Polyhalonitrobutadienes as versatile building blocks for the biotargeted synthesis of substituted N-heterocyclic compounds

molecules

Article

Polyhalonitrobutadienes as Versatile Building Blocks

for the Biotargeted Synthesis of Substituted

N-Heterocyclic Compounds ^†

Viktor A. Zapol’skii ¹, Ursula Bilitewski ², Sören R. Kupiec ¹, Isabell Ramming ²and

Dieter E. Kaufmann ^1,

*

1

Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstraße 6,

38678 Clausthal-Zellerfeld, Germany; viktor.zapolskii@tu-clausthal.de (V.A.Z.);

SOEREN104@gmail.com (S.R.K.)

Helmholtz Centre for Infection Research (HZI), Inhoﬀenstr. 7, 38124 Braunschweig, Germany;

ursula.bilitewski@helmholtz-hzi.de (U.B.); Isabell.Ramming@helmholtz-hzi.de (I.R.)

Correspondence: dieter.kaufmann@tu-clausthal.de

2

*

†

Chemistry of Polyhalogenated Nitrobutadienes, 16. Chemistry of Polyhalogenated Nitrobutadiens, 15.

Zapol’skii, V.A.; Namyslo, J.C.; Gjikaj, M.; Kaufmann, D.E. Synthesis of Novel 4-Nitro-3-amino-1H-

pyrazole-5-carbaldehydes and Pyrazolo[3,4-f]indazole-4,8- diones. Heterocycles 2016, 93, 628–646,

doi:10.3987/COM-15-S(T)46.

ꢀꢁꢂꢀꢃꢄꢅꢆꢇ

ꢀꢁꢂꢃꢄꢅꢆ

Received: 30 April 2020; Accepted: 17 June 2020; Published: 21 June 2020

Abstract: Substituted nitrogen heterocycles are structural key units in many important

pharmaceuticals. A new synthetic approach towards heterocyclic compounds displaying antibacterial

activity against Staphylococcus aureus or cytotoxic activity has been developed. The selective synthesis

of a series of 64 new N-heterocycles from the three nitrobutadienes 2-nitroperchloro-1,3-butadiene,

4-bromotetrachloro-2-nitro-1,3-butadiene and (Z)-1,1,4-trichloro-2,4-dinitrobuta-1,3-diene proved

feasible. Their reactions with N-, O- and S-nucleophiles provide rapid access to push-pull substituted

benzoxazolines, benzimidazolines, imidazolidines, thiazolidinones, pyrazoles, pyrimidines,

pyridopyrimidines, benzoquinolines, isothiazoles, dihydroisoxazoles, and thiophenes with unique

substitution patterns. Antibacterial activities of 64 synthesized compounds were examined.

Additionally, seven compounds (thiazolidinone, nitropyrimidine, indole, pyridopyrimidine, and

thiophene derivatives) exhibited a signiﬁcant cytotoxicity with IC₅₀-values from 1.05 to 20.1 µM.

In conclusion, it was demonstrated that polyhalonitrobutadienes have an interesting potential as

structural backbones for a variety of highly functionalized, pharmaceutically active heterocycles.

Keywords: polyhalonitrobutadienes; nucleophilic substitution; heterocyclization; nitrogen

heterocycles; medicinal chemistry

1. Introduction

Halogenated nitrobutadienes are part of a relatively small group of selectively reactive

aliphatic nitro compounds [

halogen groups are easily accessible by introduction of an activating and directing nitro

group into polyhalo-1,3-butadienes [ ]. These can be easily obtained in high purity and

1]. Representatives with one or two nitro and three to ﬁve

2

multigram scale by radical dimerization of industrial solvents such as trichloroethene and

1,2-dichloroethene with subsequent dehydrohalogenation-halogenation, followed by nitration reactions.

2-Nitroperchlorobutadiene (

1

) has been synthesized in three steps from trichloroethene [

3,

4] (Scheme 1 ).

4-Bromotetrachloro-2-nitrobutadiene (

2

) could be obtained from trichloroethene in ﬁve steps [

5].

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(Z)-1,1,4-Trichloro-2,4-dinitrobutadiene (

3) was made accessible in four steps from a Z,E-mixture of

1,2-dichloroethene [6].

Cl

Z, E

B

C

A

Cl

O₂N

Cl

Br

Cl

O₂N

1

2

3

A

: i) BPO ii) HSO₃Cl iii) HNO₃/H₂SO₄.

B: i) BPO ii) Zn iii) Br₂iv) KOH v) HNO₃/H₃PO₄.

C: i) BPO ii) Br₂iii) KOH iv) HNO₃/H₃PO₄.

Scheme 1. Synthesis of the polyhalonitrobutadienes 1–3.

Due to their graded reactivity in S_Nreactions, nitro-substituted polyhalo-1,3-butadienes have

proven to be valuable synthetic precursors for a variety of four- to six-membered, often pharmaceutically

active heterocycles. They bear a unique substitution pattern that cannot be accessed easily on an

alternative pathway. This structural overview for medicinal chemists demonstrates the broad synthetic

potential of the nitrodienes 1, 2, and 3 as a backbone for speciﬁcally substituted heterocycles, owing to

the additional potential for predictable successive molecular ﬁne tuning.

2. Results and Discussion

2.1. Chemistry

2.1.1. Benzoxazolines and Benzimidazolines

Due to the high electrophilicity of its nitrodichlorovinyl group,

amines which, according to Pearson’s scale, are hard nucleophiles [ ]. Thus, reactions of 2-aminophenol

derivatives with occur under mild conditions and lead to substitution of both Cl groups of the

nitrodichlorovinyl unit with formation of the corresponding (E)-2,3-di-hydrobenzoxazoles 4a in

reasonable yields [ ]. The substructure of a ß-nitro-substituted enamine within compounds 4a,b should

1 reacts readily with various

7

1

,b

8

enable a stabilization caused by a strong hydrogen bond between an oxygen atom of the nitro group

and the proton at the oxazoline nitrogen atom. The downﬁeld-shifted ¹H nmr signal for the NH-group

between 11.8 ppm in CDCl₃and 13.6 ppm in DMSO-d₆points out that H-bonding (Scheme 2) must be

important and azoles 4a

benzoxazoline 4b reacts with activated pyridine derivatives, forming betaines 5a

Treatment of 4b with nicotine under the same reaction conditions furnishes azinate 5d in 53% yield.

Synthesis of the novel and structurally interesting cross-conjugated inner salts 5a demonstrates the

broad synthetic applicability of 2-nitroperchlorobutadiene [ ]. Benzoxazoline was obtained in 73%

,

b

are obtained hereby exclusively as E-isomers. Under mild reaction conditions,

–c

in 62–74% yield.

–

d

9

6

yield as a 1:1 mixture of two isomers by the action of 2-amino-3-methylphenol on the bromonitrodiene

◦

2

−

at

−

40 C in methanol. The reaction of dinitrodiene

3

with 4-methylbenzene-1,2-diamine at

with

were obtained in acceptable yields

40 ^◦C results almost quantitatively in the formation of benzimidazoline 7a. By treatment of

3

2-aminophenol derivatives, the corresponding benzoxazolines 7b

,

c

(Scheme 2). Similar benzoxazolines and benzimidazolines exhibit herbicidal activity and act as a model

compound when exploring caseinolytic protease as target for herbicides or growth regulators [10].

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Scheme 2. Synthesis of benzoxazolines 4, 5, 6, 7 b,c and benzimidazoline 7a.

2.1.2. Imidazolidines

Imidazolidines

8

have been prepared by reaction of nitrodienes

1

–

3

with N¹,

N²-diphenylethane-1,2-diamine in methanol. Under optimized conditions, yields of the products

8

reached 86–93% (Scheme 3).

isolated in 25% yield by reaction of (1,3,4,4-tetrachloro-2-nitrobuta-1,3-dien-1-yl)(p-tolyl)sulfane

with N¹,N²-diphenylethane-1,2-di-amine.

Treatment of imidazolidine 8a with a ﬁvefold

Only compound 8a was previously prepared [11] and

excess of pyrrolidine in reﬂuxing methanol led to the formation of a S_NVin product, the

2-(3,3-dichloro-1-nitro-2-(pyrrolidin-1-yl)allylidene)-1,3-diphenylimidazolidine (9) in 50% yield.

2.1.3. Imidacloprid Analogues

The imidazolidine Imidacloprid (N-{1-[(6-chloro-3-pyridyl)methyl]-4,5-dihydroimidazol-2-yl}

-nitramide) has been the most widely used systemic insecticide worldwide. A ﬁrst synthesis of

ana-logues from nitropolychloroalkenes has been reported [12

,13], new types of derivatives are

presented here. For instance, 11a and 11b were obtained from nitrodiene

1

and chloropyridines 10a

and 10b, respectively [13]. Reaction of imidazolidine 11a with a 2.5-fold excess of N-nucleophiles

such as ethyl piperidine-4-carboxylate and 1,2,3,4-tetrahydroisoquinoline in methanol at 35–50 ^◦C

leads to compounds 12a and 12b in 60–85% yield, respectively. By using 2-mercaptoethan-1-ol as

S-nucleophile for the reaction with 11a in the presence of sodium ethanolate, the corresponding sulfane

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12c was obtained in 63% yield. Treatment of 11b with a ﬁvefold excess of dimethylamine at rt led to the

formation of oxazolidine 12d (70%). By the reaction of bromonitrodiene with an equimolar amount

2

of 4-ﬂuorobenzenethiol in DCM at rt, sulfane 13 was obtained as mixture of two isomers in a total

yield of 74%. The subsequent vinylic substitution of the monothio compound 13 by means of 10a gave

imidazolidine 14 (44%) as well as ketene dithioacetal 15 (30% yield). Arylthiols are known to be both,

good nucleophiles as well as good leaving groups. Compound 14 was previously syn-thesized in 40%

yield directly from nitrodiene

83% yield from diene and two equivalents of 4-ﬂuorobenzenethiol using sodium methanolate as a

base. The reaction of diene with diamine 16 13] at optimized conditions furnished the imidazolidine

17 as a mixture of two isomers in a total yield of 89% (Scheme 4).

2 and diamine 10a [12]. 1,1-Dithio compound 15 could be obtained in

2

[

Scheme 3. Synthesis of imidazolidines 8, 9.

2.1.4. Thiazolidinones

Thiazolidin-4-ones represent a class of compounds that has proven to exhibit distinctive bio-activity,

e.g. antifungal, antibacterial, antitubercular, and anticonvulsant properties [14

area is presented through an eﬃcient synthesis of functionalized (Z)-2-allylidene-thiazolidin-4-ones [18].

Nitrodiene reacts with ethyl 2-mercaptoacetate to give the sulfane 18 as single E-isomer [19]. For

the subsequent reactions of sulfane 18, we used two aniline derivatives, an activated (ERG) and an

desactivated (EWG) one. In both cases, the expected thiazolidinones 19a were obtained in good

yields (73–76%). Treatment of 19a with a 5– to 8–fold excess of hydrazine led to pyrazoles 20a . The

assumed mechanism for this ring-opening and subsequent ring-closure transformation forming 20a

has been presented [18]. Heating of thiazolidinones 19a with ﬁve membered 2-formyl heterocycles

in acetic acid in the presence of trimethylamine furnished hetarylmethylidenethiazolidinones 21a

–17]. Our research in this

1

,b

,

b

,b

,

b

,

b

,

f

in good to excellent yields, as single diastereomers. The Z-conﬁguration was assigned according to

literature data. The presence of only one signal for the methylidene proton at 7.72–8.15 ppm in the

¹H nmr spectra of compounds 21a

,

f

suggested the formation of a single isomer, which was assigned

to the Z-conﬁguration according to the literature for similar compounds [20 21]. Interestingly, close

analogues of these structures, i.e., the 5-arylmethylidene rhodanines, possess photosynthesis-inhibiting

,

and antialgae properties [22], show anticancer activity [23,24], and are inhibitors of bacterial enzyme

synthetase MurD with E. coli [25].

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Scheme 4. Synthesis of Imidacloprid analogues 11, 12, 14, 17.

Other thiazolidinone derivatives can be obtained by treatment of 19a and 19b with

5-formyl-pyrazole 22, previously obtained from in 48% yield, as already reported [26]. Under

standard reaction conditions, the corresponding pyrazolyl-thiazolidinones 23a were obtained as a

1

,b

mixture of two isomers in relation of 86:14. Formation of a mixture of isomers can be explained in this

case by the bulky structure of pyrazole 22 compared with 2-formyl derivatives of furan, thiophene or

1-methylpyrrole (Scheme 5).

2.1.5. Benzazetines

Functionally substituted benzazetines have also been made accessible starting from 1 [27]. The

derived bis(benzotriazole) 24 was obtained in 76% yield according to the literature [28]. Single amine

exchange of azole 24 is feasible with aromatic, aliphatic, and heteroaromatic amines in methanol at mild

reactions conditions and led to 1-benzotriazolyl-1-(organylamino)-2-nitro-3,4,4-trichloro-1,3-butadienes

25a

of nitrodienes 25a

corresponding benzazetines 26a

–

f

in good yields (75–91%). Dienes 25d and 25e have been described, already [26

in diﬀerent solvents (MeOH for 26a, EtOH for 26b, and THF for 26c) gave the

in 25-37% yield (Scheme 6). No reaction occurred in diethyl ether,

,29]. Heating

–

c

–c

while in benzene, strong tarring was observed [30]. Some details on the synthesis and chemical

transformations of benzazetines have been published, already [30]. N-Unsubstituted derivatives

are unstable. Stable substituted representatives have become accessible for the ﬁrst time in recent

years. The substructure of a ß-nitro-substituted enamine within compounds 26a–c should enable a

stabilization caused by a strong hydrogen bond between an oxygen atom of the nitro group and the

single proton at the azetine nitrogen atom. The wide-ranging synthetic possibilities of benzazetines

and benzazetes have also been discussed.

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Scheme 5. Synthesis of thiazolidinones 19, 21, 23 and pyrazoles 20 and 23.

4-Ethoxy-2-(2,3,3-trichloro-1-nitro-2-propenylidene)-benzazetine (a regioisomer of compound

26b) can modulate RNA binding proteins [31]. A new prenylated indole alkaloid taichunamide A

contains a benzazetidine unit, too [32]. It was isolated from the fungus Aspergillus taichungensis.

Scheme 6. Synthesis of benzazetines 26 and benzotriazoles 25.

2.1.6. Pyrimidines

In the course of the studies concerning polyhalogenated nitrobutadienes, a new ring closure

approach to perfunctionalized 5-nitropyrimidines was also developed [33]. Using this protocol starting

from 25c

–f

, four new nitropyrimidines 27c

–f were obtained. Even under optimum conditions, yields of

the products 27c

–f

remained moderate, reaching 49–65%. The assumed mechanism for the formation of

pyrimidines 27 has been presented in the literature [33]. 5-Nitro-substituted pyrimidines are interesting

precursors for the synthesis of a wide range of poly-substituted pyrimidines and other heterocyclic

systems with potential biological activity [34]. Among numerous applications, some examples are

noteworthy: cytotoxic activity is documented [35

,36] as well as the potential to inactivate the human

DNA repair process [37]. The broad variety of medicinal applications is further illustrated, e.g. with the

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activity against chronic obstructive pulmonary disease [38], applicability against herpes simplex [39],

and other viral diseases [40]. Furthermore, one ﬁeld of application of 5-nitropyrimidines uses their

positive modulating eﬀect of the GABAB receptor [41

class of organic compounds; to the best of our knowledge, only 4 representatives are known till

today [43 45]. With the aim to synthesize a new pyrimidin-4-yl-1H-indole with potent biological

,42]. Pyrimidin-4-yl-1H-indoles are a very rare

–

activity, we made an attempt to oxidize the 2,3-dihydroindole 27f. Indeed, by using DDQ as oxidizing

agent (ratio 27f: DDQ 1: 2.25, toluene, reﬂux 5 h), the expected indole 28 was obtained in 66% yield

(Scheme 7).

Scheme 7. Synthesis of pyrimidines 27, 28.

2.1.7. Pyrazoles

In the past ten years, diﬀerent ways to synthesize persubstituted 4-nitropyrazoles have

been developed [9,18,26,28,46]. Some of these compounds show high biological activities: they

can modulate the biological activity of IFNs-I [47], are active against mycobacterial infections

including tuberculosis [48], and are able to reduce prime virulence factors of Vibrio cholerae [49,50].

In the course of our recent studies, the three 1-amino-1-benzotriazolyldienes 25g–i were

synthesized in good yields (85–91%) from bis(benzotriazole) 24 using 4-(4-chlorophenyl)piperidin-4-ol,

piperazin-1-yl-(tetrahydrofuran-2-yl)methanone and 1-(3-chlorophenyl)piperazine, respectiv_◦ely. The

treatment of dienes 25g

led to the formation of new nitropyrazoles 29a

dichloromethyl group in compound 29c by means of 25% aqueous sulfuric acid at 95–100 C, the

aldehyde 30 was obtained (57%) (Scheme 8) [26]. Other 4-nitropyrazoles are known as hypoxia-selective

–

i

with a twofold excess of methylhydrazine in methanol at

−

10 C to rt

–

c

in good yields (74–79%). By saponiﬁcation of the

◦

cytotoxins and radiosensitizers [51]; they can be useful as herbicides [52

actions [54].

,53] or show psychosedative

2.1.8. 4H-Pyrido [1,2-a]Pyrimidines

Recently, a new pathway for the synthesis of 4-(dichloromethylene)-3-nitro-4H-pyrido[1,2-a]

pyrimidines with a unique substitution pattern at the pyrimidine ring was developed [28]. Starting with

bis(benzotriazole) 24, using a threefold excess of 2-aminopyridines two enamines 31a,b were formed in

THF in 81–86% yield. The benzotriazole unit in pyridopyrimidines 31, activated through the neighboring

nitro group, acts as a very good leaving group and can be replaced with diﬀerent nucleophiles at mild

reaction conditions. Thus, treatment of compounds 31 with 1-(4-ﬂuoro-phenyl)piperazine in methanol

at 40 ^◦C led to the piperazino-substituted pyridopyrimidines 32 in excellent yields. A S_NVin process in

pyridopyrimidines 31 under action of S-nucleophiles such as ethyl 2-mercaptoacetate using sodium

ethanolate as base furnished sulfane 33a,b in 93–97% yield. Another possibility to form compounds

33a,b is reaction of sulfane 18 with 2-aminopyridines. At optimum conditions (MeOH, threefold

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excess of amino-pyridines, rt), the yields of pyridopyrimidines 33 reached 47–55% (Scheme 9 ). Similar

pyrido[1,2-a]pyrimidines show antiviral [55], antithrombotic [56], and antibacterial [57–60] activities.

Scheme 8. Synthesis of pyrazoles 29, 30 and benzotriazoles 25.

Scheme 9. Synthesis of 4H-pyrido[1,2-a]pyrimidines 31–33.

