz, J = 1.4 Hz, H–C(8)),

and the mixture was washed with 5% LiCl/H₂O solution (5 × 7.51 (ddd, 1H, J = 8.3, 6.7 Hz, J = 1.4 Hz, H–C(6)), 7.45 (d, 2H,

3

4

3

4

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³J = 8.4 Hz, 2 × H–C(Ar)), 7.40 (d, 2H, J = 8.4 Hz, 2 × H–C(Ar)), Hz, H–C(8)), 7.61 (dd, 1H, J = 8.3, 6.9 Hz, H–C(7)), 7.55 (d, 2H,

7.27 (d, 2H, J = 8.4 Hz, 2 × H–C(Ar)), 7.24 (d, 2H, J = 8.4 Hz, ³J = 8.6 Hz, 2 × H–C(Ar)), 7.51 (d, 2H, J = 8.6 Hz, 2 × H–C(Ar)),

2 × H–C(Ar)). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ 171.3, 7.28 (dd, 1H, ³J = 8.3, 6.9 Hz, H–C(6)), 3.61–3.56 (m, 4H, 2 × H₂–

166.2, 149.3, 137.1, 136.6, 134.7, 132.5, 132.1, 129.1, 127.8, 126.7, C(1′)), 1.72–1.67 (m, 2H, H₂–C(3′)), 1.65–1.61 (m, 4H, 2 × H₂–C

125.8, 124.5, 124.0, 123.5, 121.0. IR ν (cm⁻¹): 3091, 306, (2′)). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ 165.9, 163.8, 153.0,

3046, 2943, 2911, 1614, 1554, 1518, 1471, 1434. HRMS (ESI) m/z: 137.0, 132.7, 131.8, 130.5, 127.6, 125.4, 123.9, 123.0, 114.5, 50.7,

[M + H]⁺calcd for C₂₀H₁₃Br₂N₂S₂504.8861; found 504.8857 26.0, 24.8. IR ν (cm⁻¹): 2942, 1931, 2917, 2850, 1609, 1564, 1524,

3

(0.79 ppm).

1498, 1471, 1463, 1438, 1364, 1352. HRMS (ESI) m/z: [M + H]⁺

calcd for C₁₉H₁₉BrN₃S 400.0478; found 400.0473 (1.25 ppm).

Synthesis of 2-(arylthio)-4-(piperidinyl)quinazoline derivatives 13

Synthesis of 2-amino-4-(1H-1,2,3-triazol-1-yl)quinazoline

derivatives 14

2-[(4-Chlorophenyl)thio]-4-(piperidin-1-yl)quinazoline (13a).

To a solution of 12a (280 mg, 0.68 mmol, 1.0 eq.) in DMF

(5 mL) piperidine (0.20 mL, ρ = 0.86 g mL⁻¹, 2.04 mmol, 3.0

eq.) was added and the mixture was stirred at r.t. for 5 h, con-

trolled using HPLC. After completion of the reaction brine

(25 mL) was added, and the mixture was placed in the freezer

for 2 h. Then the suspension was filtered and washed with

H₂O (5 × 5 mL) and hexane (5 × 5 mL). The solids were recrys-

tallized from EtOH (20 mL). Yield: 166 mg (69%); oﬀ-white

solid; R_f(Tol/MeCN 10 : 1) 0.73; m.p. 88–91 °C. ¹H NMR

4-(4-Phenyl-1H-1,2,3-triazol-1-yl)-2-(piperidin-1-yl)quinazo-

line (14a). To a solution of 4a (130 mg, 0.51 mmol, 1.0 eq.) in

absolute toluene (10 mL) acetic acid (0.03 mL, 0.56 mmol, 1.1

eq.), DIPEA (0.10 mL, ρ = 0.74 g mL⁻¹, 0.56 mmol, 1.1 eq.),

phenylacetylene (0.11 mL, ρ = 0.93 g mL⁻¹, 1.02 mmol, 2.0 eq.)

and CuI (5 mg, 0.026 mmol, 5 mol-%) were subsequently added

and the mixture was stirred in a high-pressure flask at 130 °C for

16 h, controlled using HPLC. After completion of the reaction

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

washed with saturated ethylenediaminetetraacetic acid (EDTA)

solution (3 × 10 mL). The aqueous layers were combined and

back-extracted with DCM (3 × 5 mL). The organic phases were

combined, dried over anhydrous Na₂SO₄, filtered, evaporated

and purified using silica gel column chromatography (Tol/EtOAc

9 → 11%). Yield: 73 mg (40%); bright yellow solid; R_f(Tol/MeCN

3

(500 MHz, CDCl₃): δ 7.74 (d, 1H, J = 8.3 Hz, H–C(5)), 7.65 (d,

1H, ³J = 8.4 Hz, H–C(8)), 7.63–7.59 (m, 3H, H–C(7), 2 × H–C

3

(Ar)), 7.37 (d, 2H, J = 8.5 Hz, 2 × H–C(Ar)), 7.28 (dd, 1H, J =

8.3, 7.0 Hz, H–C(6)), 3.60–3.56 (m, 4H, 2 × H₂–C(1′)), 1.72–1.67

(m, 2H, H₂–C(3′)), 1.66–1.61 (m, 4H, 2 × H₂–C(2′)). ¹³C{¹H}

NMR (125.7 MHz, CDCl₃): δ 165.9, 163.7, 152.9, 136.7, 134.7,

132.6, 129.8, 128.7, 127.4, 125.3, 123.9, 114.4, 50.6, 25.9, 24.7.