2.1.9. Benzo[h]quinolines

In the course of our studies on polyhalogenated nitrobutadienes, a new ring closure approach

to benzo[h]quinolines was also developed [61]. Starting from nitrodiene

benzo[h]quinolines with a unique substitution pattern at the pyridine ring were obtained in good

yields. In detail, after mono substitution of one chlorine group in diene sulfanes 34a were formed

as single isomers each in yields of about 80% according to the literature [62] for the benzyl derivative

34a and literature [ ] for the 4-chlorophenyl derivative 34b. In a second step, we synthesized the

aminothiobutadienes 35a by interaction of sulfane 34a with an excess of 1-naphthylamine in

methanol at were also formed (76–85% yield) as single E–isomers due to the

10 ^◦C to rt. Dienes 35a

1 in three steps, the target

1

,b

9

,b

−

,b

stable six membered hydrogen bridge between the amino and nitro group. Finally, the ring closure at

optimum conditions (twofold excess of triethylamine as a base) proceeded under formation of the

expected benzo[h]quinolines 36a,b in good yields (76–85%). The assumed mechanism for the formation

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of benzo[h]quinolines is depicted in the literature [61]. Benzo[h]quinolines are a precious class of

organic compounds and show interesting biological properties [63 67]. Oxidation of quinolines 36a

with excess of hydrogen peroxide in a mixture of acetic acid and chloroform lead to the formation

–

,b

of sulfoxides 37a,b in 89–91% yield. The sulﬁnyl group is known to be a good leaving group [68–70].

Indeed, treatment of sulfoxide 37a with an excess of pyrrolidine in toluene at 100 ^◦C furnished amino

derivative 38 in 77% yield (Scheme 10).

Scheme 10. Synthesis of benzo[h]quinolines 36–38 and nitrodienes 34, 35.

2.1.10. Isothiazoles

The isothiazole 39 was obtained from nitrodiene

sulfur at 200 ^◦C [71].

Subsequent reaction with fuming nitric acid provided the

4,5-dichloroisothiazole-3-carboxylic acid (40 [72], which could be easily converted into the

1 upon treatment with elemental

)

corresponding acid chloride 42 with thionyl chloride (93% yield) [28]. Acid 40 reacts with ethyl

2-bromoacetate in the presence of sodium ethanolate under reﬂux conditions to ester 41 in 58%

yield. The esteriﬁcation of acid chloride 42 with a fourfold excess of 2,2,2-triﬂuoroethan-1-ol in

reﬂuxing THF resulted in the formation of a 2,2,2-triﬂuoroethyl 4,5-dichloroisothiazole-3-carboxylate

(43) (64% yield). Acid chloride 42 smoothly reacted with aromatic and aliphatic amines to provide

the corresponding amides 44a in 68–95% yield. The reaction of chloride 42 with 2 equivalents

–

d

of 1-(6-chloropyridin-3-yl)-N-methyl-methanamine in THF furnished amide 44e as mixture of two

rotamers in relation 10: 6 with a total yield of 86%. An alternative way to obtain amide 44e is the

interaction of carbohydrazide 44a with 1-(6-chloropyridin-3-yl)-N-methylmethanamine at harder

reactions conditions (DMSO, 95–100 ^◦C). In this case, amide 44e is formed as a mixture of two rotamers

(relation 10:6), with a total yield of 69%. Reacting hydrazide 44a with a fourfold excess of morpholine

(DMSO, 90–95 ^◦C) did not lead to the formation of a product similar to amide 44e. Instead, upon

substitution of a chlorine group in 5 position of the heterocyclic ring, an isothiazole 45 was formed

(78% yield). These amides 44a

of 4-chloroisothiazol-3-carboxylic acid have been shown to exhibit high antibacterial activity [73

Finally, we investigated the interaction of amides 44a and ester 41 with S–nucleophiles such as

4-chlorobenzenethiol. In all cases, reaction products at 5 position of the heterocyclic ring were formed.

–

e

and 45 are interesting candidates for biological testing, as amides

–

75].

–d

Under optimized reaction conditions, the yields of the 5-((4-chlorophenyl)thio)isothiazoles 46a–e were

in the range of 67–89% (Scheme 11).

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Scheme 11. Synthesis of isothiazoles 39–46.

2.1.11. 4,5-Dihydroisoxazoles

Recently, we developed a novel, fairly general method for the synthesis of dihydroisoxazoles

with a chlorinated side chain in 3-position, starting from gem-dichloronitroalkenes [76]. In particular,

reaction of nitrodiene

Trapping of this nitrile oxide with an alkene resulted in 4,5-dihydroisoxazole derivatives 47

a 1,3-dipolar cycloaddition. In detail, reaction of nitrodiene with prop-1-en-2-ylbenzene at optimized

conditions furnished 4,5-dihydroisoxazole 47 in 76% yield. The interaction of the acrylonitrile oxide

with tert-butyl acrylate and 2-ethylhexyl acrylate at similar reactions conditions provided alkyl

3-(1,2,2-trichlorovinyl)-4,5-dihydroisoxazole-5-carboxylates 48 and 49 (65 and 60% yield). Upon

treatment of diene with cyclohexene, the hexahydrobenzo-[d]isoxazole 50 was isolated in 41% yield

(Scheme 12 ). The yields of 47 49 are quite similar to certain compounds in [76], whereas for 50 (in

1

with a base leads to the formation of 2,3,3-trichloroprop-2-enenitrile oxide.

–

50, due to

1

–

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analogy to the reaction with cyclopentene [76]), the yield is lower as expected. 4,5-Dihydroisoxazoles

were found to exhibit potent cytotoxic, antineoplastic [77], and antimalarial activity [78]. Additionally,

they can be used as androgenic or antiandrogenic agents or androgen receptor modulators [79] and

show antibacterial and antifungal activities [80].

Scheme 12. Synthesis of 4,5-dihydroisoxazoles 47–50.

2.1.12. Thiophenes

In the course of studying nitroperchlorobutadiene

1 as a versatile building block for the directed

synthesis of a range of persubstituted heterocycles, we also developed a three-step synthesis to

persubstituted 3-amino-4-nitrothiophenes [81]. Incorporating both, an enamine and a thioketene unit,

these thiophenes are very electron-rich heterocycles with a unique substitution pattern. Starting from 1,

the piperazine derivative 52 was obtained in 90% yield via the dithiolane 51. The push-pull substituted

thiophene 53 was eﬃciently accessible in 85% yield upon treatment of dithiolane 52 with sodium

hydroxide using DMSO as solvent. The regioselective ipso-formylation of the 2-chloro-thiophene 53

under Vilsmeier-Haack conditions led to the carbaldehyde 54 (64% yield), according to [82].

The next successive steps were performed with the most stable derivative

3-morpholino-4-nitro-5-(vinylthio)thiophene-2-carbaldehyde (55) [82]. Knoevenagel condensation of

thiophene 55 with malononitrile in ethanol in the presence of a catalytic amount of sodium ethanolate

gave the gem-dicyanovinylthiophene 56 in 68% yield [83]. Oxidation of the vinylsulfanylthiophene 56

◦

with threefold excess of hydrogen peroxide in acetic acid at 50–55 C furnished sulfone 57 in 82%

yield. Interaction of carbaldehyde 55 with an excess of dimedone, (2,4,6-trichlorophenyl)hydrazine

and Meldrum’s acid in methanol led to the formation of bis(5,5-dimethylcyclohexane-1,3-dione) 58

vinylsulfanyl-thiophene 59 and 1,3-dioxane-4,6-dione 60, respectively (Scheme 13).

,

2-Chloro-3-amino-4-nitro-5-(vinylsulfanyl)thiophenes similarly to compound 53 were identiﬁed

as anti-HIV compounds to treat drug-resistant retroviral infections [84] and show antiviral activity [85].

Other 3(4)-nitrothiophenes can be used in fungicidal and/or bactericidal compositions [86], and show

insecticidal and acaricidal activity [87].

2.2. Biological Activity of the Polyhalonitrobutadiene Derivatives

Evaluation of the biological activity of the chosen polyhalonitrobutadiene derivatives showed

that most of them did not display antibacterial or cytotoxic eﬀects, i.e., residual growth or viability

after incubation for 1 and 3 days, respectively, were higher than 50%. Tables with all primary screening

data are shown in Supplementary Figures S204–S205. None of the derivatives showed an antibacterial

activity against the uropathogenic Escherichis coli strain UPEC 796, whereas some had antibacterial

activity against Staphylococcus aureus. The cytotoxic activity of nine compounds could be proven, as

these compounds had IC₅₀–values < 50 µM in the viability assay. Among those compounds was

the “conjugate” 23b of the pyrazole 22 and the thiazolidinone 19b. Whereas the compound series

21 was more or less completely inactive, introduction of the pyrazole group proved successful. In

particular, the introduction of a CF₃substituent resulted in a compound with signiﬁcant cytotoxicity

(IC₅₀= 6.2

with the aromatic residues at the nitropyrimidine–core, namely 27c and 28 with IC₅₀-values of 1.5

0.4 M and 1.05 0.2 M, respectively. The non-aromatic nature of the ring next to the pyrimidine

core in 27f prevented the cytotoxic activity. Following the synthesis route of the pyridopyrimidines

±

1.8 µM). Similarly, among the pyrimidines 27, 28, the most potent derivatives were those

±

µ

±

µ

Molecules 2020, 25, 2863

12 of 41

32 and 33 revealed that the precursor with the leaving group benzotriazole was the only cytotoxic

compound (IC₅₀= 6.0 and 5.7 1.0 M), and that cytotoxicity was lost, when the benzotriazole group

was replaced. In addition, the benzo[h]quinolines 36 38 lost the cytotoxic activity, which was still

±

µ

,

observed for the intermediate naphthalene-aminothiobutadiene 35. All tested derivatives of both

the groups of isothiazoles and dihydroisoxazoles were inactive, whereas among the thiophenes, the

derivatives with a cyclic dione residue 58 and 60 represented cytotoxic compounds (IC₅₀= 3.1

M and 20.1 3.9 M). Obviously, the morpholino-nitrothiophene structure was not suﬃcient for

biological activity as compound 59 was completely inactive.

±

0.4

µ

±

µ

Scheme 13. Synthesis of thiophenes 53–60 and dithiolanes 51, 52.

3. Experimental

3.1. General Information

General Remarks: Solvents and reagents were used as received from commercial sources without

further puriﬁcation. TLC was performed with Merck aluminum-backed TLC plates with silica gel 60,

F254. Flash column chromatography was performed with Macherey–Nagel silica gel 60 M (0.040–0.063

mm) with appropriate mixtures of petroleum ether (PE, boiling range 60–70 ^◦C) and ethyl acetate as

eluents. Melting points (m.p.) were determined in capillary tubes with a Büchi B-520 instrument and

Molecules 2020, 25, 2863

13 of 41

were not corrected. FTIR spectra were recorded with a Bruker “Alpha-T” spectro-meter with solid

compounds measured as KBr pellets. ATR-IR spectra were measured on the same instrument with

a Bruker “Alpha Platinum ATR” single reﬂection diamond ATR module. ¹H NMR and ¹³C NMR

spectra at 600 and 150 MHz, respectively, were recorded with an “Avance III” 600 MHz FT–NMR

1

spectrometer (Bruker, Rheinstetten, Germany). H NMR and ¹³C NMR spectra at 400 and 100 MHz,

1

respectively, were recorded with an “Avance” 400 MHz FT–NMR spectrometer (also Bruker). H NMR

and ¹³C NMR spectra at 200 and 50 MHz, respectively, were recorded with an DPX 200 spectrometer

(also Bruker). ¹⁴N and ¹⁵N NMR spectra were measured at their appropriate resonance frequency on

the aforementioned spectrometers; ¹⁵N measurements were taken as gs-¹H,¹⁵N–HSQC or –HMBC

1

experiments with inverse detection. H and ¹³C NMR spectra were referenced to the residual solvent

peak: CDCl₃,

δ δ

= 7.26 (¹H) and 77.0 ppm (¹³C); DMSO-d₆, = 2.50 (¹H), and 39.7 ppm (¹³C). Mass

spectra were obtained with a Hewlett–Packard MS 5989B spectrometer, usually in direct mode with

electron impact (70 eV). For chlorinated and brominated compounds, all peak values of molecular ions

and fragments refer to the isotope ³⁵Cl and ⁷⁹Br. High resolution mass spectra were recorded with a

Waters mass spectrometer “VG Autospec” (EI), with a WATERS mass spectrometer “Q-Tof Premier”

coupled with a Waters “Acquity UPLC” (ESI), or with a Micromass mass spectrometer “LCT” coupled

with a Waters “Alliance 2965 HPLC” (ESI) at the Institute of Organic Chemistry, Leibniz University of

Hannover and at the Georg-August University of Göttingen.

3.2. Synthesis

Pentachloro-2-nitro-1,3-butadiene (

in 53% yield (b.p.

69–71 ^◦C/1 mbar) according to the literature

and (E)-4-Bromotetrachloro-2-nitrobuta-1,3-diene was obtained from (Z)- and

(E)-1-bromotetrachlorobuta-1,3-diene in 56% yield (b.p. ].

84–86 ^◦C/1.3 mbar)

was synthetized from the (Z)- and

1) was prepared from 2H-pentachloro-1,3-butadiene

[3,4]. (Z)-

(2)

[5

(Z)-1,1,4-Trichloro-2,4-dinitrobuta-1,3-diene

(3)

(E)-1-bromo-1,4,4-trichlorobuta-1,3-diene in 18% yield, m.p. 70–71 ^◦C [6].

Synthesis of 4-methyl-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-2,3-dihydro-1,3-benzoxazole (4a) (General

method). At 1 (2.71 g, 10.0 mmol) in 5 mL methanol (MeOH) was added

40 ^◦C, a solution of nitrodiene

−

dropwise to a suspension of 2-amino-3-methylphenol (3.94 g, 32.0 mmol) in 30 mL MeOH within 5

min. The resulting mixture was kept for 1 h at this temperature, and was then allowed to reach room

temperature (r.t.). After 5 h stirring, the mixture was poured into a cold solution (0 ^◦C) of 5 mL conc.

HCl in 250 mL of water. After 20 min, the precipitate was ﬁltered oﬀ, washed with cold water (3

mL) and diethyl ether (2 10 mL). Drying in vacuo gave 2.57 g of oxazole 4a, yield 80%, yellowish

solid m.p. 149–151 ^◦C; IR (KBr)

CDCl₃), = 2.61 (3H, s, CH₃Ph), 7.21–7.33 (2H, m, H Ph), 7.36–7.41 (1H, m, H Ph), 11.78 (1H, s, NH)

ppm; ¹³C NMR (50 MHz, CDCl₃)

×

40

×

1

ν

= 3089, 1612, 1382, 1079, 968, 520 cm⁻¹; H NMR (200 MHz,

max

δ

= 16.6 (CH₃), 107.0 (C NO₂), 108.7 (CH), 120.2 (CCl₂), 123.4 (C Me),

125.4 (CH), 127.4, 127.6 (CH), 128.2, 146.6, 159.0 ppm; MS m/z (I_rel, %): 320 [M⁺] (4), 285 [M

(10), 274 [M-NO₂]⁺(65), 239 [M-Cl-NO₂]⁺(100); HRMS (ESI⁻) m/z calcd for C₁₁H₆N₂O₃Cl₃[M

318.9444; found: 318.9446.

−

Cl]⁺

H]⁻:

−

5-Methyl-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-2,3-dihydro-1,3-benzoxazole (4b). Same procedure as

for 4a

,

b

ut using 2-amino-4-methylphenol (3.94 g, 32.0 mmol). Yield 2.18 g (68%), yellowish solid, m.p.

1

168–170 ^◦C. IR (KBr)

ν

= 3380, 1612, 1434, 1375, 1056, 922 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

max

δ

= 2.42 (3H, s, CH₃Ph), 7.20 (1H, d, J = 8.3 Hz, H Ph), 7.36 (1H, s, H Ph), 7.69 (1H, d, J = 8.3 Hz, H

Ph), 13.64 (1H, s, NH) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

δ

= 21.2 (CH₃), 105.4 (C NO₂), 111.0 (CH),

113.6 (CH), 122.1 (CCl₂), 126.0 (CH), 126.6, 129.8, 136.4, 144.8, 158.0 (NCO) ppm. MS m/z (I_rel, %): 320

[M⁺] (2), 285 [M-Cl]⁺(4), 274 [M-NO₂]⁺(55), 239 [M-Cl-NO₂]⁺(100), 204 [M-2Cl-NO₂]⁺(14); HRMS

(ESI⁻) m/z calcd for C₁₁H₆N₂O₃Cl₃[M − H]⁻: 318.9453; found: 318.9444.

Synthesis of [{1-(1,3-benzoxazol-2-yl)-3,3-dichloro-2-[4-(dimethylamino)pyridinium-1-yl]prop-2-en-1-yli-

dene}(oxido)-l5-azanyl]oxidanide (5a) (General method). To a suspension of benzoxazole 4b (0.322 g,

Molecules 2020, 25, 2863

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◦

1.00 mmol) in 15 mL MeOH at 0 C, a solution of 4-dimethylaminopyridine (DMAP) (0.257 g, 2.1

mmol) in 3 mL MeOH was added dropwise. The mixture was stirred for 1 h at 0 ^◦C and at r.t. for 12

h. Subsequently, the precipitate was ﬁltered oﬀ at 0 ^◦C and washed with water (2

×

10 mL) and cold

MeOH (5 mL). Finally, the product 5a was dried in vacuo. Yield 0.301 g (74%), yellowish solid, m.p.

189–190 ^◦C. IR (ATR) _max= 1641, 1531, 1355, 1139, 1055, 790 cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆)

ν

δ =

2.38 (3H, s, CH₃Ph), 3.23 (6H, s, N(CH₃)₂), 6.99 (1H, d, J = 7.8 Hz, H Ph), 7.06 (2H, d, J = 6.7 Hz, H

pyr), 7.33 (1H, s, H Ph), 7.43 (1H, d, J = 7.9 Hz, H Ph), 8.29 (2H, d, J = 6.7 Hz, H pyr) ppm; ¹³C NMR

(100 MHz, DMSO-d₆)

δ = 39.7 (CH₃), 40.2 (NCH₃), 103.7, 107.3 (CH), 109.3 (CH), 117.8 (CH), 122.7,

123.6 (CH), 133.2, 135.8, 142.3 (CH), 142.5, 147.8, 156.4, 160.9 ppm; MS m/z (I_rel, %): 406 [M⁺] (1), 273

[M-benzoxazole-H]⁺(5), 238 [M-benzoxazole-HCl]⁺(3), 122 [DMAP]⁺(73), 100 (100); HRMS (ESI⁺)

m/z calcd for C₁₈H₁₇N₄O₃Cl₂[M + H]⁺: 407.0672; found: 407.0675.

[{1-(1,3-Benzoxazol-2-yl)-3,3-dichloro-2-[4-(morpholin-4-yl)pyridinium-1-yl]prop-2-en-1-ylidene}

(oxido)-l5-azanyl]oxidanide (5b). Following the typical procedure for 5a, using 4b (0.322 g,

1.00 mmol) and 4-(4-morpholinyl)pyridine (0.345 g, 2.1 mmol) at

−

18 ^◦C and holding at this

temperature for 3 h. Yield 0.270 g (62%), yellowish solid, m.p. 180–181 ^◦C. IR (ATR)

ν

= 1640, 1548,

max

1

1348, 1253, 1156, 792 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ = 2.38 (3H, s, CH₃Ph), 3.73 (8H, s, H

morph), 7.00 (1H, dd, J = 8.1 Hz, J = 1.3 Hz, H Ph), 7.25 (2H, d, J = 7.8, H pyr), 7.34 (1H, s, H Ph), 7.43

(1H, d, J = 8.2, H Ph), 8.34 (2H, d, J = 7.6, H pyr) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

δ

= 21.3 (CH₃),

46.6 (N(CH₂)₂), 65.6 (O(CH₂)₂), 103.8, 107.5 (CH), 109.3 (CH), 117.8 (CH), 122.9, 123.9 (CH), 133.2, 135.7,

142.5, 143.0 (CH), 147.8, 156.1, 160.8 ppm; MS m/z (I_rel, %): 448 [M⁺] (1), 325 [M-HCl-morpholine]⁺(1),

316 [M-methylbenzoxazole]⁺(1), 269 [M-pyridine+H]⁺(4), 165 (100), 132 [methylbenzoxazole]⁺(12);

HRMS (ESI⁺) m/z calcd for C₂₀H₁₉N₄O₄Cl₂[M + H]⁺: 449.0778; found: 449.0780.

1-(Pyridin-4-yl)pyrrolidin-2-one as starting material for the synthesis of azinate 5c was obtained from

4-aminopyridine and 4-chlorobutanoyl chloride according to the literature [88]. Yield 65%, colorless

1

liquid. H NMR (600 MHz, CDCl₃)

δ = 2.17 (2H, t, J = 7.7 Hz, CH₂pyrro), 2.61 (2H, t, J = 8.2 Hz, CH₂

pyrro), 3.82 (2H, t, J = 7.1 Hz, CH₂pyrro), 7.57 (2H, d, J = 4.9 Hz, H pyr), 8.50 (2H, d, J = 4.9 Hz, H

pyr) ppm; ¹³C NMR (150 MHz, CDCl₃)

δ = 17.6 (CH₂), 32.8 (CH₂), 47.4 (CH₂), 112.8 (CH), 145.8, 150.4

(CH), 175.2 (CO) ppm; MS m/z (I_rel, %): 162 [M⁺] (31), 147 [M-OH]⁺(25), 119 [M-CH₂CHO]⁺(10), 107

[M-CH₂CH₂CO+H]⁺(100).

[{1-(1,3-Benzoxazol-2-yl)-3,3-dichloro-2-[4-(2-oxopyrrolidin-1-yl)pyridinium-1-yl]prop-2-en-1-ylidene}-

(oxido)-l5-azanyl]oxidanide (5c). Same procedure as for 5a, using 1-(pyridin-4-yl)pyrrolidin-2-one (0.341

g, 2.1 mmol) at

−

18 ^◦C and holding this temperature for 2 h. Stirring was continued for 24 h at r.t.

1

Yield 67%, yellow solid, m.p. 157–158 ^◦C. IR (ATR)

ν

= 1733, 1627, 1550, 1349, 1257, 1157 cm⁻¹. H

max

NMR (600 MHz, DMSO-d₆)

δ = 2.13 (2H, t, J = 7.6 Hz, CH₂pyrro), 2.39 (3H, s, CH₃Ph), 2.67 (2H, t, J =

8.0 Hz, CH₂pyrro), 3.99 (2H, t, J = 7.2 Hz, CH₂pyrro), 7.01 (1H, dd, J = 8.2 Hz, J = 0.8 Hz, H Ph), 7.35

(1H, s, H Ph), 7.45 (1H, d, J = 8.2 Hz, H Ph), 8.25 (2H, d, J = 7.0, H pyr), 8.99 (2H, d, J = 7.5 Hz, H pyr)

ppm; ¹³C NMR (150 MHz, DMSO-d₆)

δ

= 17.1 (CH₂), 21.2 (CH₃), 32.7 (CH₂), 48.1 (CH₂), 104.0, 109.4

(CH), 113.9 (CH), 117.9 (CH), 123.8 (CH), 124.0, 133.3, 136.2, 142.5, 145.7 (CH), 147.8, 152.6, 160.5, 177.5

ppm; ¹⁵N NMR (43.4 MHz, DMSO-d₆, doped with nitromethane (0.0 ppm))

δ

= 187.0 (N-pyridine),

−

-235.2 (N-pyrrolidine) ppm, other N-atoms could not be detected; MS m/z (I_rel, %): 446 [M⁺] (1), 411

[M-Cl]⁺(1), 162 [pyridinyl–pyrrolidinone]⁺(45), 133 [methylbenzoxazole+H]⁺(6), 107 (100); HRMS

(ESI⁺) m/z calcd for C₂₀H₁₇N₄O₄Cl₂[M + H]⁺: 447.0621; found: 447.0623.

[{1-(1,3-Benzoxazol-2-yl)-3,3-dichloro-2-[3-(1-methylpyrrolidin-2-yl)pyridinium-1-yl]prop-2-en-1- ylidene}-

(oxido)-λ

⁵-azanyl]oxidanide (5d). To a suspension of benzoxazole 4b (0.322 g, 1.0 mmol) in MeOH (10

mL) at

−

18 ^◦C, a solution of (-)-nicotine (0.324 g, 2.0 mmol) in MeOH (5 mL) was added dropwise.

18 ^◦C for 2 h and at r.t. for 18 h. After completion of the

Subsequently, the mixture was stirred at

reaction water (10 mL), NaHCO₃(0.184 g, 2.2 mmol) were added and the mixture was stirred for 10

min, following extraction with chloroform (3 15 mL). The combined organic phases were dried over

−

×

Molecules 2020, 25, 2863

15 of 41

calcium chloride and puriﬁed by column chromatography using DCM–petroleum ether (1:1). The

product 5d was dried in vacuo. Yield 0.237 g (53%), yellow solid, m.p. 96–98 ^◦C. IR (ATR)

ν

=

max

1

1622, 1516, 1354, 1259, 1141, 1062 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ = 1.64–1.77 (1H, m, CH₂pyrro),

1.83–2.01 (2H, m, NCH₂), 2.26 (3H, s, NCH₃pyrro), 2.43 (3H, s, Ph-CH₃), 2.43–2.49 (1H, m, CH₂pyrro),

3.24–3.34 (1H, m, CH₂pyrro), 3.42–3.57 (1H, m, CH₂pyrro), 3.63–3.89 (1H, m, CH₂pyrro), 7.00 (1H,

dd, J = 1.0 Hz, J = 8.2 Hz, CH₃C-C

= 5.6 Hz, J = 7.8 Hz, H pyr), 8.48 (1H, d, J = 7.8 Hz, H pyr), 9.03 (1H, d, J = 5.6 Hz, H pyr), 9.15 (1H, s,

H pyr) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 21.5 (CH₃Ph), 23.1 (CH₂), 35.8 (CH₂), 40.3 (CH₃pyrro),

56.6 (CH₂), 67.1 (CH pyrro), 104.6 (CNO₂), 109.8 (CH Ph), 118.0 (CH Ph), 124.0 (CH Ph), 127.0 (CH pyr),

128.5 (CCl₂), 133.7 ( CH₃), 136.3, 142.2, 143.6 (CH pyr), 145.2 (CH pyr), 145.5 (CH pyr), 145.7, 148.3

(C-pyrro), 160.1 (NCO) ppm; MS (ESI⁺) m/z calcd for C₂₁H₂₁N₄O₃Cl₂[M + H]⁺: 447.1; found 447.1.

H), 7.37 (1H, s, H Ph), 7.39 (1H, d, J = 8.2 Hz, OCCH), 7.96 (1H, dd, J

δ

C

2-[3-Bromo-2,3-dichloro-1-nitroprop-2-en-1-ylidene]-4-methyl-2,3-dihydro-1,3-benzoxazole ( ). Same

proce-dure as for 4a, but starting from (316 mg, 1.00 mmol, a 47: 53 mixture of isomers) using

2-amino-3-methylphenol (394 mg, 3.20 mmol). A 1:1 mixture of isomers was obtained. Yield 73%,

yellowish solid, m.p. 145–146 ^◦C. IR (KBr) _max= 3329, 1620, 1571 (NO₂), 1376, 1320, 1047 cm⁻¹; ¹H

NMR (200 MHz, CDCl₃) = 2.61 (3H, s, CH₃Ph), 7.22–7.41 (3H, m, H Ph), 11.77 (1H, s, NH) ppm;

¹³C NMR (50 MHz,CDCl₃)

= 16.6 (CH₃); 106.9 (CNO₂); 108.7 (CH); 114.9, 115.8 (CClBr); 121.8, 123.7

(CCl); 123.4 (C Me); 125.4 (CH), 127.4, 127.6 (CH), 146.7, 158.7, 158.9 (NCO) ppm; MS m/z (I_rel, %):

364 [M⁺] (2), 329 [M Cl]⁺(4), 318 [M-NO₂]⁺(19), 285 [M Br]⁺(25), 283 [M-Cl-NO₂]⁺(50), 239

[M-Br-NO₂]⁺(100); HRMS (ESI⁻) m/z calcd for C₁₁H₆N₂O₃Cl₂Br [M H]⁻: 362.8944; found: 362.8948.

2-((Z)-3-chloro-1,3-dinitroallylidene)-5-methyl-2,3-dihydro-1H-benzo[d]imidazole (7a). Same procedure as

6

2

ν

δ

−

for 4a, but starting from 3 (247 mg, 1.00 mmol, only Z-isomer) using 4-methylbenzene-1,2-diamine (257

mg, 2.10 mmol). Yield 93%, red solid, m.p. 163–165 ^◦C. IR (KBr)

ν

_max= 3330, 1602, 1577 (NO₂), 1410,

1

1268, 987 cm⁻¹. H NMR spectrum (200 MHz, DMSO-d₆)

δ = 2.49 (3H, s, CH₃Ph), 7.36 (1H, d, J = 8.5

Hz, H Ph), 7.58 (1H, s, H Ph), 7.67 (1H, d, J = 8.5 Hz, H Ph), 9.14 (1H, s, CH), 14.45 (2H, s, NH) ppm;

¹³C NMR (50 MHz, DMSO-d₆)

δ

= 21.4 (CH₃), 106.9 (C NO₂), 113.4 (CH), 113.6 (CH), 120.1 (CClNO₂),

127.5 (CH), 129.1 (C Me), 129.2 (CH), 131.2, 136.1, 142.3 (NCN) ppm; MS m/z (I_rel, %): 296 [M⁺] (5), 250

[M-NO₂]⁺(55), 233 [M-NO₂-OH]⁺(12), 204 [M-2NO₂]⁺(60), 169 [M-2NO₂-Cl]⁺(48), 157 (100); HRMS

(ESI⁻) m/z calcd for C₁₁H₈N₄O₄Cl [M − H]⁻: 295.0240; found: 295.0248.

2-(3-Chloro-1,3-dinitroprop-2-en-1-ylidene)-5-methyl-2,3-dihydro-1,3-benzoxazole (7b). Same procedure as

for 4a, but using

3 (247 mg, 1.00 mmol, only Z-isomer) and 2-amino-4-methylphenol (394 mg, 3.20

mmol). Yield 67%, yellow solid, m.p. 110–112 ^◦C. IR (KBr)

ν

_max= 3250, 1602, 1545 (NO₂), 1289, 1065,

1

871 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ = 2.45 (3H, s, CH₃Ph), 7.25 (1H, d, J = 8.3 Hz, H Ph), 7.55

(1H, s, H Ph), 7.63 (1H, d, J = 8.5 Hz, H Ph), 9.09 (1H, s, CH), 10.66 (1H, s, NH); ¹³C NMR (50 MHz,

DMSO-d₆) = 21.2 (CH₃), 110.8 (CH), 112.5 (CNO₂), 118.5 (CClNO₂), 119.1 (CH), 126.8 (CH), 129.5

δ

(CH), 134.5 (C Me), 139.5, 148.2, 157.2 (NCO) ppm; MS m/z (I_rel, %): 297 [M⁺] (3), 251 [M

−

NO₂]⁺

(45), 234 [M-NO₂-OH]⁺(13), 158 (100); HRMS (ESI⁻) m/z calcd for C₁₁H₇N₃O₅Cl [M

−

H]⁻: 296.0072;

found: 296.0070.

2-(3-Chloro-1,3-dinitroprop-2-en-1-ylidene)-4-methyl-2,3-dihydro-1,3-benzoxazole (7c). Same procedure as

for 4a, using

3 (247 mg, 1.00 mmol, only Z-isomer) and 2-amino-3-methylphenol (394 mg, 3.20 mmol).

Yield 85%, yellow solid, m.p. 102–103 ^◦C. IR (KBr)

ν

= 3254, 1625, 1579 (NO ), 1520, 1077, 646

max

2

1

cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ = 2.53 (3H, s, CH₃Ph), 7.19 (1H, d, J = 7.5 Hz, H Ph), 7.30

(1H, t, J = 7.5 Hz, H Ph), 7.52 (1H, d, J = 8.0 Hz, H Ph), 9.20 (1H, s, CH), 10.19 (1H, s, NH) ppm; ¹³

C

NMR (50 MHz, DMSO-d₆) δ = 16.5 (CH₃), 108.5 (CH), 113.6 (CNO₂), 115.9 (CClNO₂), 125.0 (CH), 125.5

(CH), 130.3 (CH), 140.3, 150.3, 156.3 (NCO) ppm; MS m/z (I_rel, %): 297 [M⁺] (3), 251 [M-NO₂]⁺(40), 234

[M-NO₂-OH]⁺(12), 158 (100); MS (ESI⁻) m/z calcd for C₁₁H₇N₃O₅Cl [M − H]⁻: 296.0; found: 296.0.

Synthesis of 2-(3-bromo-2,3-dichloro-1-nitroprop-2-en-1-ylidene)-1,3-diphenylimidazolidine (8b) (General

method). To a solution of N,N’-diphenylethane-1,2-diamine (0.446 g, 2.1 mmol) in 10 mL MeOH at

Molecules 2020, 25, 2863

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−

40 ^◦C a solution of nitrodiene

2

(0.316 g, 1.0 mmol) in 5 mL MeOH was added dropwise. After 1 h of

stirring at

−

40 ^◦C, the solution was allowed to reach r.t. and stirred for another 5 h. The precipitate

was ﬁltered oﬀ, washed with water (3

×

20 mL), MeOH (1

×

10 mL), diethyl ether (2

×

10 mL) and

dried in vacuo. A 1:1 mixture of isomers was obtained. Yield 0.410 g (90%), yellow solid, m.p. 222–223

^◦C. IR (KBr)

ν

= 3455, 3059, 1594, 1523, 1295, 761 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ

= 4.37

= 51.0, 50.9 (CH₂), 104.4,

105.9 (CNO₂), 107.2, 107.7 (CBrCl), 122.4, 122.5 (CH), 127.0 (CH), 127.8, 129.5, 129.6 (CH), 139.9, 140.0

1

max

(4H, s, CH₂), 7.25–7.47 (10H, m, H Ph) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

δ

(NC Ph), 155.6, 155.7 (NCN) ppm; MS m/z (I_rel, %): 453 [M⁺] (3), 418 [M

−

Cl]⁺(3), 374 [M-Br]⁺(45),

339 [M-Cl-Br]⁺(8), 279 [M-C₂Cl₂Br]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₈H₁₅N₃O₂Cl₂Br [M + H]⁺:

453.9719; found: 453.9728.

2-(3-Chloro-1,3-dinitroprop-2-en-1-ylidene)-1,3-diphenylimidazolidine (8c). Same procedure as for 8b, using

dinitrodiene

3

(0.247 g, 1.0 mmol). Yield 86%, yellow solid, m.p. 236–237 ^◦C. IR (KBr)

ν

= 3054,

max

1

1570, 1491, 1349, 1193, 999 cm⁻¹. H NMR (200 MHz, CDCl₃)

δ

= 4.58 (4H, s, CH₂), 7.29–7.33 (4H, m, H

= 50.6 (CH₂), 105.1,

117.8 (CClNO₂), 123.2 (CH), 128.4 (CH), 129.0 (CH), 130.0 (CH), 136.7 (NC Ph), 158.7 (NCN) ppm; MS

Ph), 7.39–7.45 (6H, m, H Ph), 8.69 (1H, s, CH) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

δ

m/z (I_rel, %): 386 [M⁺] (20), 340 [M

−

NO₂]⁺(60), 305 [M-NO₂-Cl]⁺(3), 281 [M-(CH=CClNO₂)+H]⁺(20),

247 [M-(CH=CClNO₂)-2OH]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₈H₁₆N₄O₄Cl [M + H]⁺: 387.0855;

found: 387.0865.

Synthesis of 2-[3,3-dichloro-2-nitro-1-(pyrrolidin-1-yl)prop-2-en-1-ylidene]-1,3-diphenylimidazolidine (9). To a

suspension of imidazolidine 8a (0.387 g, 1.0 mmol) in 10 mL MeOH at r.t. a solution of pyrrolidine

(0.356 g, 5.0 mmol) in 5 mL MeOH was added. Subsequently, the mixture was stirred for 3 h at r.t.

and 4 h at reﬂux. After cooling to 10 ^◦C, the pH was adjusted to 6–7 with HCl (5%). The resulting

precipitate was ﬁltered oﬀ and washed with water (3

vacuo. Yield 0.223 g (50%), yellow solid, m.p. 156–159 ^◦C. IR (KBr)

1347, 908 cm^{−1 1}H NMR (200 MHz, DMSO-d₆)

= 1.52–1.56 (4H, m, CH₂pyr), 2.68–2.73 (4H, m,

CH₂pyr), 4.29 (4H, s, CH₂im), 7.21–7.44 (10H, m, H Ph) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

×

20 mL), MeOH (2

×

10 mL) and dried in

ν

= 2968, 2868, 1597, 1497,

max

.

δ

=

25.0 (CH₂), 50.1 (CH₂), 51.0 (CH₂), 98.6 (CCl₂), 104.7 (CNO₂), 122.8 (CH), 126.7 (CH), 129.2 (CH),

140.2, 140.6, 157.1 (NCN) ppm; MS m/z (I_rel, %): 444 [M⁺] (2), 427 [M-OH]⁺(2), 408 [M-HCl]⁺(3),

373 [M-pyrrolidine]⁺(22), 281 [M-(CCl₂=C)-pyrrolidine+H]⁺(20), 264 [M-(CCl₂=C)-pyrrolidine-O]⁺

(85), 248 [M-(CCl₂=C)-pyrrolidine-2O]⁺(100); HRMS (ESI⁺) m/z calcd for C₂₂H₂₃N₄O₂Cl₂[M + H]⁺:

445.1193; found: 445.1190.

Synthesis

of

ethyl

1-(1,1-dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]imidazolidin-2-ylidene}-3

-nitroprop-1-en-2-yl)piperidine-4-carboxylate (12a) (General method). To a suspension of compound 11a

(0.384 g, 1.0 mmol) and piperidine-4-carboxylic acid ethyl ester (0.393 g, 2.5 mmol) in 15 mL MeOH

at r.t., a solution of sodium ethanolate (0.177 g, 2.6 mmol) in 5 mL MeOH was added, and stirred

◦

for 24 h at 35 C. At r.t. 3 drops of conc. HCl were added before adding 50 mL cold water. The

resulting precipitate was ﬁltered oﬀ and washed with cold MeOH (2

×

7 mL) and water (3

×

10 mL).