IR ν (cm⁻¹): 2936, 2861, 1608, 1557, 1500, 1476, 1429, 1389,

1357, 1343, 1290. HRMS (ESI) m/z: [M + H]⁺calcd for

C₁₉H₁₉ClN₃S 356.0983; found 356.0982 (0.28 ppm).

1

10 : 1) 0.77; m.p. 175–178 °C. H NMR (500 MHz, CDCl₃): δ 8.89

3

(d, 1H, J = 8.3 Hz, H–C(5)), 8.78 (s, 1H, H–C(triazole)), 8.00 (d,

2H, ³J = 7.5 Hz, 2 × H–C(Ph)), 7.71 (dd, 1H, ³J = 8.3, 7.6 Hz, H–C

(8)), 7.64 (d, 1H, ³J = 8.3 Hz, H–C(7)), 7.50 (t, 2H, ³J = 7.5 Hz, 2 ×

3

H–C(Ph)), 7.41 (t, 1H, J = 7.5 Hz, H–C(Ph)), 7.28 (dd, 1H, J =

3

8.3, 7.6 Hz, H–C(6)), 3.95 (dd, 4H, J = 5.5, 4.8 Hz, 2 × H₂–C(1′)),

1.77–1.67 (m, 6H, 2 × H₂–C(2′), H₂–C(3′)). ¹³C{¹H} NMR

(125.7 MHz, CDCl₃): δ 157.8, 156.6, 154.3, 147.1, 134.8, 130.0,

129.1, 128.8, 127.4, 126.3, 126.2, 123.5, 119.6, 111.3, 45.3, 26.0,

25.0. IR ν (cm⁻¹): 3148, 3103, 3061, 2931, 2851, 1619, 1589, 1548,

1514, 1483, 1452, 1422, 1351. HRMS (ESI) m/z: [M + H]⁺calcd for

C₂₁H₂₁N₆357.1822; found 357.1796 (7.28 ppm).

2-[(4-Bromophenyl)thio]-4-(piperidin-1-yl)quinazoline (13b).

To a solution of 12b (150 mg, 0.30 mmol, 1.0 eq.) in DMF

(10 mL) piperidine (0.09 mL, ρ = 0.86 g mL⁻¹, 0.90 mmol, 3.0

eq.) was added and the mixture was stirred at r.t. for 5 h, con-

trolled using HPLC. After completion of the reaction brine

(25 mL) was added, and the mixture was placed in the freezer for

2 h. Then the suspension was filtered and washed with H₂O (5 ×

5 mL). The solids were purified using silica gel column chrom-

atography (Tol/MeCN 3%). Yield: 70 mg (58%); oﬀ-white solid; R_f

(Tol/MeCN; 10 : 1) 0.63; m.p. 114–116 °C. ¹H NMR (500 MHz,

3

CDCl₃): δ 7.74 (d, 1H, J = 8.3 Hz, H–C(5)), 7.65 (d, 1H, J = 8.3

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Paper

4-(4-Phenyl-1H-1,2,3-triazol-1-yl)-2-(4-methylpiperazin-1-yl)

with HSQC spectrum), 24.3, 16.8. IR ν (cm⁻¹): 3164, 3118,

quinazoline (14b). 4d (35 mg, 0.13 mmol, 1.0 eq.), absolute 3073, 3009, 2939, 2916, 2854, 2249, 1621, 1587, 1547, 1516,

toluene (4 mL), acetic acid (0.01 mL, 0.14 mmol, 1.1 eq.), 1486, 1466, 1429. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₉H₂₂N₇

DIPEA (0.02 mL, ρ = 0.74 g mL⁻¹, 0.14 mmol, 1.1 eq.), phenyl- 348.1931; found 348.1934 (0.86 ppm).

acetylene (0.03 mL, ρ = 0.93 g mL⁻¹, 0.26 mmol, 2.0 eq.), and

CuI (1 mg, 0.01 mmol, 5 mol-%) were combined and reacted

for 16 h. Purified using silica gel column chromatography

(DCM : MeOH 0 → 5%). Yield: 23 mg (48%); bright yellow

solid; R_f(EtOAc) 0.15; m.p. 180–182 °C.