The product was dried in vacuo. Yield 0.303 g (60%), yellow solid, m.p. 60–62 ^◦C. IR (KBr)

ν

=

max

1

3319, 1726, 1561, 1319, 1177, 1043 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ = 1.16 (3H, t, J = 6.9 Hz, CH₃

Et), 1.53–1.76 (4H, m, CH₂pip), 2.28–2.42 (1H, m, CH pip), 2.73 (4H, s, CH₂pip), 3.35 (2H, s, CH₂imi),

3.67 (2H, s, CH₂imi), 4.06 (2H, q, J = 6.9 Hz, CH₂Et), 4.37–4.47 (2H, m, pyr-CH₂-imi), 7.56 (1H, d, J =

8.1 Hz, H pyr), 7.81 (1H, d, J = 8.2 Hz, H pyr), 8.36 (1H, s, H pyr), 9.43 (1H, s, NH) ppm; ¹³C NMR (50

MHz, DMSO-d₆)

δ = 14.3 (CH₃), 28.4 (CH₂), 40.5 (CH), 42.2 (CH₂), 48.0 (CH₂pip), 48.4 (CH₂), 49.8

(CH₂), 60.1 (CH₂), 102.8 (CNO₂), 103.6 (CCl₂), 124.4 (CH), 131.4, 138.8 (CH), 141.3, 148.9 (CH), 149.7,

160.1, 174.4 ppm; MS m/z (I_rel, %): 503 [M⁺] (3), 467 [M

−

HCl]⁺(3), 377 [M-CH₂pyridine]⁺(2), 254

[M-C₂Cl₂-piperidine]⁺(18), 126 [CH₂pyridine]⁺(100); HRMS (ESI⁻) m/z calcd for C₂₀H₂₃N₅O₄Cl₃[M

− H]⁻: 502.0821; found: 502.0818.

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2-(1,1-Dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]imidazolidin-2-ylidene}-3-nitroprop-1-en-2-yl)-

1,2,3,4-tetrahydroisoquinoline (12b). Same procedure as for 12a, using 11a (0.384 g, 1.00 mmol)

and 1,2,3,4-tetrahydroisoquinoline (0.368 g, 2.50 mmol) and stirring for 4 h at 50 ^◦C. Yield 85%, orange

1

solid, m.p. 146–148 ^◦C. IR (KBr)

ν

= 3318, 2895, 1559, 1460, 1320, 749 cm⁻¹. H NMR spectrum

max

(200 MHz, CDCl₃)

δ = 2.70–3.16 (2H, m, CH₂pip), 3.30–3.55 (2H, m, CH₂pip), 3.59–3.90 (4H, m, CH₂

imi), 4.08 (1H, d, J = 15.2 Hz, NCH₂); 4.26–4.38 (2H, m, CH₂pip), 4.67 (1H, d, J = 15.2 Hz, NCH₂),

6.91–6.97 (1H, m, H Ph), 7.07–7.15 (3H, m, H Ph), 7.32 (1H, d, J = 8.2 Hz, H pyr), 7.60 (1H, dd, J = 8.3 Hz,

J = 2.5 Hz, H pyr), 8.30 (1H, d, J = 2.4 Hz, H pyr), 9.56 (1H, s, NH) ppm. ¹³C NMR (50 MHz, CDCl₃)

δ

= 29.7 (CH₂), 41.7 (CH₂), 48.7 (CH₂), 49.6 (CH₂), 49.9 (CH₂), 51.3 (CH₂), 105.1, 105.7, 124.7 (CH), 125.7

(CH), 126.7 (CH), 126.3 (CH), 128.8 (CH), 129.6, 133.9, 134.9, 138.2 (CH), 139.7, 148.9 (CH), 151.6, 160.2

ppm; MS m/z (I_rel, %): 479 [M⁺] (2), 443 [M

−

HCl]⁺(3), 407 [M-2(HCl)]⁺(5), 254 [M-C₂Cl₂-isoquinoline

+ H]⁺(7), 126 [Cl-pyr-CH₂]⁺(100); HRMS (ESI⁻) m/z calcd for C₂₁H₁₉N₅O₂Cl₃[M

−

H]⁻: 478.0610;

found: 478.0606.

2-[(1,1-Dichloro-3-{1-[(6-chloropyridin-3-yl)methyl]imidazolidin-2-ylidene}-3-nitroprop-1-en-2- yl)sulfanyl]-

ethanol (12c). Same procedure as for 12a, using 11a (0.384 g, 1.00 mmol), 2-mercaptoethanol (0.086 g,

1.1 mmol) and sodium ethanolate (0.082 g, 1.2 mmol) in EtOH. The mixture was stirred for 12 h at 40

^◦C. Yield 0.268 g (63%), orange solid, m.p. 185–187 ^◦C. IR (KBr)

ν

= 3220, 2974, 1575, 1299, 1125,

max

1

844 cm⁻¹. H NMR spectrum (200 MHz, DMSO-d₆)

δ = 2.77 (2H, t, J = 6.4 Hz, SCH₂), 3.53 (2H, t, J

= 6.4 Hz, CH₂OH), 3.73 (4H, s, CH₂), 4.30 (2H, s, NCH₂), 4.70 (1H, s, OH), 7.53 (1H, d, J = 8.3 Hz),

7.75 (1H, dd, J = 8.3 Hz, J = 2.5 Hz), 8.33 (1H, d, J = 2.3 Hz), 9.55 (1H, s, NH) ppm; ¹³C NMR (50 MHz,

DMSO-d₆)

δ = 34.9 (CH₂), 42.4 (CH₂), 48.9 (CH₂), 50.8 (CH₂), 60.1 (CH₂), 102.8 (CNO₂), 115.1 (CCl₂),

124.3 (CH), 131.6, 131.9, 138.1 (CH), 148.0 (CH), 149.5, 159.7 ppm; MS m/z (I_rel, %): 424 [M⁺] (1), 254

[M-C₂Cl₂-mercaptoethanol + H]⁺(27), 235 [M

(ESI⁻) m/z calcd for C₁₄H₁₄N₄O₃SCl₃[M − H]⁻: 422.9858; found: 422.9854.

−

C₂Cl₂S-H₂O]⁺(12), 126 [Cl-pyr-CH₂]⁺(100); HRMS

1,1-Dichloro-3-{3-[(6-chloropyridin-3-yl)methyl]-1,3-oxazolidin-2-ylidene}-N,N-dimethyl-3-nitroprop-1-

en-2-amine (12d). Same procedure as for 12a, using pyridine 11b (0.385 g, 1.00 mmol) and

dimethylamine (0.366 g, 5.00 mmol) and stirring at r.t. for 5 h. Yield 70%, yellow solid, m.p. 127–129 ^◦C.

1

IR (KBr)

ν

= 2868, 1597, 1561, 1298, 1118, 903 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ

= 2.59 (6H, s,

max

NCH₃), 3.96–4.10 (2H, m, CH₂oxa), 4.52–4.81 (4H, m, CH₂oxa, NCH₂), 7.59 (1H, d, J = 7.7 Hz, H pyr),

7.91 (1H, d, J = 7.5 Hz, H pyr), 8.41 (1H, s, H pyr) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

= 42.0 (CH₃),

49.3 (CH₂), 50.8 (CH₂), 68.2 (CH₂), 104.0, 105.1, 124.4 (CH), 130.0, 139.8 (CH), 142.1, 149.8 (CH), 150.1,

δ

165.4 ppm; MS m/z (I_rel, %): 392 [M⁺] (1), 311 [M

−

Cl-NO₂]⁺(1), 254 [M

−

C₂Cl₂-N(CH₃)₂]⁺(2), 126

[Cl-pyr-CH₂]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₄H₁₆N₄O₃Cl₃[M + H]⁺: 393.0283; found: 393.0280.

Synthesis of 1-[(4-bromo-1,3,4-trichloro-2-nitrobuta-1,3-dien-1-yl)sulfanyl]-4-ﬂuorobenzene (13). To a solution

of nitrodiene 2

(0.316 g, 1.0 mmol) in dry DCM (15 mL) at 0 ^◦C, a solution of 4-ﬂuorothiophenole (0.128

g, 1.0 mmol) in 5 mL of dry DCM was added and stirred for 3 h. After reaching r.t. and further stirring

for 24 h the mixture was concentrated and water (20 mL) was added before extraction with chloroform

(3

×

10 mL). The product was puriﬁed by column chromatography using petroleum ether-ethyl acetate

(10:1) and dried in vacuo. A 1:1 mixture of isomers was obtained. Yield 0.301 g (74%), yellow solid,

m.p. 98–99 ^◦C. IR (ATR)

1

ν

= 1587, 1527, 1292, 1223, 815, 526 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

=

max

7.11–7.25 (2H, m, H Ph), 7.48–7.64 (2H, m, H Ph) ppm; ¹³C NMR (101 MHz, CDCl₃)

(CClBr), 117.0, 117.2 (CH), 124.0, 124.1, 124.2, 124.5, 138.3, 138.4 (CH), 157.3, 157.8 (CClS), 163.4, 165.9

(CF) ppm, CNO₂could not be detected; MS m/z (I_rel, %): 405 [M⁺] (1), 370 [M Cl]⁺(1), 326 [M Br]⁺

(6), 291 [M

Br-Cl]⁺(3), 127 [S-Ph-F]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₀H₅NO₂Cl₃SBrF [M + H]⁺:

405.8269; found: 405.8286.

δ = 115.2, 116.4

−

Synthesis of 5-(((2E)-2-(3-bromo-2,3-dichloro-1-nitroallylidene)imidazolidin-1-yl)methyl)-2-chloropyridine (14

)

and 1,1’-[(4-bromo-3,4-dichloro-2-nitrobuta-1,3-diene-1,1-diyl)disulfanediyl]bis(4-ﬂuorobenzene) (15). A

solution of N-[(6-chloropyridin-3-yl)methyl]ethane-1,2-diamine 10a (0.515 g, 3.0 mmol) in MeOH

Molecules 2020, 25, 2863

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(5 mL) was added to a suspension of diene 13 (0.407 g, 1.0 mmol, a 1: 1 mixture of isomers ) in MeOH

(10 mL) at –10 ^◦C and stirred for 1 h at the same temperature. The precipitated bisthiodiene 15 was

ﬁltered oﬀ, washed with water and cold MeOH (2

×

3 mL), and dried under reduced pressure to yield

diene 15. The collected ﬁltrates were carefully neutralized by means of hydrochloric acid and stirred

with additional 50 mL of water. Again, the solid was ﬁltered oﬀ, and then washed with water and

diethyl ether (3 × 5 mL). Recrystallization from methanol gave imidazolidine 14.

Imidazolidine 14. A 1: 1 mixture of isomers was obtained. Yield 0.189 g (44%), white solid, m.p. 172–173

1

^◦C. IR (KBr)

ν

_max= 3312, 3055, 2917, 1588, 1420, 1137, 824 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ

=

3.67–3.90 (4H, m, CH₂imi), 4.46-4.60 (2H, m, NCH₂-pyr), 7.48–7.60 (1H, m, H pyr), 7.71–7.81 (1H, m, H

pyr), 8.24–8.39 (1H, m, H pyr), 9.41 (1H, s, NH) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

= 42.7 (CH₂imi),

δ

49.4 (NCH₂-pyr), 50.8 (CH₂imi), 103.4, 105.2 (CNO₂), 113.0, 113.8 (CClBr), 124.3, 124.4 (CH), 126.6,

128.7, 131.4, 131.5, 137.9, 138.0 (CH), 147.9, 148.0, 149.6, 159.6, 159.7 (NCN) ppm; MS m/z (I_rel, %): 426

[M⁺] (1), 380 [M-NO₂]⁺(1), 347 [M-Br]⁺(20), 314 [M-pyr]⁺(3), 312 [M-Br-Cl]⁺(3), 254 [M-C₂Cl₂Br+H]⁺

(35), 126 [Cl-pyr-CH₂]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₂H₉N₄O₂Cl₃Br [M-H]⁻: 424.8980; found:

424.8967.

Bisthiodiene 15. A 1: 1 mixture of isomers was obtained. Yield 0.150 g (30%), yellow solid, m.p.

1

141–142 ^◦C. IR (ATR)

ν

= 1589, 1489, 1293, 1230, 823, 505 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

=

max

6.84–7.01 (6H, m, H Ph), 7.05–7.17 (2H, m, H Ph) ppm; ¹³C NMR (101 MHz, CDCl₃)

(CClBr), 116.3–116.7 (CH Ph), 123.4, 125.5, 126.1 (C_Ph-S), 133.4, 133.5, 136.5, 136.6, 136.7 (C Ph), 138.3,

138.4 (CNO₂), 159.1, 159.5 (CSS), 163.1 (CF, J_C,F= 251.5 Hz), 163.1 (CF, J_C,F= 252.3 Hz) ppm; MS, m/z (I_rel

%): 497 [M⁺] (2), 462 [M Cl]⁺(2), 418 [M Br]⁺(30), 383 [M Br-Cl]⁺(3), 372 [M Br-NO₂]⁺(4), 127

[S-Ph-F]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₆H₉NO₂BrCl₂F₂S₂[M + H]⁺: 497.8598; found 497.8588.

δ = 115.1, 117.2

,

−

Alternative synthesis of diene 15: To a solution of bromonitrodiene

2 (0.316 g, 1.0 mmol, a 47: 53 mixture

of isomers) and 4-ﬂuorobenzenethiol (0.256 g, 2.0 mmol) in MeOH (10 mL) at 0 ^◦C, a solution of sodium

methanolate (0.108 g, 2.0 mmol) in MeOH (5 mL) was added. The solution was stirred for 3 h at 0 ^◦C

and at r.t. for 1 d. Subsequently, the solution was concentrated and the precipitate ﬁltered oﬀ and

washed with diluted HCl (5 mL) and cold MeOH (2

Yield of bisthiodiene 15 is 0.414 g (83%, a 1:1 mixture of isomers).

×

2 mL). A mixture of both isomers was obtained.

N,N’-Bis[(2-chloro-1,3-thiazol-5-yl)methyl]ethane-1,2-diamine (16) was prepared according to the

literature [13] in 70% yield.

Synthesis

of

5,5’-{[2-(3-bromo-2,3-dichloro-1-nitroprop-2-en-1-ylidene)imidazolidine-1,3-diyl]

dimethanediyl}-bis(2-chloro-1,3-thiazole) (17). To a solution of diene

2 (0.166 g, 0.5 mmol) in a mixture of

MeOH and water (10 mL, 10: 1) at 0 ^◦C N,N’-bis[(2-chloro-1,3-thiazol-5-yl)methyl]ethane-1,2-diamine

◦

(16) (0.170 g, 0.5 mmol) and Na₂CO₃(0.112 g, 2.0 mmol) were added carefully. After 1 h at 0 C,

the mixture was allowed to reach r.t. and stirred for another 5 h. Subsequently, the mixture was

concentrated in vacuo and the resulting precipitate was ﬁltered oﬀ and washed with cold MeOH (2

mL), water (2 5 mL) and again MeOH (1 5 mL). A 1: 1 mixture of isomers was obtained. Yield 0.252

g (89%), white solid, mp 162–163 ^◦C. IR (ATR)

×

5

×

1

ν

= 1569, 1533, 1325, 1143, 1046, 770 cm⁻¹. H NMR

max

(400 MHz, DMSO-d₆)

¹³C NMR (100 MHz, DMSO-d₆)

99.7 (CNO₂), 109.7, 110.6 (CClBr), 127.0, 128.8 (CCl), 133.6, 133.7 (SC thiaz), 141.8, 141.9 (NC thiaz),

151.7, 151.8 (NCS), 161.6, 161.8 (NCN) ppm; MS m/z (I_rel, %): 563 [M⁺] (1), 527 [M Cl]⁺(1), 484 [M

Br]⁺(1), 132 [thiazole-Cl-CH₂]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₄H₁₁N₅O₂Cl₄BrS₂[M + H]⁺:

563.8286; found: 563.8284.

δ

= 3.73–3.96 (4H, m, CH₂), 4.58–4.80 (4H, m, imi-CH₂), 7.69 (2H, s, CH) ppm;

δ

= 45.2, 45.4 (CH₂imi), 45.2, 45.4 (CH₂imi), 47.2, 47.3 (imi-CH₂), 98.1,

−

Ethyl [(1,3,4,4-tetrachloro-2-nitrobuta-1,3-dien-1-yl)sulfanyl]acetate (18) was prepared according to the

literature [18] in 80% yield.

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Synthesis of 3-[4-(propan-2-yl)phenyl]-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-1,3-thiazolidin-4-one (19a

(General method). To a suspension of the acetate 18 (0.355 g, 1.0 mmol) in MeOH (3 mL) at

18 ^◦C a

solution of 4-(propan-2-yl)aniline (0.297 g, 2.2 mmol) in MeOH (3 mL) was added dropwise within 10

min. The mixture was stirred for 3 h at

18 ^◦C and 12 h at r.t. before it was concentrated. The resulting

precipitate was ﬁltered oﬀ and washed with cold MeOH (1 5 mL), water (2 5 mL) and again MeOH

(2

5 mL). The product was dried in vacuo. Yield 0.298 g (73%), beige solid, m.p. 208–209 ^◦C. IR (ATR)

_max= 2962, 1758, 1520, 1289, 1167, 686 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

)

−

×

1

ν

δ = 1.22 (3H, d, J = 6.9

Hz, i-Pr), 1.23 (3H, d, J = 6.9 Hz, i-Pr), 2.95 (1H, sep, J = 6.8 Hz, i-Pr), 4.13 (1H, d, J = 18.7 Hz, SCH₂),

4.17 (1H, d, J = 18.7 Hz, SCH₂), 7.28–7.33 (2H, m, H Ar), 7.34–7.40 (2H, m, H Ar) ppm; ¹³C NMR (100

MHz, DMSO-d₆)

δ = 23.6, 23.8 (CH₃), 32.5 (CH₂), 33.6 (CH i-Pr), 121.3 (CCl₂), 121.4 (CNO₂), 126.9

(CH), 127.3 (CH), 127.4 (CH), 128.4, 128.8 (CH), 132.1, 150.6, 165.8 (NCS), 174.1 (C=O) ppm; MS m/z

(I_rel, %): 406 [M⁺] (10), 389 [M-OH]⁺(5), 371 [M-Cl]⁺(5), 278 [M-C₂Cl₃+H]⁺(15), 261 [M-C₂Cl₃-O]⁺

(100); MS (ESI⁻) m/z calcd for C₁₅H₁₂N₂O₃Cl₃S 405.0; found: 405.0.

2-(2,3,3-Trichloro-1-nitroprop-2-en-1-ylidene)-3-[4-(triﬂuoromethyl)phenyl]-1,3-thiazolidin-4-one (19b). Same

procedure as for 19a, using 4-(triﬂuoromethyl)aniline (0.355 g, 2.2 mmol) at 0 ^◦C for 3 h and 15 h at r.t..