Method B: To a solution of 4d (75 mg, 0.30 mmol, 1.0 eq.) in

absolute toluene (2 mL), phenylacetylene (0.07 mL, ρ = 0.93 g

mL⁻¹, 0.60 mmol, 2.0 eq.) and CpRuCl(PPh₃)₂(11 mg,

0.015 mmol, 5 mol%) were added and the mixture was stirred

in a high-pressure flask at 140 °C for 48 h, controlled using

HPLC. After completion of the reaction the mixture was evap-

Synthesis of 4-amino-2-[(4-chlorophenyl)thio]quinazoline (15)

Method A: To a solution of 3 (90 mg, 0.29 mmol, 1.0 eq.) in

orated and purified using silica gel column chromatography

absolute THF (2 mL) tributylphosphine (0.11 mL, ρ = 0.82 g

1

(DCM/EtOAc 0 → 5%). Yield: 26 mg (24%) H NMR (500 MHz,

mL⁻¹, 0.43 mmol, 1.5 eq.) was added and the yellow mixture

CDCl₃): δ 8.93 (d, 1H, ³J = 8.3 Hz, H–C(5)), 8.79 (s, 1H, H–C(tri-

was stirred at r.t. under argon for 10 min, until the color dis-

appeared. Then 1 M HCl/H₂O solution (2 mL) was added and

the mixture was stirred at r.t. for 24 h, controlled using HPLC.

After completion of the reaction the mixture was evaporated,

suspended in EtOAc (20 mL) and washed with a saturated

NaHCO₃/H₂O solution (5 × 5 mL). The organic phase was dried

over anhydrous Na₂SO₄, filtered, evaporated and recrystallized

from CHCl₃(20 mL). Yield: 66 mg (80%); oﬀ-white solid; R_f

(Tol/MeCN; 10 : 1) 0.31; decomposes at 255 °C.

azole)), 8.00 (d, 2H, ³J = 7.6 Hz, 2 × H–C(Ph)), 7.74 (dd, 1H, ³J =

3

8.3, 7.4 Hz, H–C(8)), 7.67 (d, 1H, J = 8.3 Hz, H–C(7)), 7.50 (t,

2H, ³J = 7.6 Hz, 2 × H–C(Ph)), 7.41 (t, 1H, ³J = 7.6 Hz, H–C(Ph)),

3

7.32 (dd, 1H, J = 8.3, 7.4 Hz, H–C(6)), 4.02 (dd, 4H, J = 4.8,

3

4.5 Hz, 2 × (H₂–C(1′))), 2.56 (dd, 4H, J = 4.8, 4.5 Hz, 2 × (H₂–C

(2′))), 2.39 (s, 3H, (–CH₃)). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ

157.7, 156.4, 154.4, 147.1, 135.0, 129.9, 129.1, 128.9, 127.4,

126.31, 126.26, 124.0, 119.6, 111.6, 55.1, 46.4, 44.3. IR ν

(cm⁻¹): 3149, 3058, 3002, 2956, 2932, 2795, 1619, 1594, 1547,

1520, 1484, 1456, 1429. HRMS (ESI) m/z: [M − H]⁻calcd for

C₂₁H₂₀N₇370.1786; found 370.1784 (0.54 ppm).

Method B: To a solution of 3 (110 mg, 0.35 mmol, 1.0 eq.) in

THF (5 mL) solutions of CuSO₄·5H₂O (9 mg, 0.04 mmol,

10 mol–%) in H₂O (1 mL) and sodium ascorbate (76 mg,

0.39 mmol, 1.1 eq.) in H₂O (1 mL) were subsequently added

and the mixture was stirred at r.t. for 16 h, controlled using

HPLC. After completion of the reaction the mixture was evap-

orated, suspended in EtOAc (20 mL) and washed with satu-

rated EDTA/H₂O solution (2 × 5 mL) and water (2 × 5 mL). The

organic phase was dried over anhydrous Na₂SO₄, filtered and

the solvent was evaporated. Yield: 91 mg (90%). ¹H NMR

3

(500 MHz, DMSO-d₆): δ 8.13 (d, 1H, J = 8.4 Hz, H–C(5)), 7.92

3

(br.s., 2H, (–NH₂)), 7.67 (dd, 1H, J = 8.1, 7.5 Hz, H–C(7)), 7.64

(d, 2H, ³J = 8.5 Hz, 2 × H–C(Ar)), 7.50 (d, 2H, ³J = 8.5 Hz, 2 × H–

C(Ar)), 7.40–7.35 (m, 2H, H–C(6), H–C(8)). ¹³C{¹H} NMR

(125.7 MHz, DMSO-d₆): δ 165.9, 161.5, 150.1, 136.2, 133.4,

133.3, 129.7, 128.9, 126.2, 124.7, 123.8, 112.8. IR ν (cm⁻¹):

3398, 3312, 3120, 1648, 1615, 1568, 1538, 1505, 1476, 1460,

1444. HRMS (ESI) m/z: [M + H]⁺calcd for C₁₄H₁₁ClN₃S

288.0357; found 288.0343 (4.86 ppm).

4-[4-(3-Cyanoprop-1-yl)-1H-1,2,3-triazol-1-yl]-2-(piperidin-1-

yl)quinazoline (14c). 4a (66 mg, 0.26 mmol, 1.0 eq.), absolute

toluene (4 mL), acetic acid (0.02 mL, 0.31 mmol, 1.1 eq.),

DIPEA (0.05 mL, ρ = 0.74 g mL⁻¹, 0.29 mmol, 1.1 eq.), 5-hexy-

nenitrile (0.08 mL, ρ = 0.89 g mL⁻¹, 0.78 mmol, 2.0 eq.), and

CuI (2 mg, 0.013 mmol, 5 mol-%) were combined and reacted

time for 72 h. Purified using silica gel column chromatography

(Tol/MeCN 1 → 6%). Yield: 47 mg (52%); bright yellow solid; R_f

(Tol/MeCN 10 : 1) 0.40; m.p. 182–184 °C. ¹H NMR (500 MHz,

CDCl₃): δ 8.82 (d, 1H, ³J = 8.6 Hz, H–C(5)), 8.41 (s, 1H, H–C(tri-

3

azole)), 7.69 (dd, 1H, J = 8.6, 8.5 Hz, H–C(7)), 7.63 (d, 1H, J =

8.5 Hz, H–C(8)), 7.28–7.24 (m, 1H, H–C(6)), 3.95–3.90 (m, 4H, 2

3

× H₂–C(1′)), 3.04 (t, 2H, J = 7.2 Hz, H₂–C(1″)), 2.52 (t, 2H, J =

7.2 Hz, H₂–C(3″)), 2.22 (quintet, 2H, ³J = 7.2 Hz, H₂–C(2″)),

1.75–1.66 (m, 6H, 2 × H₂–C(2′), H₂–C(3′)). ¹³C{¹H} NMR

Synthesis of quinazoline iminophosphorane derivatives 16

2-[(4-Chlorophenyl)thio]-4-[(tributylphosphoronylidene)

(125.7 MHz, CDCl₃): δ 157.7, 156.6, 154.2, 145.1, 134.8, 127.3, amino]-quinazoline (16a). To

a solution of 3 (120 mg,

126.2, 123.5, 121.7, 119.4, 111.2, 45.3, 26.0, 25.0 (2C, assigned 0.382 mmol, 1.0 eq.) in absolute THF (3 mL) tributylphosphine

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(0.19 mL, ρ = 0.82 g mL⁻¹, 0.76 mmol, 2.0 eq.) was added and Synthesis of 4-(alkyl/aryloxy)-2-(1H-1,2,3-triazol-1-yl)

the yellow mixture was stirred at r.t. under argon for 10 min, quinazoline derivatives 17

until the colour disappears. After completion of the reaction

the mixture was evaporated, suspended in hexane (20 mL) and

left in the freezer for 1 h. The white suspension was filtered

2-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-4-(phenyloxy)quinazo-

line (17a). To a solution of 9a (75 mg, 0.29 mmol, 1.0 eq.) and

cyclopropylacetylene (0.05 mL, ρ = 0.78 g mL⁻¹, 0.58 mmol, 2.0

and washed with hexane (2 × 3 mL). Yield: 136 mg (73%);