Yield 0.330 g (76%), yellowish solid, m.p. 228–229 ^◦C. IR (ATR)

ν

= 3058, 1737, 1515, 1285, 1170,

max

1

691 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ

= 4.13 (1H, d, J = 18.7 Hz, SCH₂), 4.20 (1H, d, J = 18.7 Hz,

= 32.8

(CH₂), 121.2 (CNO₂), 121.3 (CCl₂), 123.9 (J_C,F= 272.4 Hz, CF₃), 126.2 (J_C,F= 3.9 Hz, CH), 126.6 (J_C,F

4.2 Hz, CH), 128.9 (CH), 129.1, 130.2 (CH), 130.7 (J_C,F= 32.3 Hz, CF₃- ), 138.1, 165.4 (NCS), 173.9 (C=O)

ppm; MS m/z (I_rel, %): 432 [M⁺] (3); 397 [M Cl]⁺(12); 304 [M-C₂Cl₃+H]⁺(30); 287 [M-C₂Cl₃-O]⁺(93);

SCH₂), 7.67–7.74 (2H, m, H Ar), 7.91–7.98 (2H, m, H Ar) ppm; ¹³C NMR (400 MHz, DMSO-d₆)

δ

=

C

−

145 (100); HRMS (ESI⁻) m/z calcd for C₁₃H₅N₂O₃Cl₃SF₃[M − H]⁻: 430.9044; found: 430.9062.

Synthesis of 3-(hydrazinylidenemethyl)-4-nitro-N-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (20a). To a

stirred suspension of thiazolidinone 19a (0.408 g, 1.0 mmol) in MeOH (10 mL) at

18 ^◦C, a solution of

−

hydrazine hydrate (0.400 g, 8.0 mmol) in MeOH (5 mL) was added dropwise within 5 min. Subsequently,

the mixture was allowed to reach 0 ^◦C. After 5 h, and 18 h at r.t., the solution was concentrated and

neutralized to pH 7 with HCl (5%), then extracted with ethyl acetate (3

×

10 mL). The combined organic

phases were puriﬁed over a short column chromatography using ethyl acetate-petroleum ether (1:1).

Subsequently, the obtained solution was concentrated and the resulting precipitate was ﬁltered and

washed with diethyl ether (2

×

3 mL). Yield 0.150 g (52%), red solid, m.p. 194–195 ^◦C. IR (ATR)

ν

=

max

1

3365, 2956, 1597, 1562, 1461, 1350, 579 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ = 1.18 (6H, d, J = 6.9 Hz,

CH₃i-Pr), 2.83 (1H, sep, J = 6.8 Hz, CH i-Pr), 7.16 (2H, d, J = 8.5 Hz, H Ar), 7.61 (2H, d, J = 8.4 Hz, H

Ar), 8.07 (1H, s, NCH), 8.15 (2H, s, N-NH₂), 8.53 (1H, s, NH anil), 13.29 (1H, s, NH pyr) ppm; ¹³C NMR

(100 MHz, DMSO-d₆)

126.7 (2

δ

=24.2 (CH₃), 32.9 (CH i-Pr), 117.4 (CNO₂), 118.0 (2

×

CH Ph), 122.7 (NCH),

×

CH Ph), 138.3, 138.7, 141.4, 147.4 (NNHC) ppm; MS m/z (I_rel, %): 288 [M⁺] (60), 273 [M

−

CH₃]⁺(100), 256 [M-CH₃-OH]⁺(5), 245 [M-i-Pr]⁺(8), 169 [M-NH-Ph-i-Pr]⁺(5); HRMS (ESI⁻) m/z calcd

for C₁₃H₁₅N₆O₂[M − H]⁻: 287.1261; found: 287.1272.

Synthesis of 3-(hydrazinylidenemethyl)-4-nitro-N-[4-(triﬂuoromethyl)phenyl]-1H-pyrazol-5-amine (20b). To a

stirred suspension of thiazolidinone 19b (0.434 g, 1.0 mmol) in MeOH (10 mL) at

18 ^◦C, a solution of

−

hydrazine hydrate (0.250 g, 5.0 mmol) in MeOH (5 mL) was added dropwise within 5 min. Subsequently,

the mixture was allowed to reach 0 ^◦C. After 5 h with stirring at 0 ^◦C and 18 h at r.t., the solution was

concentrated and the resulting precipitate ﬁltered oﬀ. Washing the product with cold MeOH (2

×

5

mL) and drying in vacuo yielded the pyrazole 20b. Yield 0.145 g (46%), yellow solid, m.p. 248–250

1

^◦C. IR (ATR)

ν

_max= 3440, 1602, 1516, 1327, 1160, 832 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ

= 7.63

(2H, d, J = 8.7 Hz, H Ph), 7.91 (2H, d, J = 8.6 Hz, H Ph), 8.07 (1H, s, NCH), 8.21 (2H, s, NH₂), 8.97 (1H,

s, Ph-NH), 13.45 (1H, s, NH Pyr) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

= 117.6 (2 CH Ph), 117.8

(CNO₂), 121.0 (J_C,F= 32.1 Hz, CF₃), 122.2 (J_C,F= 270.7 Hz, CF₃), 122.5 (NCH), 126.2 (J_C,F= 3.7 Hz,

CH Ph), 139.0, 144.2, 146.4 (NNHC) ppm;. MS m/z (I_rel, %): 314 [M⁺] (2), 270 [M-CH₂=N-NH₂]⁺

δ

×

C

2

×

Molecules 2020, 25, 2863

20 of 41

(3), 254 [M-CH₂=N-NH₂-O]⁺(14), 161 [CF₃-Ph-NH₂]⁺(60), 142 [CF₂-Ph-NH₂]⁺(27), 96 (100); HRMS

(ESI⁻) m/z calcd for C₁₁H₈N₆O₂F₃[M − H]⁻: 313.0665; found: 313.0666.

Synthesis

of

5-(furan-2-ylmethylidene)-3-[4-(propan-2-yl)phenyl]-2-(2,3,3-trichloro-1-nitroprop-2-en-

1-ylidene)-1,3-thiazolidin-4-one (21a) (General method). To a suspension of thiazolidinone 19a (0.408 g, 1.0

mmol) in acetic acid (15 mL) furan-2-carbaldehyde (0.115 g, 1.2 mmol) and triethylamine (0.152 g, 1.5

mmol) were added. The resulting mixture was reﬂuxed for 4 h. After concentration of this mixture

in vacuo to a volume of about 3 mL and cooling to r.t., the resulting precipitate was ﬁltered oﬀ and

washed with water (2

0.466 g (96%), orange solid, m.p. 228–229 ^◦C. IR (ATR)

¹H NMR (400 MHz, DMSO-d₆)

= 1.24 (3H, d, J = 6.9 Hz, CH₃i-Pr), 1.25 (3H, d, J = 6.9 Hz, CH₃i-Pr),

×

10 mL) and cold MeOH (1

×

2 mL). The product was dried in vacuo. Yield

ν

_max= 2958, 1718, 1598, 1519, 1167, 764 cm⁻¹

.

δ

2.97 (1H, sep, J = 6.8 Hz, CH i-Pr), 6.86 (1H, dd, J = 1.8 Hz, J = 3.6 Hz, H fur), 7.34 (1H, d, J = 3.5 Hz, H

fur), 7.37–7.45 (4H, m, H Ar), 7.90 (1H, s, =CH), 8.30 (1H, d, J = 1.7 Hz, H fur) ppm; ¹³C NMR (100

MHz, DMSO-d₆)

δ

= 23.6 (CH₃), 23.9 (CH₃), 33.6 (CH i-Pr), 114.4 (CH), 116.7, 120.8 (CNO₂), 121.0

Cl-CCl₂), 132.1,

(CCl₂), 121.8 (CH), 122.8 (CH), 126.9 (CH), 127.3 (CH), 127.4 (CH), 128.8 (CH), 128.8 (

C

149.4 (CH), 149.9, 150.8, 158.5 (NCS), 166.5 (C=O) ppm; MS m/z (I_rel, %): 484 [M⁺] (6), 449 [M-Cl]⁺(2),

339 [M-C₂Cl₃-O]⁺(75), 325 [M-furan-CH=C=S-Cl]⁺(7), 124 [furan-CH=C=S]⁺(100). HRMS (ESI⁺) m/z

calcd for C₂₀H₁₅N₂O₄SCl₃Na [M + Na]⁺: 506.9716; found: 506.9712.

3-[4-(Propan-2-yl)phenyl]-5-(thiophen-2-ylmethylidene)-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)

-1,3-thiazolidin-4-one (21b). Same procedure as for 21a, using thiophene-2-carbaldehyde (0.135 g, 1.2

mmol). After ﬁltration of the product, it was further puriﬁed by column chromatography using

chloroform. Yield 0.462 g (92%), dark yellow solid, m.p. 221–223 ^◦C. IR (ATR)

ν

= 2963, 1717, 1586,

max

1525, 1258, 729 cm⁻¹. H NMR (400 MHz, CDCl₃) δ = 1.29 (6H, d, J = 6.7 Hz, CH₃i-Pr), 2.99 (1H, sep,

J = 6.9 Hz, CH i-Pr), 7.16–7.20 (1H, m, H Ar), 7.24–7.27 (1H, m, H thien), 7.27–7.30 (1H, m, H Ar),

7.35–7.39 (2H, m, H Ar), 7.56 (1H, d, J = 3.7 Hz, H thien), 7.78 (1H, d, J = 5.0 Hz, H thien), 8.12 (1H, s,

1

=CH) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 23.5 (CH₃), 23.7 (CH₃), 34.1 (CH i-Pr), 117.6, 120.6 (CCl₂),

122.6 (CNO₂), 126.8 (CH), 127.4 (CH), 127.8 (CH), 127.9 (CH), 129.1 (CH), 129.6 (CH), 129.7 ( ClCCl₂),

), 155.3 (NCS), 166.7 (C=O) ppm; MS m/z (I_rel, %): 500

C

131.6, 133.6 (CH), 134.8 (CH), 137.6, 151.4 (i-Pr-

C

[M⁺] (3), 465 [M-Cl]⁺(2), 372 [M-C₂Cl₃+H]⁺(4), 355 [M-C₂Cl₃-O]⁺(73), 140 [thienyl-C=CS]⁺(100).

HRMS (ESI⁺) m/z calcd for C₂₀H₁₅N₂O₃Cl₃S₂Na [M + Na]⁺: 522.9487; found: 522.9482.

5-[(1-Methyl-1H-pyrrol-2-yl)methylidene]-3-[4-(propan-2-yl)phenyl]-2-(2,3,3-trichloro-1-nitroprop-2

-en-1-ylidene)-1,3-thiazolidin-4-one

(21c).

Same

procedure

as

for

21a

,

using

1-methyl-1H-pyrrole-2-carbaldehyde (0.328 g, 3.0 mmol) and triethylamine (0.304 g, 3.0 mmol). The

mixture was reﬂuxed for 6 h. Yield 0.459 g (92%), red solid, m.p. 244–246 ^◦C. IR (ATR)

ν

_max= 2986,

1

1700, 1584, 1520, 1273, 745 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ = 1.24 (3H, d, J = 6.9 Hz, CH₃i-Pr),

1.25 (3H, d, J = 6.9 Hz, CH₃i-Pr), 2.98 (1H, sep, J = 6.9 Hz, CH i-Pr), 3.83 (3H, s, NCH₃), 6.47 (1H, dd, J =

2.6 Hz, J = 4.2 Hz, H pyrr), 6.88 (1H, dd, J = 1.1 Hz, J = 4.2 Hz, H pyrr), 7.36–7.44 (5H, m, 4H Ph, H pyrr),

7.84 (1H, s, =CH) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

δ

= 23.6 (CH₃), 23.9 (CH₃i-Pr), 33.6 (NCH₃),

34.3 (CH i-Pr), 111.5 (CCl₂), 111.9 (CH), 118.0 (CH), 120.2 (CNO₂), 121.2, 124.9 (CH), 126.9 (CH), 127.4

(2

×

CH), 128.0, 128.6, 128.7 (CH), 131.8 (CH), 132.2, 150.7 (i-Pr-C), 157.5 (NCS), 166.5 (C=O) ppm; MS

m/z (I_rel, %): 497 [M⁺] (10), 462 [M-Cl]⁺(1), 361 [M-pyrrol-CH=C=S+H]⁺(3), 352 [M-C₂Cl₃-CH₄]⁺(25),

137 [Me-pyrrol-CH=C=S]⁺(100); HRMS (ESI⁺) m/z calcd for C₂₁H₁₈N₃O₃Cl₃SNa [M + Na]⁺: 520.0032;

found: 520.0018.

5-(Furan-2-ylmethylidene)-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-3-[4-(triﬂuoromethyl)

phenyl]-1,3-thiazolidin-4-one (21d). Same procedure as for 21a, using thiazolidinone 21b (0.433

g, 1.0 mmol), furan-2-carbaldehyde (0.115 g, 1.2 mmol) and triethylamine (0.152 g, 1.5 mmol). Yield

0.374 g (73%), orange solid, m.p. 227–229 ^◦C. IR (ATR)

¹H NMR (400 MHz, CDCl₃)

fur), 7.41–7.45 (1H, m, H Ar), 7.50–7.55 (1H, m, H Ar), 7.72 (1H, s, =CH), 7.78–7.84 (2H, m, H Ar), 7.85

ν

_max= 3130, 1720, 1525, 1286, 1162, 622 cm⁻¹

.

δ

= 6.67 (1H, dd, J = 1.8 Hz, J = 3.6 Hz, H fur), 6.98 (1H, d, J = 3.6 Hz, H

Molecules 2020, 25, 2863

21 of 41

(1H, d, J = 1.8 Hz, H fur) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 113.9 (CH), 116.9, 120.4 (CH), 120.6

(CCl₂), 123.4 (J_C,F= 272.8 Hz, CF₃), 122.5 (CNO₂), 122.9 (CH), 126.4 (J_C,F= 3.7 Hz, CH), 126.9 (J_C,F

=

3.7 Hz, CH), 127.8 (CH), 128.8 (CH), 130.2 (CClCCl₂), 132.6 (J_C,F= 33.0 Hz, CF₃C), 137.2, 148.0 (CH),

149.9, 156.0, 166.4 (C=O)ppm; MS m/z (I_rel, %): 510 [M⁺] (3), 475 [M-Cl]⁺(1), 429 [M-Cl-NO₂]⁺(1), 382

[M-C₂Cl₃+H]⁺(5), 365 [M-C₂Cl₃-O]⁺(37), 145 [Ph-CF₃]⁺(24), 124 [furan-CH=C=S]⁺(100); HRMS

(ESI⁺) m/z calcd for C₁₈H₈N₂O₄Cl₃SF₃Na [M + Na]⁺: 532.9120; found: 532.9117.

5-(Thiophen-2-ylmethylidene)-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-3-[4-(triﬂuoromethyl)-

phenyl]-1,3-thiazolidin-4-one (21e). Same procedure as for 21a, using thiazolidinone 21b (0.433

g, 1.0 mmol), thiophene-2-carbaldehyde (0.135 g, 1.2 mmol) and triethylamine (0.152 g, 1.5 mmol).

After ﬁltration, the product was puriﬁed by column chromatography using chloroform. The fraction

containing the product was dried, suspended in MeOH (2 mL), ﬁltered, and the solid washed with

cold MeOH (1

×

2 mL). Yield 0.449 g (85%), orange solid, m.p. 245–246 ^◦C. IR (ATR)

ν

= 3076, 1699,

max

1

1522, 1281, 1126, 730 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ = 7.28 (1H, dd, J = 3.8 Hz, J = 5.0 Hz, H

thien), 7.43–7.45 (1H, m, H Ar), 7.52–7.54 (1H, m, H Ar), 7.58 (1H, d, J = 3.7 Hz, H thien), 7.79–7.84 (2H,

m, H Ar), 7.84–7.86 (1H, m, H thien), 8.15 (1H, s, =CH) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 116.9,

120.4 (CCl₂), 123.3 (J_C,F= 271.9 Hz, CF₃), 126.4 (J_C,F= 3.9 Hz, CH), 126.9 (J_C,F= 4.2 Hz, CH), 127.8

(CH), 128.8 (CH), 129.3 (CH), 130.3 (CH), 130.4 ( ClCCl₂), 132.3 (J_C,F= 32.0 Hz, CF₃- ), 134.1 (CH),

δ

C

135.3 (CH), 137.2, 137.4, 154.5 (NCS), 166.2 (C=O) ppm, CNO₂could not be detected; MS m/z (I_rel, %):

526 [M⁺] (4), 491 [M-Cl]⁺(1), 398 [M-C₂Cl₃+H]⁺(5), 381 [M-C₂Cl₃-O]⁺(48), 140 [thienyl-C=CS]⁺(100);

HRMS (ESI⁺) m/z calcd for C₁₈H₈N₂O₃Cl₃S₂F₃Na [M + Na]⁺: 548.8892; found, m/z: 548.8888.

5-[(1-Methyl-1H-pyrrol-2-yl)methylidene]-2-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-3-

[4-(tri

ﬂuoro-methyl)-phenyl]-1,3-thiazolidin-4-one (21f). Same procedure as for 21a, using thiazolidinone 21b

(0.433 g, 1.0 mmol), 1-methyl-1H-pyrrole-2-carbaldehyde (0.262 g, 2.4 mmol) and triethylamine (0.152

g, 1.5 mmol). The mixture was reﬂuxed for 8 h. Yield 0.289 g (55%), red solid, shows ﬂuorescence, m.p.

1

241–242 ^◦C. IR (ATR)

ν

= 1688, 1589, 1521, 1269, 1064, 620 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ

max

= 3.84 (3H, s, NCH₃), 6.48 (1H, dd, J = 2.3 Hz, J = 4.1 Hz, H pyrr), 6.90 (1H, dd, J = 1.3 Hz, J = 4.1 Hz, H

pyrr), 7.39 (1H, dd, J = 1.3 Hz, J = 2.3 Hz, H pyrr), 7.78–7.86 (2H, m, H Ar), 7.87 (1H, s, =CH), 7.94–8.00

(2H, m , H Ph) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

δ = 34.3 (NCH₃), 111.3, 112.1 (CH), 118.2 (CH),

120.0 (CNO₂), 121.2 (CCl₂), 123.9 (J_C,F= 273.1 Hz, CF₃), 125.1 (CH), 126.2 (CH), 126.7 (CH), 128.0, 129.0

(CH), 129.2, 130.1 (CH), 130.8 (J_C,F= 32.3 Hz, CCF₃), 132.0 (CH), 138.2, 157.2 (NCS), 166.2 (C=O) ppm;

MS m/z (I_rel, %): 523 [M⁺] (5), 458 [M-F-NO₂]⁺(2), 378 [M-Ph-CF₃]⁺(12), 287 (100), 145 [Ph-CF₃]⁺(90);

HRMS (ESI⁺) m/z calcd for C₁₉H₁₁N₃O₃Cl₃SF₃Na [M + Na]⁺: 545.9436; found: 545.9433.

1-Methyl-4-nitro-3-(morpholin-4-yl)-1H-pyrazole-5-carbaldehyde (22) was prepared according to the

literature [26] in 48% yield.