eq.) in THF (10 mL) solutions of CuSO₄·5H₂O (4 mg,

1

colorless solid; R_f(Tol/MeCN; 10 : 1) 0.38; m.p. 132–134 °C. H

0.014 mmol, 5 mol-%) in H₂O (1 mL) and sodium ascorbate

NMR (500 MHz, CDCl₃): δ 8.20 (d, 1H, ³J = 7.9 Hz, H–C(5)),

(6 mg, 0.029 mmol, 10 mol-%) in H₂O (1 mL) were sub-

3

7.61 (d, 2H, J = 8.3 Hz, 2 × H–C(Ar)), 7.58–7.53 (m, 2H, H–C

sequently added and the mixture was stirred at 40 °C for 24 h,

3

(7), H–C(8)), 7.35 (d, 2H, J = 8.3 Hz, 2 × H–C(Ar)), 7.23 (ddd,

controlled using HPLC. After completion of the reaction the

3

4

1H, J = 7.9, 6.5 Hz, J = 1.7 Hz, H–C(6)), 1.75–1.67 (m, 6H, 3 ×

H₂–C(1′)), 1.41–1.33 (m, 12H, 3 × H₂–C(2′), 3 × H₂–C(3′)), 0.92

(t, 9H, ³J = 6.8 Hz, 3 × H₃–C(4′)). ¹³C{¹H} NMR (125.7 MHz,

mixture was evaporated, suspended in DCM (20 mL) and

washed with saturated EDTA solution (4 × 10 mL). The

aqueous phases were combined and back-extracted with DCM

(3 × 5 mL). Organic phases were combined, dried over anhy-

drous Na₂SO₄, filtered, evaporated and purified using silica gel

column chromatography (Tol/MeCN 14%) and recrystallization

from hexane (30 mL). Yield: 77 mg (82%); oﬀ-white solid; R_f

(Tol/MeCN 10 : 1) 0.19; m.p. 162–164 °C. ¹H NMR (500 MHz,

2

4

CDCl₃): δ 168.5 (D, J_C–P= 8 Hz), 167.1, 151.1 (D, J_C–P= 3 Hz),

137.9, 134.8, 132.5, 130.8, 129.1, 126.4, 125.7, 124.0, 120.5 (D,

2

3

³J_C–P= 21 Hz), 24.3 (D, J_C–P= 16 Hz), 23.9 (D, J_C–P= 4 Hz),

23.5 (D, J_C–P= 61 Hz), 13.8. ³¹P NMR (202 MHz, CDCl₃): δ

1

37.02. IR ν (cm⁻¹): 2956, 2930, 2899, 2867, 1609, 1566, 1499,

1478, 1456, 1428, 1350, 1337. HRMS (ESI) m/z: [M + H]⁺calcd

for C₂₆H₃₆ClN₃PS 488.2051; found 488.2061 (2.23 ppm).

3

CDCl₃): δ 8.41 (d, 1H, J = 8.1 Hz, H–C(5)), 8.15 (d, 1H, J = 8.3

Hz, H–C(8)), 7.97 (dd, 1H, ³J = 8.3, 7.4 Hz, H–C(7)), 7.89 (s, 1H,

3

H–C(triazole)), 7.68 (dd, 1H, J = 8.1, 7.4 Hz, H–C(6)), 7.52 (t,

2H, ³J = 7.5 Hz, 2 × H–C(Ph)), 7.37 (t, 1H, ³J = 7.5 Hz, H–C(Ph)),

3

7.34 (d, 2H, J = 7.5 Hz, 2 × H–C(Ph)), 1.98 (tt, 1H, J = 8.9, 4.4

Hz, H–C(1′)), 0.99–0.93 (m, 2H, 2 × H_a), 0.90–0.85 (m, 2H, 2 ×

H_b). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ 168.6, 152.5, 152.2,

150.4, 149.7, 135.5, 129.9, 128.4, 127.8, 126.4, 124.1, 121.8,

119.0, 115.5, 7.9, 6.8. IR ν (cm⁻¹): 3053, 2914, 1619, 1597,

1571, 1509, 1493, 1472, 1456, 1429, 1391, 1376. HRMS (ESI) m/

z: [M + H]⁺calcd for C₁₉H₁₆N₅O 330.1349; found 330.1360

(3.33 ppm).

2-[(4-Chlorophenyl)thio]-4-[(triphenylphosphoronylidene)-

amino]quinazoline (16b). To

a solution of 3 (150 mg,

0.48 mmol, 1.0 eq.) in absolute THF (4 mL) triphenyl-

phosphine (250 mg, 0.96 mmol, 2.0 eq.) was added and the

mixture was stirred at r.t. under argon for 1 h, controlled using

HPLC. After completion of the reaction the mixture was evap-

orated, suspended in MeCN (20 mL) and left in the freezer for

1 h. The white suspension was filtered and washed with MeCN

(5 × 3 mL) and hexane (2 × 5 mL). Yield: 182 mg (69%); color-

less solid; R_f(Tol/MeCN; 10 : 1) 0.50; m.p. 247–249 °C. ¹H NMR

(500 MHz, CDCl₃): δ 8.60 (d, 1H, ³J = 8.1 Hz, H–C(5)), 7.65–7.55

3

4-(Benzyloxy)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)quinazoline (17b).

To a solution of 9b (55 mg, 0.20 mmol, 1.0 eq.) and phenyl-

acetylene (0.04 mL, ρ = 0.93 g mL⁻¹, 0.40 mmol, 2.0 eq.) in

THF (10 mL) solutions of CuSO₄·5H₂O (3 mg, 0.01 mmol,

5 mol-%) in H₂O (1 mL) and sodium ascorbate (4 mg,

0.02 mmol, 10 mol-%) in H₂O (1 mL) were subsequently added

and the mixture was stirred at 60 °C for 16 h, controlled using

HPLC. After the completion of the reaction DCM (30 mL) and

saturated NaHS/H₂O solution (10 mL) were added and the

mixture was stirred for 3 min, filtered through Celite and then

the layers were separated. The organic phase was washed with

water (3 × 5 mL). The aqueous phases were combined and

back-extracted with DCM (3 × 5 mL). The organic phases were

combined, dried over anhydrous Na₂SO₄, filtered, evaporated

and recrystallized from hexane (30 mL). Yield: 69 mg (91%);

(m, 11H, H–C(7), H–C(8), 9 × H–C(Ph)), 7.43 (td, 6H, J = 7.7

3

Hz, ⁴J = 3.0 Hz, 6 × H–C(Ph)), 7.36 (dd, 1H, J = 8.1, 7.4 Hz, H–

C(6)), 7.18 (d, 2H, ³J = 8.4 Hz, 2 × H–C(Ar)), 6.89 (d, 2H, ³J = 8.4

Hz, 2 × H–C(Ar)). ¹³C{¹H} NMR (125.7 MHz, CDCl₃): δ 167.3 (D,

4

²J_C–P= 7 Hz), 166.4, 151.1 (D, J_C–P= 3 Hz), 136.0, 133.7, 133.2

3

4

(D, J_C–P= 10 Hz), 132.7, 132.3 (D, J_C–P= 3 Hz), 130.2, 128.7

(D, ²J_C–P= 13 Hz), 128.4 (D, ¹J_C–P= 101 Hz), 128.0, 126.8, 126.0,

124.3, 121.4 (D, J_C–P= 22 Hz). ³¹P NMR (202 MHz, CDCl₃): δ

3

16.5. IR ν (cm⁻¹): 3060, 1608, 1566, 1498, 1474, 1449, 1434,

1354, 1330, 1261. HRMS (ESI) m/z: [M + H]⁺calcd for

C₃₂H₂₄ClN₃PS 548.1112; found 548.1100 (2.19 ppm).

1

oﬀ-white solid; R_f(Tol/MeCn 10 : 1) 0.47; m.p. 135–138 °C. H

NMR (500 MHz, CDCl₃): δ 8.88 (s, 1H, H–C(triazole)), 8.26 (d,

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3

1H, J = 8.1 Hz, H–C(5)), 8.06 (d, 1H, J = 8.3 Hz, H–C(8)), 8.00

Acknowledgements

3

(d, 2H, J = 7.5 Hz, 2 × H–C(Ph)), 7.91 (dd, 1H, J = 8.3, 7.4 Hz,

H–C(7)), 7.63 (d, 2H, J = 7.4 Hz, 2 × H–C(Bn)), 7.60 (dd, 1H, J The authors thank the Latvian Council of Science grant LZP-

= 8.1, 7.4 Hz, H–C(6)), 7.49 (t, 2H, J = 7.5 Hz, 2 × H–C(Ph)), 2020/1-0348 for financial support, Dr chem. Kristīne Lazdoviča

3

7.45 (t, 2H, J = 7.4 Hz, 2 × H–C(Bn)), 7.42–7.37 (m, 2H, H–C for IR analysis and Mr Dāgs Dāvis Līpiņš for assistance in

(Ph), H–C(Bn)), 5.82 (s, 2H, (–CH₂–)). ¹³C{¹H} NMR acquiring the experimental data.

(125.7 MHz, CDCl₃): δ 168.8, 151.7, 150.1, 148.0, 135.5, 135.1,

130.3, 129.0, 128.90, 128.85, 128.8, 128.7, 128.0, 127.5, 126.2,

124.2, 118.7, 115.9, 70.1. IR ν (cm⁻¹): 3104, 3057, 3004, 2968,

1618, 1601, 1571, 1548, 1499, 1478, 1468, 1455, 1436, 1421.

Notes and references

HRMS (ESI) m/z: [M + H]⁺calcd for C₂₃H₁₈N₅O 380.1506;

found 380.1500 (1.57 ppm).

1 I. Khan, S. Zaib, S. Batool, N. Abbas, Z. Ashraf, J. Iqbal and

A. Saeed, Bioorg. Med. Chem., 2016, 24, 2361–2381.

2 S. Ravez, O. Castillo-Aguilera, P. Depreux and L. Goossens,

Expert Opin. Ther. Pat., 2015, 25, 789–804.

3 O. O. Ajani, D. V. Aderohunmu, E. N. Umeokoro and

A. O. Olomieja, Bangladesh J. Pharmacol., 2016, 11, 716–

733.

4 J. J. Cui, ACS Med. Chem. Lett., 2014, 5, 272–274.

5 R. S. M. Ismail, N. S. M. Ismail, S. Abuserii and D. A. Abou

El Ella, Future J. Pharm. Sci., 2016, 2, 9–19.

6 S. Mehndiratta, S. Sapra, G. Singh, M. Singh and K. Nepali,

Recent Pat. Anti-Cancer Drug Discov., 2015, 11, 2–66.

7 J. F. M. da Silva, M. Walters, S. Al-Damluji and

C. R. Ganellin, Bioorg. Med. Chem., 2008, 16, 7254–7263.

8 A. K. Parhi, Y. Zhang, K. W. Saionz, P. Pradhan, M. Kaul,

K. Trivedi, D. S. Pilch and E. J. Lavoie, Bioorg. Med. Chem.

Lett., 2013, 23, 4968–4974.