Synthesis of 5-{[3-(Morpholin-4-yl)-4-nitro-1H-pyrazol-5-yl]methylidene}-3-[4-(propan-2-yl)phenyl]-2-

(2,3,3-trichloro-1-nitropropylidene)-1,3-thiazolidin-4-one (23a) (General method).

of thiazolidinone 19a (0.408 g, 1.0 mmol) in acetic acid (10 mL),

To a suspension

solution of

a

1-methyl-3-(morpholin-4-yl)-4-nitro-1H-pyrazole-5-carbaldehyde (0.240 g, 1.0 mmol) in acetic

acid (5 mL) and triethylamine (0.152 g, 1.5 mmol) was added. Subsequently, the mixture was reﬂuxed

for 4 h. After cooling, the solvent was removed and MeOH (5 mL) added. The resulting precipitate

was ﬁltered oﬀ and washed with cold MeOH (2

×

5 mL). The product was dried in vacuo. Yield 0.592 g

(94%), orange solid, mixture of two isomers (100: 16), m.p. 212–213 ^◦C. IR (ATR)

ν

= 2961, 1735,

max

1

1535, 1290, 1178, 683 cm⁻¹. H NMR major isomer (400 MHz, DMSO-d₆)

δ

= 1.21 (6H, d, J = 6.9 Hz,

CH₃i-Pr), 2.99 (1H, sep, J = 6.8 Hz, CH i-Pr), 3.22–3.28 (4H, m, NCH₂), 3.72–3.78 (4H, m, OCH₂), 3.85

(3H, s, NCH₃), 7.33–7.53 (4H, m, H Ar), 7.90 (1H, s, =CH) ppm; ¹³C NMR major isomer (100 MHz,

DMSO-d₆)

121.4 (CH), 121.8, 123.5 (CNO₂), 127.0 (CH), 127.4 (2

-i-Pr), 153.2 (N-N-C-N), 156.5 (NCS), 165.1 (C=O) ppm; MS m/z (I_rel, %): 628 [M⁺] (55), 613 [M-CH₃]⁺

δ

= 23.5, 23.8 (CH₃i-Pr), 33.6 (CH i-Pr), 39.0 (NCH₃), 49.9 (NCH₂), 65.9 (OCH₂), 120.1,

×

CH), 128.9 (CH), 129.5, 130.9, 131.7, 137.4, 151.1

(C

Molecules 2020, 25, 2863

22 of 41

(83), 598 [M-2(CH₃)]⁺(22), 582 [M-NO₂]⁺(20), 499 [M-C₂Cl₃]⁺(10), 146 (100); HRMS (ESI⁺) m/z calcd

for C₂₄H₂₃N₆O₆Cl₃SNa [M + Na]⁺: 651.0363; found: 651.0360.

5-{[3-(Morpholin-4-yl)-4-nitro-1H-pyrazol-5-yl]methylidene}-2-

(2,3,3-trichloro-1-nitropropylidene)

-3-[4-(triﬂuoromethyl)phenyl]-1,3-thiazolidin-4-one (23b). Same procedure as for 23a, using thiazolidinone

19b (0.434 g, 1.0 mmol), 1-methyl-3-(morpholin-4-yl)-4-nitro-1H-pyrazole-5-carbaldehyde (0.240 g, 1.0

mmol) and triethylamine (0.152 g, 1.5 mmol). The mixture was reﬂuxed for 2 h. Yield 0.636 g (97%),

mixture of two isomers (100: 17), orange solid, m.p. 226–227 ^◦C. IR (ATR)

ν

_max= 1733, 1538, 1291, 1171,

1

1065, 630 cm⁻¹. H NMR major isomer (400 MHz, DMSO-d₆)

δ = 3.22–3.29 (4H, m, NCH₂), 3.72–3.79

(4H, m, OCH₂), 3.85 (3H, s, NCH₃), 7.81–8.04 (4H, m, 4H Ar), 7.93 (1H, s, =CH) ppm; ¹³C NMR major

isomer (100 MHz, DMSO-d₆) = 39.1 (NCH₃), 49.9 (NCH₂), 65.9 (OCH₂), 120.1, 121.6 (pyr-CH), 121.7

(CH), 123.9 (J_C,F= 272.7 Hz, CF₃), 123.6 (CNO₂), 126.3 (J_C,F= 3.9 Hz, CH), 126.8 (J_C,F= 3.9 Hz, CH),

129.0 (CH), 130.2, 130.3 (CH), 130.8, 131.2 (J_C,F= 32.1 Hz, CF₃), 137.3, 137.7, 153.2, 156.2 (NCS), 164.9

δ

C

(C=O) ppm; MS m/z (I_rel, %): 654 [M⁺] (35), 639 [M

−

CH₃]⁺(60), 619 [M

−

Cl]⁺(8), 145 [Ph-CF₃]⁺(50),

127 (100); HRMS (ESI⁺) m/z calcd for C₂₂H₁₆N₆O₆Cl₃SF₃Na [M + Na]⁺: 676.9767; found: 676.9769.

1,1’-(3,4,4-Trichloro-2-nitrobuta-1,3-diene-1,1-diyl)bis(1H-benzotriazole) (24) was prepared according to the

literature [28] in 76% yield.

Synthesis of N-[1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-dien-1-yl]-2-methoxyaniline (2_◦5a

(General method). To a suspension of azole 24 (0.437 g, 1.0 mmol) in MeOH (10 mL) at 0 C,

2-methoxyaniline (0.129 g, 1.05 mmol) was slowly added. The mixture was allowed to reach r.t.

and stirred for another 3 h. After evaporation of the solvent, HCl (10%, 10 mL) was added and the

resulting sludge was stirred for 20 min. The precipitate was then ﬁltered oﬀ and washed with HCl

)

(10%, 5 mL), cold water (5 mL) and cold Et₂O (2

×

5 mL). The product was dried in vacuo. Yield 0.392

1

g (89%), yellow solid, m.p. 128–129 ^◦C. IR (KBr)

ν

= 1621, 1580, 1463, 1252, 1023, 753 cm⁻¹. H

max

NMR (200 MHz, CDCl₃) δ = 3.91 (3H, s, OCH₃), 6.15 (1H, dd, J = 1.3 Hz, J = 8.0 Hz, H Ar), 6.46 (1H,

ddd J = 7.7 Hz, J = 1.2 Hz, J = 7.5 Hz, H Ar), 6.82 (1H, dd, J = 1.5 Hz, J = 8.3 Hz, H Ar), 7.00 (1H,

ddd, J = 8.3 Hz, J = 1.4 Hz, J = 7.5 Hz, H Ar), 7.27–7.42 (3H, m, H Bzt), 8.02–8.06 (1H, m, H Bzt), 11.65

(1H, s, NH) ppm; ¹³C NMR (50 MHz, CDCl₃)

δ

= 55.9 (OCH₃), 109.8 (CH Bzt), 111.3 (CH Ar), 120.6

(CH Ar), 120.9 (CH Bzt), 122.2 (CH Ar), 123.8 (CNH), 125.3 (CH Bzt), 128.6 (CH Ar), 129.5 (CH Bzt),

131.9, 145.3 (NCN), 145.9, 151.4 (COCH₃) ppm, three C signals from butadiene-chain due to their low

intensity could not be detected; MS m/z (I_rel, %): 439 [M⁺] (4), 403 [M-HCl]⁺(3), 358 [M-Cl-NO₂]⁺(3),

331 [M-Ph-OCH₃]⁺(6), 122 [H₂NPhOCH₃]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₇H₁₃N₅O₃Cl₃[M +

H]⁺: 440.0079; found: 440.0077.

N-[1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-dien-1-yl]-2-ethoxyaniline (25b). Same procedure

as for 25a, using 2-ethoxyaniline (0.144 g, 1.05 mmol). Yield 0.355 g (78%), orange solid, m.p. 145–146

1

^◦C. IR (ATR)

ν

= 1620, 1583, 1471, 1241, 1147, 741 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 1.56 (3H, t,

max

J = 7.0 Hz, OCH₂CH₃), 4.15 (2H, q, J = 6.7 Hz, OCH₂CH₃), 5.99 (1H, dd, J = 1.0 Hz, J = 8.0 Hz, H Ar),

6.41 (1H, ddd, J = 7.6 Hz, J = 1.0 Hz, J = 7.9 Hz, H Ar), 6.82 (1H, dd, J = 8.3 Hz, J = 0.9 Hz, H Ar), 6.97

(1H, ddd, J = 8.0 Hz, J = 1.2 Hz, J = 7.8 Hz, H Ar), 7.31 (1H, d, J = 8.0 Hz, H Bzt), 7.37 (ddd, J = 7.0 Hz, J

= 1.1 Hz, J = 8.1 Hz, H Bzt), 7.43 (1H, t, J = 7.36 Hz, H Bzt), 8.06 (1H, d, J = 8.2 Hz, H Bzt) ppm; ¹³

C

NMR (100 MHz, CDCl₃) δ = 14.7 (CH₃), 64.7 (OCH₂), 109.8 (CH), 112.2 (CH), 120.6 (CH), 120.7 (CH),

121.5 (CH), 124.0, 125.3 (CH), 128.3 (CH), 129.5 (CH), 131.9, 145.3, 145.6, 150.6 ppm, three C signals

from butadiene-chain due to their low intensity could not be detected; MS m/z (I_rel, %): 453 [M⁺] (1),

417 [M

−

HCl]⁺(1), 390 [M-Cl-N₂]⁺(1), 135 [NPhOEt₂]⁺(38), 100 (100); HRMS (ESI⁺) m/z calcd for

C₁₈H₁₅N₅O₃Cl₃[M + H]⁺: 454.0235; found: 454.0234.

N’-[1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-dien-1-yl]-N,N-dimethylbenzene-1,4-di- amine

(

25c). Same procedure as for 25a, using N,N-dimethylbenzene-1,4-diamine (0.143 g, 1.05 mmol) keeping

the reaction mixture at 0 ^◦C until completion. Yield 0.413 g (91%), dark red solid, m.p. 147–148 ^◦C.

1

IR (ATR)

ν

= 2891, 1620, 1491, 1358, 1168, 818 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 2.81 (6H, s,

max

Molecules 2020, 25, 2863

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NCH₃), 6.31 (2H, d, J = 9.0 Hz, H Ar), 6.60 (2H, d, J = 9.0 Hz, H Ar), 7.35–7.44 (3H, m, H Bzt), 8.04 (1H,

d, J = 8.4 Hz, H Bzt), 11.88 (1H, s, NH) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 40.1 (CH₃), 109.8 (CH),

δ

112.2 (CH), 117.0, 120.6 (CH), 120.9, 123.8 (CH), 125.2 (CH), 128.0, 129.3 (CH), 129.5, 145.3, 146.8, 149.4

ppm, three C signals from butadiene-chain due to their low intensity could not be detected; MS m/z

(I_rel, %): 452 [M⁺] (2), 416 [M

−

Cl]⁺(1), 388 [M-HCl-N₂]⁺(1), 119 [Bzt + H]⁺(100); HRMS (ESI⁺) m/z

calcd for C₁₈H₁₆N₆O₂Cl₃[M + H]⁺: 453.0395; found: 453.0395.

1-[3,4,4-Trichloro-1-(2,3-dihydro-1H-indol-1-yl)-2-nitrobuta-1,3-dien-1-yl]-1H-benzotriazole (25f). Same

procedure as for 25a, using 1H-indoline (0.125 g, 1.05 mmol). Yield 0.354 g (87%), yellow solid, m.p.

1

178–179 ^◦C. IR (ATR)

ν

= 3065, 1533, 1295, 1023, 905, 655 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

=

max

3.34–3.46 (2H, m, CH₂ind), 3.89–4.25 (2H, m, CH₂ind), 5.06–6.38 (1H, s, H ind), 6.66–7.00 (1H, m, H

Bzt), 7.06 (1H, s, H ind), 7.29–7.36 (1H, m, H ind), 7.40–7.88 (3H, m, 2H Bzt, 1H ind), 8.16 (1H, d, J

= 8.1 Hz, H Bzt) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 29.2 (CH₂), 54.5 (CH₂), 113.9 (CNO₂), 121.1

(2

×

CH), 123.2, 125.9 (2

×

CH), 126.0 (CH), 127.9 (CH), 128.0 (CH), 130.0 (CH), 131.8 (CCl₂), 141.2

(NCN), 146.1, 146.2 ppm; MS m/z (I_rel, %): 435 [M⁺] (12), 289 [M-indolin-N₂]⁺(34), 271 [M-Bzt-NO₂]⁺

(79), 118 [benzotriazole]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₈H₁₃N₅O₂Cl₃[M + H]⁺: 436.0129; found:

436.0127.

Synthesis of 5-Methoxy-8-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-7-azabicyclo[4.2.0]octa-1,3,5- triene (26a

)

(General method). A suspension of azole 25a (0.441 g, 1.0 mmol) in MeOH (10 mL) was stirred at reﬂux

for 5 h. Subsequently, the mixture was concentrated and cooled to 0 ^◦C. The precipitate was ﬁltered oﬀ

and washed with diethyl ether (2

×

5 mL). Yield 0.119 g (37%), yellow solid, m.p. 168–169 ^◦C. IR (KBr)

1

ν

= 3112, 1637, 1536, 1395, 1083, 859 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ

= 3.96 (3H, s, OCH₃),

max

7.30–7.42 (2H, m, CH), 7.74 (1H, dd, J = 2.3 Hz, J = 7.6 Hz, CH), 12.40 (1H, s, NH) ppm; ¹³C NMR (50

MHz, DMSO-d₆) = 57.0 (OCH₃), 110.9 (CH), 114.3 (CH), 119.5, 123.9 (CH), 124.0, 125.9, 130.6, 134.0,

147.3, 153.9 (

δ

C

OCH₃) ppm; MS m/z (I_rel, %): 320 [M⁺] (1), 284 [M

−

HCl]⁺(12), 256 [M-NO₂-NH₂+H]⁺

(40), 64 (100); HRMS (ESI⁺) m/z calcd for C₁₁H₈N₂O₃Cl₃[M + H]⁺: 320.9595; found: 320.9594.

5-Ethoxy-8-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-7-azabicyclo[4.2.0]octa-1,3,5-triene (26b). Same

procedure as for 26a, using azole 25b (0.455, 1.0 mmol) and reﬂuxing in EtOH for 10 h. Yield

0.091 g (27%), yellow solid, m.p. 204–205 ^◦C. IR (KBr)

ν

_max= 2992, 1647, 1533, 1378, 1234, 554 cm⁻¹

H₂CH₃),

7.30–7.38 (2H, m, CH), 7.71 (1H, dd, J = 1.5 Hz, J = 8.2 Hz, CH), 12.37 (1H, s, NH) ppm; ¹³C NMR (100

MHz, DMSO-d₆) = 14.5 (CH₃), 65.4 (OCH₂), 110.7 (CH), 114.9 (CH), 119.5, 123.9 (CH), 124.0, 125.9,

.

¹H NMR (400 MHz, DMSO-d₆)

δ = 1.42 (3H, t, J = 7.0 Hz, OCH₂CH₃), 4.16–4.26 (2H, m, OC

δ

130.6, 133.9, 146.5, 153.9 ppm; MS m/z (I_rel, %): 334 [M⁺] (3), 299 [M

−

Cl]⁺(52), 271 [M-Cl-EtO+H]⁺

(100); HRMS (ESI⁺) m/z calcd for C₁₂H₁₀N₂O₃Cl₃[M + H]⁺: 334.9752; found: 334.9750.

Synthesis of N,N-Dimethyl-8-(2,3,3-trichloro-1-nitroprop-2-en-1-ylidene)-7-azabicyclo[4.2.0]octa-1,3,5-

trien-3-amine (26c). A suspension of azole 25c (0.454 g, 1.0 mmol) in THF (20 mL) was stirred at

reﬂux for 10 h. After evaporation of the solvent, dilute HCl (10 mL) was added and the mixture

stirred for 15 min. Subsequently, the mixture was extracted with chloroform and puriﬁed by column

chromatography using petroleum ether - ethyl acetate (1:1). Yield 0.084 g (25%), red solid, m.p. 171–173

1

^◦C. IR (KBr)

ν

= 2856, 1567, 1369, 1063, 846, 550 cm⁻¹. H NMR (400 MHz, DMSO-d₆)

δ

= 2.97 (6H,

max

s, N(CH₃)₂), 7.22 (1H, d, J = 2.0 Hz, CH), 7.32 (1H, d, J = 9.0 Hz, CH), 7.36 (1H, dd, J = 2.1 Hz, J = 9.2

Hz, CH), 12.65 (1H, s, NH) ppm; ¹³C NMR (100 MHz, DMSO-d₆)

= 40.3 (Me), 98.6 (CH), 117.8 (CH),

119.9, 121.1 (CH), 124.0, 125.6, 130.9, 133.5, 147.5 (

NMe₂), 153.1 ppm; MS m/z (I_rel, %): 333 [M⁺] (27),

298 [M

Cl]⁺(40), 270 [M-NO₂-NH₃]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₂H₁₁N₃O₂Cl₃[M + H]⁺:

333.9917; found: 333.9919.

δ

C

−

Synthesis of N’-[6-(Dichloromethyl)-2-methyl-5-nitropyrimidin-4-yl]-N, N-dimethylbenzene-1,4- diamine (27c).

To a solution of the nitrobutadiene 25c (0.454 g, 1.0 mmol) and acetamidine hydrochloride (0.284 g, 3.0

mmol) in 20 mL dry THF, sodium hydride (0.160 g, 4.0 mmol, 60%) was added at 0 ^◦C. The solution

was thoroughly stirred for 1 h at 0 ^◦C and then at r.t. for 2 d. After evaporation of the solvent and

Molecules 2020, 25, 2863

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addition of 10% HCl (5 mL) the precipitate was ﬁltered oﬀ and washed with 10% HCl (2

×

10 mL),

cold water (10 mL), cold MeOH (2

×

5 mL) and dried in vacuo. Yield 0.232 g (65%), yellow solid, m.p.

1

124–125 ^◦C. IR (KBr) = 3321, 1612, 1573 (NO ), 1517, 1204, 746 cm⁻¹. H NMR (400 MHz, CDCl₃)

ν

max

2

δ

= 2.64 (3H, s, CCH₃), 2.99 (6H, s, NCH₃), 6.74 (2H, d, J = 9.0 Hz, H Ar), 7.40 (2H, d, J = 8.9 Hz, H Ar),

7.42 (1H, s, CHCl₂), 9.73 (1H, s, NH) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 26.5 (CH₃), 40.5 (NCH₃),

66.8 (CHCl₂), 112.3 (CH), 122.8, 124.5 (CH), 125.3, 148.9, 153.2, 160.6, 171.0 ppm; MS m/z (I_rel, %): 355

[M⁺] (39), 136 [phenylendiamine+H]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₄H₁₆N₅O₂Cl₂[M + H]⁺:

356.0676; found: 356.0674.

6-(Dichloromethyl)-N,N,2-trimethyl-5-nitropyrimidin-4-amine (27d). Same procedure as for 27c, using

diene 25d (0.363 g, 1.0 mmol). The precipitate was further puriﬁed by column chromatography using

petroleum ether - ethyl acetate, 5: 1. Yield 0.148 g (56%), yellowish solid, m.p. 82–83 ^◦C. IR (ATR)

ν

= 3048, 1579 (NO₂), 1500, 1338 (NO₂), 1195, 746 cm⁻¹

.