Conclusions

In conclusion, we have demonstrated the dual nucleophile/

nucleofuge nature of the azide and arylthiolate groups and

developed synthetic approaches towards a variety of 5-substi-

tuted

tetrazolo[1,5-c]quinazolines

(4-azido-2-N-,

O-,

S-substituted quinazolines). This results from the intrinsic

property of the azido substituent that allows it to reach azidoa-

zomethine-tetrazole tautomeric equilibrium and is due to the

electron-withdrawing characteristics of the fused tetrazolo

system, which facilitates S_NAr substitution reactions. In this

context the azide substituent can be regarded as an activating

group or reactivity switch, which through the tautomerism

facilitates quinazoline S_NAr reactions at the less accessible C2

position. Many of the amino-substituted compounds demon-

strated a media-controlled azide-tetrazole tautomeric equili-

brium that allowed the use of a hidden azido group in the tet-

razolo[1,5-c]quinazoline core and was able to facilitate CuAAC

and Staudinger iminophosporane synthesis. Structural eluci-

dation and the synthesis of opposite regioisomers also led to

the development of the synthetic method for 5-(alkyl/aryloxy)

tetrazolo[1,5-a]quinazolines from 2,4-diazidoquinazoline. The

developed synthetic procedures for 5-substituted tetrazolo[1,5-

a/c]quinazolines will be a valuable addition to the medicinal

chemistry tool-box, but the photophysical properties of the

described compound classes revealed in this research can

serve as a starting point for further applications in materials

science.

9 E.

Jafari,

M.

R.

Khajouei,

F.

Hassanzadeh,

G. H. Hakimelahi and G. A. Khodarahmi, Res. Pharm. Sci.,

2016, 11, 1–14.

10 J. P. Michael, Nat. Prod. Rep., 2007, 24, 223–246.

11 Y. Zheng, M. Bian, X. Q. Deng, S. B. Wang and Z. S. Quan,

Arch. Pharm., 2013, 346, 119–126.

12 V. P. Krivopalov, S. G. Baram, A. Y. Denisov and

V. I. Mamatyuk, Bull. Acad. Sci. USSR, Div. Chem. Sci., 1989,

38, 1839–1844.

13 J. S. Bindra, U.S. Patent US4085213, 1976.

14 L. M. Antypenko, Sci. Pharm., 2013, 81, 15–42.

15 O. M. Antypenko, L. M. Antypenko, S. I. Kovalenko,

A. M. Katsev and O. M. Achkasova, Arabian J. Chem., 2016,

9, 792–805.

16 S. Jantová, L. Čipák, D. Slameňová, V. Horváth and

P. Rauko, Toxicol. In Vitro, 2003, 17, 457–463.

17 E. Wagner, U.S. Patent US3835138A, 1974.

18 H.-J. Wang, C.-X. Wei, X.-Q. Deng, F.-L. Li and Z.-S. Quan,

Arch. Pharm., 2009, 342, 671–675.

19 M. A. El-Hashash, D. B. Guirguis and Y. A. El-Badry, Der

Pharma Chem., 2011, 3, 147–159.

20 M. A. El-Hashash, K. M. Darwish, S. A. Rizk and F. A. El-

Bassiouny, Org. Chem. Int., 2011, 2011, 1–7.

21 K. H. Ang, C. Donati, A. Donkor and R. H. Prager,

Aust. J. Chem., 1992, 45, 2037–2048.

22 Z. K. Wan, S. Wacharasindhu, C. G. Levins, M. Lin,

K. Tabei and T. S. Mansour, J. Org. Chem., 2007, 72, 10194–

10210.

Conﬂicts of interest

There are no conflicts to declare.

Org. Biomol. Chem.

View Article Online

Paper

Organic & Biomolecular Chemistry

23 A. M. Alanazi, A. A. M. Abdel-Aziz, I. A. Al-Suwaidan, 38 A. Šišuļins, J. Bucevičius, Y.-T. Tseng, I. Novosjolova,

S. G. Abdel-Hamide, T. Z. Shawer and A. S. El-Azab,

Eur. J. Med. Chem., 2014, 79, 446–454.

K. Traskovskis, Ē. Bizdēna, H.-T. Chang, S. Tumkevičius

and M. Turks, Beilstein J. Org. Chem., 2019, 15, 474–489.

24 Š. Stankovsky and K. Špirkova, Monatsh. Chem. – Chem. 39 J. Bucevicius, M. Turks and S. Tumkevicius, Synlett, 2018,

Mon., 1991, 122, 849–852.

29, 525–529.

25 F. Ahmadi and A. Bazgir, RSC Adv., 2016, 6, 61955–61958.

26 T. Vlaar, L. Bensch, J. Kraakman, C. M. L. Vande Velde,

B. U. W. Maes, R. V. A. Orru and E. Ruijter, Adv. Synth.

Catal., 2014, 356, 1205–1209.

27 A. L. Chandgude and A. Dömling, Eur. J. Org. Chem., 2016,

2383–2387.

40 J. M. Zaķis, K. Ozols, I. Novosjolova, R. Vilšķērsts,

A. Mishnev and M. Turks, J. Org. Chem., 2020, 85, 4753–

4771.

41 D. Cīrule, I. Novosjolova, Ē. Bizdēna and M. Turks, Beilstein

J. Org. Chem., 2021, 17, 410–419.

42 A. Sebris and M. Turks, Chem. Heterocycl. Compd., 2019, 55,

1041–1043.

28 A. I. Sánchez, V. Martínez-Barrasa, C. Burgos, J. J. Vaquero,

J. Alvarez-Builla, E. Terricabras and V. Segarra, Bioorg. Med. 43 S. N. Sirakanyan, D. Spinelli, A. Geronikaki, V. G. Kartsev,

Chem., 2013, 21, 2370–2378.

H. A. Panosyan, A. G. Ayvazyan, R. A. Tamazyan, V. Frenna

29 D. Kang, H. Zhang, Z. Zhou, B. Huang, L. Naesens, P. Zhan

and A. A. Hovakimyan, Tetrahedron, 2016, 72, 1919–1927.

and X. Liu, Bioorg. Med. Chem. Lett., 2016, 26, 5182– 44 A. Thomann, J. Zapp, M. Hutter, M. Empting and

5186. R. W. Hartmann, Org. Biomol. Chem., 2015, 13, 10620–10630.

30 S. Gatadi, J. Gour, M. Shukla, G. Kaul, S. Das, A. Dasgupta, 45 T. Kanzian, T. A. Nigst, A. Maier, S. Pichl and H. Mayr,

S. Malasala, R. S. Borra, Y. V. Madhavi, S. Chopra and

S. Nanduri, Eur. J. Med. Chem., 2018, 157, 1056–1067.

31 P. S. Auti, G. George and A. T. Paul, RSC Adv., 2020, 10,

41353–41392.

32 A. Kalniņa, Ē. Bizdēna, G. Kiselovs, A. Mishnev and

M. Turks, Chem. Heterocycl. Compd., 2014, 49, 1667–1673.

33 A. Jeminejs, S. M. Goliškina, I. Novosjolova, D. Stepanovs,

Ē. Bizdēna and M. Turks, Synthesis, 2021, 53, 1443–1456.

34 I. Novosjolova, Ē. Bizdēna and M. Turks, Tetrahedron Lett.,

2013, 54, 6557–6561.

35 A. Kovaļovs, I. Novosjolova, Ē. Bizdēna, I. Bižāne,

L. Skardziute, K. Kazlauskas, S. Jursenas and M. Turks,

Tetrahedron Lett., 2013, 54, 850–853.

36 D. Cīrule, K. Ozols, O. Platnieks, Ē. Bizdēna, I. Māliņa and

M. Turks, Tetrahedron, 2016, 72, 4177–4185.

Eur. J. Org. Chem., 2009, 6379–6385.

46 M. J. O’Neil and P. E. Heckelman, J. Am. Chem. Soc., 2007,

129, 2197–2197.

47 V. P. Krivopalov, V. I. Mamatyuk and E. B. Nikolaenkova,

Russ. Chem. Bull., 1995, 44, 1435–1443.

48 Q. Zhang, X. Wang, C. Cheng, R. Zhu, N. Liu and Y. Hu,

Org. Biomol. Chem., 2012, 10, 2847.

49 H. Khatua, S. K. Das, S. Roy and B. Chattopadhyay, Angew.

Chem., 2021, 60, 304.

50 A. A. Nazarova, K. N. Sedenkova, D. A. Vasilenko,

Y. K. Grishin, T. S. Kuznetsova and E. Averina, Mendeleev

Commun., 2020, 30, 714–716.

51 K. Ozols, D. Cīrule, I. Novosjolova, D. Stepanovs,

E. Liepinsh, Ē. Bizdēna and M. Turks, Tetrahedron Lett.,

2016, 57, 1174–1178.

37 I. Novosjolova, Ē. Bizdēna and M. Turks, Eur. J. Org. Chem., 52 D. Cīrule, I. Novosjolova, A. Spuris, A. Mishnev, Ē. Bizdēna

2015, 3629–3649.

and M. Turks, Chem. Heterocycl. Compd., 2021, 57, 292–297.

Org. Biomol. Chem.

Article Doi

Nucleophile-nucleofuge duality of azide and arylthiolate groups in the synthesis of quinazoline and tetrazoloquinazoline derivatives

DOI: 10.1039/d1ob01315g

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Article abstract of DOI:10.1039/d1ob01315g

Full text of DOI:10.1039/d1ob01315g

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