¹H NMR (400 MHz, CDCl₃)

= 26.1 (CH₃),

39.3 (NCH₃), 65.4 (CHCl₂), 125.6 (CNO₂), 154.7, 156.2, 168.1 ppm; MS m/z (I_rel, %): 264 [M⁺] (55), 218

δ = 2.61

max

(3H, s, CCH₃), 3.09 (6H, s, NCH₃), 6.98 (1H, s, CHCl₂); ¹³C NMR (100 MHz, CDCl₃)

δ

[M

−

NO₂]⁺(30), 182 [M-CHCl₂+H]⁺(63), 135 [M-CHCl₂-NO₂]⁺(52). HRMS (ESI⁺) m/z calcd for

C₈H₁₁N₄O₂Cl₂[M + H]⁺: 265.0254; found: 265.0255.

N-[6-(Dichloromethyl)-2-methyl-5-nitropyrimidin-4-yl]quinolin-8-amine (27e). Same procedure as for 27c

,

using azole 25e (0.462 g, 1.0 mmol) as starting material. Yield 0.178 g (49%), yellow solid, m.p. 217–219

1

^◦C. IR (KBr)

ν

_max= 3262, 1573 (NO₂), 1298 (NO₂), 1208, 766, 590 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

=

2.82 (3H, s, CCH₃), 7.37 (1H, s, CHCl₂), 7.52 (1H, dd, J = 8.3 Hz, J = 4.2 Hz, H quin), 7.58–7.63 (2H, m,

H quin), 8.21 (1H, dd, J = 8.3 Hz, J = 1.6 Hz, H quin), 8.94 (1H, dd, J = 4.2 Hz, J = 1.6 Hz, H quin),

9.04–9.07 (1H, m, H quin), 12.17 (1H, s, NH) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 26.6 (CH₃), 66.4

(CHCl₂), 118.4 (CH), 122.0 (CH), 122.93 (CH), 124.6, 127.0 (CH), 128.1, 134.0, 136.4 (CH), 139.3, 149.0

(CH), 152.1, 159.7, 170.9 ppm; MS m/z (I_rel, %): 363 [M⁺] (15), 317 [M-NO₂]⁺(100), 281 [M CHCl₂]⁺

(25), 235 [M

quin]⁺(12), 128 [quinoline]⁺(45); HRMS (ESI⁺) m/z calcd for C₁₅H₁₂N₅O₂Cl₂[M + H]⁺:

364.0368; found: 364.0368.

−

1-[6-(Dichloromethyl)-2-methyl-5-nitropyrimidin-4-yl]-2,3-dihydro-1H-indole (27f). Same procedure as for

27c, using diene 25f (0.437 g, 1.0 mmol), DMSO (25 mL) and NaOH (30%, 4 mmol). Yield 0.216 g (64%),

1

yellow solid, m.p. 132–133 ^◦C. IR (ATR)

ν

_max= 3048, 1562 (NO₂), 1529, 1340 (NO₂), 1209, 768 cm⁻¹. H

NMR (400 MHz, CDCl₃)

ind), 7.04 (1H, s, CHCl₂), 7.11 (1H, t, J = 7.4 Hz, H ind), 7.24–7.29 (2H, m, H ind), 7.93 (1H, d, J = 8.1 Hz,

H ind) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 26.0 (CH), 28.8 (CH₂), 50.2 (CH₂), 65.3 (CHCl₂), 117.6

δ = 2.72 (3H, s, CCH₃), 3.20 (2H, t, J = 7.9 Hz, H ind), 3.86 (2H, t, J = 7.9 Hz, H

δ

(CH), 124.8 (CH), 125.1 (CH), 126.4, 127.1 (CH), 132.3, 142.1, 151.6, 156.8, 168.7 ppm; MS m/z (I_rel, %):

338 [M⁺] (100), 323 [M-CH₃]⁺(13), 257 [M-NO₂-Cl] (48), 118 [indole]⁺(24); HRMS (ESI⁺) m/z calcd for

C₁₄H₁₃N₄O₂Cl₂[M + H]⁺: 339.0416; found: 339.0413.

Synthesis of 1-[6-(Dichloromethyl)-2-methyl-5-nitropyrimidin-4-yl]-1H-indole (28). A solution of pyrimidine

27f (0.400 g, 1.2 mmol) and DDQ (0.600 g, 2.7 mmol) in toluene (10 mL) was heated to reﬂux for 5

h, allowed to cool down to r.t., and the precipitate ﬁltered oﬀ. The ﬁltrate was puriﬁed by column

chromatography using petroleum ether–ethyl acetate, 25: 1. The product was dried in vacuo. Yield

0.267 g (66%), m.p. 103–104 ^◦C. IR (ATR)

¹H NMR (600 MHz, CDCl₃)

= 2.92 (3H, s, CCH₃), 6.79 (1H, dd, J = 3.7 Hz, J = 0.7 Hz, H ind), 7.01

(1H, s, CHCl₂), 7.12 (1H, d, J = 3.7 Hz, H ind), 7.30 (1H, t, J = 8.0 Hz, H ind), 7.36 (1H, t, J = 8.4 Hz, H

ind), 7.63 (1H, d, J = 8.2 Hz, H ind), 8.10 (1H, d, J = 9.1 Hz, H ind) ppm; ¹³C NMR (150 MHz, CDCl₃)

ν .

_max= 3022, 1589 (NO₂), 1342, 1261 (NO₂), 1099, 745 cm⁻¹

δ

= 26.2 (CH₃), 64.8 (CHCl₂), 110.9 (CH), 114.1 (CH), 121.6 (CH), 123.8 (CH), 124.5 (CH), 124.9 (CH),

128.3, 130.4, 135.4, 150.5, 157.6, 170.5 ppm; MS m/z (I_rel, %): 336 [M⁺] (100), 291 [M + H-NO₂]⁺(42),

238 [M-CH₃-CHCl₂]⁺(48), 116 [indole]⁺(62); HRMS (ESI⁺) m/z calcd for C₁₄H₁₁N₄O₂Cl₂[M + H]⁺:

337.0259; found: 337.0261.

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Synthesis of 1-[1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-dien-1-yl]-4-(4-chlorophenyl)-

piperidin-4-ol (25g). Same procedure as for 25a, using 4-(4-chlorophenyl)piperidin-4-ol (0.223 g, 1.05

mmol). Yield 0.482 g (91%), yellowish solid, m.p. 149–150 ^◦C. IR (ATR) ν

= 2931, 1565, 1498, 1290,

max

1

1005, 749 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ = 1.83–2.03 (2H, m, H pip), 2.33–2.61 (2H, m, H pip),

2.95–3.25 (2H, m, NCH₂), 3.76–4.08 (3H, m, OH + NCH₂), 7.35–7.38 (2H, m, H Ar), 7.45–7.47 (2H, m, H

Ar), 7.47–7.79 (3H, m, H Bzt), 8.10–8.13 (1H, m, H Bzt) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 38.3

(CH₂), 47.3 (CH₂), 70.4 (COH), 110.4 (CH), 111.89 (CNO₂), 120.9 (CH), 124.8 (CCl), 125.9 (2 CH),

δ

×

126.0 (CH), 126.2 (CCl₂), 128.8 (2

×

CH), 130.6 (CH), 132.4, 133.6 (CCl), 144.8, 146.1, 148.0 (CNN) ppm;

MS m/z (I_rel, %): 527 [M⁺] (1), 499 [M-N₂]⁺(1), 453 [M-N₂-NO₂]⁺(1), 416 [M-Ph-Cl]⁺(1), 111 [PhCl]⁺

(20), 91 (100); HRMS (ESI⁺) m/z calcd for C₂₁H₁₈N₅O₃Cl₄[M + H]⁺: 538.0158; found: 528.0156.

{4-[1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-dien-1-yl]piperazin-1-yl}(tetrahydrofuran-2-

yl)-methanone (25h). Same procedure as for 25a, using piperazin-1-yl(tetrahydrofuran-2-yl)methanone

(0.193 g, 1.05 mmol). Yield 0.426 g (85%), yellow solid, m.p. 170–172 ^◦C. IR (KBr)

ν

_max= 2871, 1657,

1

1560, 1290, 1006, 747 cm⁻¹. H NMR (200 MHz, CDCl₃)

δ = 1.80–2.11 (3H, m, CH₂fur), 2.30–2.49 (1H,

m, CH₂fur), 3.18–3.60 (4H, m, NCH₂), 3.72–4.41 (6H, m, 2NCH₂, OCH₂), 4.52–4.67 (1H, m, OCH),

7.48–7.80 (3H, m, H Bzt), 8.17–8.20 (1H, m, H Bzt) ppm; ¹³C NMR (50 MHz, CDCl₃)

25.7 (CH₂), 27.7

δ

(CH₂), 41.8 (NCH₂), 45.2 (NCH₂), 50.6 (NCH₂), 69.2 (OCH₂), 76.1 (OCH), 110.2 (CH), 116.2 (CCl₂),

120.6 (CNO₂), 121.1 (CH), 125.5, 126.1 (CH), 129.9, 130.7 (CH), 146.3, 147.5 (CNN), 169.7 (C=O) ppm;

MS m/z (I_rel, %): 500 [M⁺] (1), 465 [M-Cl]⁺(1), 426 [M-NO₂-N₂]⁺(1), 337 [M-Bzt-NO₂+H]⁺(4), 119 [Bzt

+ H]⁺(16), 92 (100); HRMS (ESI⁺) m/z calcd for C₁₉H₂₀N₆O₄Cl₃[M + H]⁺: 501.0606; found: 501.0605.

1-{3,4,4-Trichloro-1-[4-(3-chlorophenyl)piperazin-1-yl]-2-nitrobuta-1,3-dien-1-yl}-1H-benzotriazole

(25i).

Same procedure as for 25a, using 1-(3-methylphenyl)piperazine (0.207 g, 1.05 mmol). Yield 0.452 g

1

(88%), yellow solid, m.p. 68–70 ^◦C. IR (KBr)

ν

_max= 2916, 1594, 1560, 1291, 942, 768 cm⁻¹. H NMR (200

MHz, CDCl₃)

(1H, m, H Ar), 7.40–7.68 (3H, m, H Bzt), 8.16 (1H, d, J = 8.1 Hz, H Bzt) ppm; ¹³C NMR (50 MHz, CDCl₃)

= 49.2 (NCH₂), 49.4 (NCH₂), 110.3 (CH), 115.1 (CH), 117.2 (CH), 121.1 (CH), 121.6 (CH), 124.3 (CCl₂),

δ = 3.41–3.61 (8H, m, NCH₂), 6.75–6.90 (1H, m, H Ar), 6.91–6.98 (2H, m, H Ar), 7.18–7.24

δ

125.3 (CCl), 126.1 (CH), 130.4 (CH), 130.7 (CH), 132.4, 135.2 (CCl), 146.3, 147.6 (CNN), 150.7 ppm,

CNO₂could not be detected; MS m/z (I_rel, %): 512 [M⁺] (2), 449 [M-Cl-N₂]⁺(1), 401 [M-PhCl]⁺(2), 138

[PhClNCH]⁺(100); HRMS (ESI⁺) m/z calcd for C₂₀H₁₇N₆O₂Cl₄[M + H]⁺: 512.0078; found: 512.0075.

Synthesis of 4-(4-Chlorophenyl)-1-[5-(dichloromethyl)-1-methyl-4-nitro-1H-pyrazol-3-yl]piperidin-4-ol (2_◦9a

)

(General method). To a suspension of azole 25g (0.529 g, 1.0 mmol) in MeOH (10 mL) at

−

10 C,

methylhydrazine (0.921 g, 2.0 mmol) was added dropwise. After 2 h, the solution was allowed reach

r.t. and stirred for 1 d. The solution was then concentrated and 10% HCl (5 mL) was added. The

resulting precipitate was ﬁltered oﬀ, washed with water, and puriﬁed by column chromatography

using chloroform. Yield 0.311 g (74%), yellow solid, m.p. 95–96 ^◦C. IR (ATR)

ν

_max= 2951, 1553, 1484,

1348, 1024, 746 cm⁻¹. H NMR (400 MHz, CDCl₃) δ = 1.65 (1H, s, OH), 1.78–1.85 (2H, m, CCH₂), 2.28

(2H, ddd, J = 13.1 Hz, J = 4.2 Hz, J = 13.1 Hz, CCH₂), 3.33 (2H, ddd, J = 12.5 Hz, J = 2.5 Hz, J = 12.5 Hz,

NCH₂), 3.51–3.59 (2H, m, NCH₂), 4.12 (3H, s, NCH₃), 7.34 (2H, d, J = 8.7 Hz, H Ar), 7.47 (2H, d, J = 8.7

1

Hz, H Ar), 7.88 (1H, s, CHCl₂) ppm; ¹³C NMR (100 MHz, CDCl₃)

(2

δ

= 38.0 (2

×

CH₂), 39.7 (NCH₃), 46.0

×

NCH₂), 57.8 (CHCl₂), 71.1 (HO-C), 120.4 (CNO₂), 126.1 (CH), 129.2 (CH), 133.0 (CCl), 137.9, 146.5,

152.8 (NC-pyr) ppm; MS m/z (I_rel, %): 418 [M⁺] (3), 401 [M-OH]⁺(6), 383 [M

−

Cl]⁺(5), 367 [M-Cl-O]⁺

(4), 347 [M-Cl-HCl]⁺(4), 100 (100); HRMS (ESI⁺) m/z calcd for C₁₆H₁₈N₄O₃Cl₃[M + H]⁺: 419.0439;

found: 419.0437.

{4-[5-(Dichloromethyl)-1-methyl-4-nitro-1H-pyrazol-3-yl]piperazin-1-yl}(tetrahydrofuran-2-yl)methanone

(

29b). Same procedure as for 29a, using diene 25h (0.502 g, 1.0 mmol) and DCM as the eluent. Yield

1

0.310 g (79%), yellowish oil. IR (ATR)

ν

= 2954, 1647, 1551, 1341, 1198, 745 cm⁻¹. H NMR (400

max

MHz, CDCl₃)

δ = 1.86–2.12 (3H, m, CH₂Fur), 2.25–2.35 (1H, m, CH₂Fur), 3.17–3.31 (4H, m, NCH₂),

3.63–3.73 (2H, m, NCH₂), 3.79–3.98 (4H, m, NCH₂, OCH₂), 4.10 (3H, s, NCH₃), 4.64 (1H, dd, J = 5.6

Molecules 2020, 25, 2863

26 of 41

Hz, J = 7.5 Hz, COCHO), 7.84 (1H, s, CHCl₂) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 25.7 (CH₂), 28.4

(CH₂), 39.7 (NCH₃), 41.6 (NCH₂), 45.0 (NCH₂), 49.6 (NCH₂), 50.0 (NCH₂), 57.6 (CH), 69.1 (OCH₂), 75.9

(OCH), 120.5 (CNO₂), 138.1, 152.1, 170.1 (C=O) ppm; MS m/z (I_rel, %): 391 [M⁺] (100), 374 [M

−

OH]⁺

(20), 356 [M

−

Cl]⁺(65), 320 [M

−

furan]⁺(20), 292 [M-CO-furan]⁺(35); HRMS (ESI⁺) m/z calcd for

C₁₄H₂₀N₅O₄Cl₂[M + H]⁺: 392.0887; found: 392.0889.

1-(3-Chlorophenyl)-4-[5-(dichloromethyl)-1-methyl-4-nitro-1H-pyrazol-3-yl]piperazine

(29c).

Same

proce-dure as for 29a, using diene 25i (0.514 g, 1.0 mmol) and a mixture of petroleum ether and

ethyl acetate (5: 1) as the eluent. Yield 0.299 g (74%), yellow solid, m.p. 162–163 ^◦C. IR (ATR)

ν

max

1

= 2832, 1552, 1475, 1338, 936, 737 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ = 3.31–3.36 (4H, m, NCH₂),

3.38–3.43 (4H, m, NCH₂), 4.13 (3H, s, NCH₃), 6.81–6.86 (2H, m, H Ar), 6.93 (1H, t, J = 2.1 Hz, H Ar),

7.18 (1H, t, J = 8.0 Hz, H Ar), 7.87 (1H, s, CHCl₂) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 39.7 (CH₃),

48.5 (NCH₂), 49.5 (NCH₂), 57.7 (CHCl₂), 114.1 (CH), 116.1 (CH), 119.7 (CH), 120.5 (CNO₂), 130.1 (CH),

δ

135.0 (CCl), 138.0, 152.2 (CN), 152.3 (CN) ppm; MS m/z (I_rel, %): 403 [M⁺] (45), 357 [M

−

NO₂]⁺(6),

322 [M-NO₂-Cl]⁺(22), 138 [PhClNCH]⁺(100); HRMS (ESI⁺) m/z calcd for C₁₅H₁₇N₅O₂Cl₃[M + H]⁺:

404.0442; found: 404.0444.

Synthesis of 3-[4-(3-Chlorophenyl)piperazin-1-yl]-1-methyl-4-nitro-1H-pyrazole-5-carbaldehyde (30). Pyrazole

29c (0.405 g, 1.0 mmol) was suspended in 10 mL sulfuric acid (25%) and heated to 95–100 ^◦C for 10 h.

After cooling to r.t., the solution was extracted with chloroform (3

chromatography using petroleum ether - ethyl acetate (5: 1). The product was dried in vacuo. Yield

0.199 g (57%), yellow solid, m.p. 159–160 ^◦C. IR (ATR) _max= 2827, 1683, 1546, 1474, 1236, 775 cm⁻¹

¹H NMR (400 MHz, CDCl₃)

= 3.32–3.38 (4H, m, NCH₂), 3.45–3.5 (4H, m, NCH₂), 6.81–6.87 (2H, m, H

Ph), 6.93 (1H, t, J = 2.0 Hz, H Ph), 7.19 (1H, t, J = 8.1 Hz, H Ph), 10.43 (1H, s, CHO) ppm; ¹³C NMR (100

MHz, CDCl₃) = 40.9 (NCH₃), 48.5 (2 NCH₂), 49.4 (2 NCH₂), 114.2 (CH), 116.1 (CH), 119.8 (CH),

125.7 (CNO₂), 130.1 (CH), 135.0 (CCl), 135.2 ( CHO), 151.9, 152.1, 181.8 (CHO) ppm; MS m/z (I_rel, %):

×

10 mL) and puriﬁed by column

ν

.

δ

×

C

−

349 [M⁺] (100), 332 [M

HRMS (ESI⁺) m/z calcd for C₁₅H₁₇N₅O₃Cl [M + H]⁺: 350.1014; found: 350.1016.

−

OH]⁺(5), 314 [M

Cl]⁺(4), 304 [M-NO₂+H]⁺(20), 138 [ClPhNCH]⁺(75);

Synthesis of 2-(1H-Benzotriazol-1-yl)-4-(dichloromethylidene)-3-nitro-4H-pyrido[1,2-a]pyrimidine (31a

)

(General method). To a solution of azole 24 (0.437 g, 1.0 mmol) in THF (10 m), 2-aminopyridine

(0.282 g, 3.0 mmol) was added at r.t. The solution was stirred for 8 h, then concentrated, and the residue

treated with dilute HCl for 1 h, ﬁltered oﬀ and washed with water (2

×

10 mL) and cold MeOH (5

mL). The product was dried in vacuo. Yield 0.304 g (81%), red solid, m.p. 158–160 ^◦C. IR (KBr)

ν

=

max

1

3082, 1628, 1552, 1434, 1307, 1215 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ

= 7.50–7.64 (2H, m, H Ar),

7.64–7.75 (1H, m, H Bzt), 7.87 (1H, d, J = 8.3 Hz, H Ar), 7.90–7.95 (1H, m, H Bzt), 8.21 (1H, d, J = 7.8

Hz, H Bzt), 8.22–8.32 (1H, m, H Bzt), 8.99 (1H, dd, J = 6.8 Hz, 0.9 Hz, H Ar) ppm; ¹³C NMR (50 MHz,

DMSO-d₆)

δ = 102.3 (CCl₂), 113.0 (CH), 119.2 (CH), 120.0 (CH), 121.3 (CNO₂), 123.7 (CH), 125.5 (CH),

126.3, 129.6 (CH), 132.3, 138.8 (CH), 143.6 (CH), 145.6, 148.0, 151.3 ppm; MS m/z (I_rel, %): m/z (%) = 374

[M⁺] (1), 256 [M–benzotriazole]⁺(14), 219 (18), 119 [benzotriazole] (14), 92 (100); HRMS (ESI⁺) m/z

calcd for C₁₅H₉N₆O₂Cl₂[M + H]⁺: 375.0164; found: 375.0164.

2-(1H-Benzotriazol-1-yl)-7-chloro-4-(dichloromethylidene)-3-nitro-4H-pyrido[1,2-a]pyrimidine (31b). Same

procedure as for 31a, using 2-amino-5-chloropyridine (0.386 g, 3.0 mmol) and heating the reaction

mixture to 45 ^◦C. Yield 0.352 g (86%), orange solid, m.p. 182–184 ^◦C. IR (KBr)

ν

= 3066, 1505, 1437,

max

1

1318, 1238, 1222 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ = 7.55 (1H, t, J = 7.9 Hz, H Bzt), 7.71 (1H, t, J =

8.1 Hz, H Bzt), 7.86 (1H, d, J = 9.3 Hz, H pyr), 7.92 (1H, d, J = 8.2 Hz, H Bzt), 8.23 (1H, d, J = 8.2 Hz, H

Bzt), 8.35 (1H, dd, J = 9.4 Hz, J = 2.3 Hz, H pyr), 9.35 (1H, d, J = 2.3 Hz, H pyr) ppm; ¹³C NMR (50

MHz, DMSO-d₆)

(CH), 129.6 (CH), 132.3, 136.6 (CH), 143.1 (CH), 145.6, 147.7 (NC), 150.6 ppm; MS m/z (I_rel, %): 408 [M⁺]

(1), 380 [M

N₂]⁺(1), 373 [M Cl]⁺(2), 334 [M-N₂-NO₂]⁺(7), 112 (100); HRMS (ESI⁺) m/z calcd for

C₁₅H₈N₆O₂Cl₃[M + H]⁺: 408.9769; found: 408.9768.

δ = 102.8 (CCl₂), 112.9 (CH), 119.9 (CH), 122.2 (CNO₂), 124.7 (CCl), 124.8 (CH), 125.6

−

Molecules 2020, 25, 2863

27 of 41

Synthesis of 4-(dichloromethylidene)-2-[4-(4-ﬂuorophenyl)piperazin-1-yl]-3-nitro-4H-pyrido[1,2-a]pyrimi- dine

(

32a) (General method). To a solution of pyrimidine 31a (0.375 g, 1 mmol) in MeOH (1_◦0 mL)

1-(4-ﬂuorophenyl)piperazine (0.216 g, 1.2 mmol) was added and the mixture stirred at 40 C for

5 h. Subsequently, the mixture was cooled to 0 ^◦C and treated with dilute HCl for 1 h. The precipitate

was ﬁltered oﬀ and washed with water (2

×

5 mL) and cold MeOH (5 mL). The product was dried

in vacuo. Yield 0.423 g (97%), yellow solid, m.p. 126–127 ^◦C. IR (KBr)

ν

_max= 1639, 1551, 1504, 1253,

1

1145, 933 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ = 3.15–3.50 (4H, m, NCH₂), 3.78–4.31 (4H, m, NCH₂),

6.78–7.18 (5H, m, H Pyr, 4H Ph-F), 7.31 (1H, d, J = 8.6 Hz, H pyr), 7.94 (1H, ddd, J = 8.6 Hz, J = 1.3 Hz,

J = 7.3 Hz, H pyr), 8.60 (1H, dd, J = 7.2 Hz, J = 1.3 Hz, H pyr) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

δ

= 49.5 (4

×

NCH₂), 94.9 (CCl₂), 114.7 (CH), 115.6 (J_C,F= 21.6 Hz, 2

×

CH Ph), 118.1 (J_C,F= 7.9 Hz,

2

×

CH Ph), 120.5 (CNO₂), 122.7 (CH), 128.2 (C

CCl₂), 137.1 (CH), 142.0 (CH), 147.3 (NC Ph), 151.5,

156.6 (J_C,F= 235.9 Hz, CF), 156.1 (NCN) ppm; MS m/z (I_rel, %): 435 [M⁺] (7), 256 [M-morph-Ph-F]⁺(10),

179 [Morph-Ph-F]⁺(15), 95 (100); HRMS (ESI⁺) m/z calcd for C₁₉H₁₇N₅O₂Cl₂F [M + H]⁺: 436.0738;

found: 436.0736.

7-Chloro-4-(dichloromethylidene)-2-[4-(4-ﬂuorophenyl)piperazin-1-yl]-3-nitro-4H-pyrido[1,2-a]pyrimidine

(

32b). Same procedure as for 32a, using compound 31b (0.410 g, 1.0 mmol) but without adding HCl.

Yield 0.447 g (95%), yellow solid, m.p. 141–142 ^◦C. IR (KBr)

ν

_max= 1635, 1563, 1493, 1373, 1237, 827

cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ

= 3.14–3.29 (4H, m, NCH₂), 3.50–4.33 (4H, m, NCH₂), 6.95–7.14

1

(4H, m, H Ph), 7.31 (1H, d, J = 9.4 Hz, H pyr), 7.99 (1H, dd, J = 9.5 Hz, J = 2.3 Hz, H pyr); 8.92 (1H, d, J

= 8.9 Hz, H pyr) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

= 49.4 (4 NCH₂), 94.7 (CCl₂), 115.3 (J_C,F

21.9 Hz, 2 FC H), 117.6 (J_C,F= 7.7 Hz, 2 CH Ph), 120.1 (CCl), 121.1 (CNO₂), 123.9 (CH), 127.6,

δ

×

=

×

C

×

134.7 (NCH), 141.8 (CH), 147.3 (J_C,F= 1.8 Hz, NC Ph), 150.4, 156.2 (J_C,F= 236.4 Hz, CF), 156.0 ppm; MS

m/z (I_rel, %): 469 [M⁺] (8), 290 [M-piperazine-Ph-F]⁺(3), 179 [piperazine-Ph-F]⁺(20), 112 (100); HRMS

(ESI⁺) m/z calcd for C₁₉H₁₆N₅O₂Cl₃F [M + H]⁺: 470.0348; found: 470.0350.

Synthesis of Ethyl {[4-(dichloromethylidene)-3-nitro-4H-pyrido[1,2-a]pyrimidin-2-yl]sulfanyl}acetate (33a

(General method). To a solution of pyrimidine 31a (0.375 g, 1.0 mmol) in EtOH (10 mL), ethyl

2-mercaptoacetate (0.240 g, 2.0 mmol) and sodium ethanolate (0.204 g, 3.0 mmol) were added. The

solution was stirred at r.t. for 3 d. Subsequently, dilute HCl (5 mL) was added under stirring for 30

)

min. The resulting precipitate was ﬁltered oﬀ, washed with water (2

and dried in vacuo. Yield 0.365 g (97%).

×

5 mL) and cold MeOH (3 mL),

Alternative synthesis of pyrimidine 33a from nitrodiene 18. To a solution of nitrobutadiene 18 (0.355 g, 1.0

mmol) in MeOH (10 mL) 2-aminopyridine (0.282 g, 3.0 mmol) was added. After stirring at r.t. for 1 d,

the solution was concentrated and the resulting precipitate ﬁltered oﬀ, washed with water (2

×

3 mL),

cold MeOH (3 mL) and dried in vacuo. Yield 0.177 g (47%) of 33a, orange solid, m.p. 147–148 ^◦C. IR

1

(ATR)

ν

= 1731, 1597, 1451, 1202, 1141, 764 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 1.27 (3H, t, J = 7.1

max

Hz, OCH₂CH₃); 3.85 (2H, s, SCH₂), 4.20 (2H, q, J = 7.1 Hz, OCH₂), 7.00 (1H, ddd, J = 1.3 Hz, J = 6.9 Hz,

J = 6.9 Hz, CH), 7.23 (1H, ddd, J = 1.2 Hz, J = 0.6 Hz, J = 9.0 Hz, CH), 7.72 (1H, ddd, J = 1.7 Hz, J = 7.1

Hz, J = 8.8 Hz, CH), 8.04 (1H, ddd, J = 1.6 Hz, J = 0.7 Hz, J = 6.9 Hz, NCH) ppm; ¹³C NMR (100 MHz,

CDCl₃) δ = 14.2 (CH₃), 33.7 (SCH₂), 61.5 (OCH₂), 114.5 (CH), 117.1 (CCl₂), 123.0 (CH), 125.1 (CNO₂),

135.6 (NCH), 140.0 (CH), 149.7 (NCN), 164.1 (SCN), 169.3 (C=O) ppm, NCCHCl₂could not be detected;

MS m/z (I_rel, %): 375 [M⁺] (10), 340 [M-Cl]⁺(9), 288 [M-CH₂CO₂Et]⁺(25), 209 [M-HNO₂-SCH₂CO₂Et]⁺

(95), 149 (100); HRMS (ESI⁺) m/z calcd for C₁₃H₁₁N₃O₄Cl₂SNa [M + Na]⁺: 397.9745; found: 397.9746.

Ethyl {[7-chloro-4-(dichloromethylidene)-3-nitro-4H-pyrido[1,2-a]pyrimidin-2-yl]sulfanyl}acetate (33b). Same

procedure as for 33a,but starting from compounds 31b (Yield 0.382 g, 93%), or 18 (Yield 0.226 g, 55%),

1

orange solid, m.p. 171–172 ^◦C. IR (ATR)

ν

_max= 3074, 1727, 1626, 1489, 1235, 741 cm⁻¹. H NMR (200

MHz, CDCl₃)

(1H, dd, J = 9.4 Hz, J = 0.5 Hz, CH), 7.63 (1H, dd, J = 9.5 Hz, J = 2.3 Hz, CH), 8.05 (1H, dd, J = 2.3 Hz, J =

0.6 Hz, NCH) ppm; ¹³C NMR (50 MHz, CDCl₃)

= 14.3 (CH₃), 33.6 (SCH₂), 61.6 (OCH₂), 117.5 (CCl₂),

δ = 1.27 (3H, t, J = 7.1 Hz, CH₃), 3.83 (2H, s, SCH₂), 4.19 (2H, q, J = 7.2 Hz, OCH₂), 7.17

δ

Molecules 2020, 25, 2863

28 of 41

121.4 (CNO₂), 122.2 (CCl), 123.2 (CH), 124.4 (NC), 133.0 (CH), 140.5 (CH), 148.2, 163.7 (SC), 169.2 (C=O)

ppm; MS m/z (I_rel, %): 409 [M⁺] (10), 373 [M-HCl]⁺(18), 363 [M-NO₂]⁺(15), 321 [M-CH₃CO₂Et]⁺(45),

242 (100); HRMS (ESI⁺) m/z calcd for C₁₃H₁₀N₃O₄Cl₃SNa [M + Na]⁺: 431.9355; found: 431.9357.

Synthesis of N-[1-(benzylsulfanyl)-3,4,4-trichloro-2-nitrobuta-1,3-dien-1-yl]naphthalen-1-amine (35a) (General

method). To a solution of diene 34a (0.359 g, 1.0 mmol) in MeOH (10 mL) at

(0.315 g, 2.2 mmol) was added. The solution was kept at

10 ^◦C for 2 h and then allowed to warm up

to r.t. for 8 h. Subsequently, the solution was concentrated and the resulting precipitate was ﬁltered

−

10 ^◦C, naphthalen-1-amine

−

oﬀ, washed with water (2

×

5 mL) and cold MeOH (5 mL), and dried in vacuo. Yield 0.428 g (92%),

green-yellow solid, m.p. 132–133 ^◦C. IR (ATR)

(400 MHz, CDCl₃)

7.14–7.25 (3H, m, H Ar), 7.57 (1H, dd, J = 7.8 Hz, J = 7.8 Hz, H Ph), 7.59–7.65 (2H, m, H Ph), 7.73 (1H, d,

J = 7.4 Hz, H Ar), 7.93 (1H, d, J = 8.2 Hz, H Ar), 7.94–7.99 (2H, m, H Ar), 13.32 (1H, s, NH) ppm; ¹³

NMR (100 MHz, CDCl₃) = 38.5 (CH₂), 121.5 (CH), 122.0 (CNO₂), 122.9 (CH), 123.9 (CCl₂), 125.4 (CH),

127.2 (CH), 127.8 (CH), 128.0 (CCl), 128.2 (CH), 128.5, 128.6 (CH), 128.7 (2

ν

_max= 1536, 1332, 1149, 939, 768, 702 cm⁻¹. H NMR

1

δ

= 3.47 (2H, q, J = 12.4 Hz, SCH₂), 6.86 (2H, dd, J = 7.7 Hz, J = 1.7 Hz, H Ph),

C

δ

×

CH), 128.7 (CH), 128.9 (2

OH]⁺(1), 418 [M

×

−

CH), 133.4, 134.1, 134.2, 159.7 (NCS) ppm; MS m/z (I_rel, %): 464 [M⁺] (1), 447 [M

−

NO₂]⁺(1), 127 [naphthalene]⁺(11), 91 [PhCH₂]⁺(100); HRMS (ESI⁺) m/z calcd for C₂₁H₁₆N₂O₂Cl₃S [M

+ H]⁺: 464.9993; found: 464.9991.

N-{3,4,4-Trichloro-1-[(4-chlorophenyl)sulfanyl]-2-nitrobuta-1,3-dien-1-yl}naphthalen-1-amine (35b). Same

procedure as for 33a, but starting from 34b. Yield 0.423 g (87%), green-yellow solid, m.p. 185–186 ^◦C.

1

IR (ATR)

ν

= 1538, 1472, 1345, 1161, 824, 767 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 6.68 (2H, d, J =

max

8.8 Hz, H Ar), 6.71 (2H, d, J = 8.8 Hz, H Ar), 7.33–7.43 (3H, m, H Ar), 7.48 (1H, ddd, J = 6.8 Hz, J =

1.2 Hz, J = 8.1 Hz, H Ar), 7.55 (1H, d, J = 8.5 Hz, H Ar), 7.71–7.80 (2H, m, H Ar), 11.96 (1H, s, NH)

ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 121.4, 121.3 (CH), 123.8 (CNO₂), 124.6 (CH), 124.9 (CH), 125.6,

126.8 (CH), 126.9 (CH), 128.2 (CH), 128.4, 128.5, 128.7 (CH), 129.1 (2 CH), 133.2, 133.6, 134.3 (2 CH),

×

135.4, 160.8 (NCS) ppm; MS m/z (I_rel, %): 484 [M⁺] (5), 449 [M-Cl]⁺(5), 438 [M-NO₂]⁺(3), 356 [M

−

naphthalene]⁺(2), 143 [naphthylamine]⁺(60), 127 [naphthalene]⁺(100); HRMS (ESI⁺) m/z calcd for

C₂₀H₁₃N₂O₂Cl₄S [M + H]⁺: 484.9446; found: 484.9443.

Synthesis of 2-(Benzylsulfanyl)-4-(dichloromethyl)-3-nitrobenzo[h]quinoline (36a) (General method). To a

solution of diene 35a (0.466 g, 1.0 mmol) in chloroform (10 mL) at 0 ^◦C, triethylamine (0.202 g, 2.0

mmol) was added. The solution was kept at 0 ^◦C for 2 h and then allowed to warm to r.t. for 3 h.

Subsequently, the solution was concentrated and diluted with 5 mL MeOH. The resulting precipitate

was ﬁltered oﬀ, washed with 10% aq. HCl (2

×

5 mL), water (2

×

5 mL) and cold MeOH (5 mL), and

dried in vacuo to give benzoquinoline 36a. Yield 0.326 g (76%), yellow solid, m.p. 173–174 ^◦C. IR

1

(ATR)

ν

= 3033, 1541, 1336, 1198, 828, 711 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 4.78 (2H, s, SCH₂),

max

7.12 (1H, s, CHCl₂), 7.27–7.36 (3H, m, H Ph), 7.48–7.52 (2H, m, H Ph), 7.57 (1H, ddd, J = 7.2 Hz, J =

1.1 Hz, J = 7.9 Hz, H Ar), 7.79 (1H, ddd, J = 7.3 Hz, J = 1.4 Hz, J = 7.3 Hz, H Ar), 7.95 (2H, d, J = 9.0

Hz, H Ar), 8.64 (1H, d, J = 9.4 Hz, H Ar), 9.18 (1H, dd, J = 7.6 Hz, J = 0.8 Hz, H Ar) ppm; ¹³C NMR

(100 MHz, CDCl₃)

δ = 35.8 (SCH₂), 63.4 (CHCl₂), 119.2, 122.3 (CH), 125.4 (CH), 127.7 (CH), 127.9 (CH),

128.0 (CH), 128.5 (CH), 128.7 (2

×

CH), 129.0 (2

×

CH), 130.1 (CH), 130.4, 134.2, 134.8, 136.1, 139.4, 147.7,

149.8 ppm; MS m/z (I_rel, %): 428 [M⁺] (2), 344 [M-CH₂Cl₂]⁺(2), 91 [PhCH₂]⁺(100); HRMS (ESI⁺) m/z

calcd for C₂₁H₁₄N₂O₂Cl₂SNa [M + Na]⁺: 451.0051; found: 451.0050.

2-[(4-Chlorophenyl)sulfanyl]-4-(dichloromethyl)-3-nitrobenzo[h]quinoline (36b). Same procedure as for 36a

,

but starting from 35b. Yield 0.382 g (85%), yellow solid, m.p. 162–163 ^◦C. IR (ATR)

ν

= 3073, 1572,

max

1

1541, 1388, 1028, 739 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ = 7.19 (1H, s, CHCl₂), 7.53 (2H, d, J = 8.6 Hz,

H Ph), 7.58 (1H, ddd, J = 7.1 Hz, J = 1.3 Hz, J = 8.3 Hz, H Ph), 7.63 (2H, d, J = 8.6 Hz, H Ph), 7.72 (1H,

ddd, J = 7.0 Hz, J = 1.1 Hz, J = 8.1 Hz, H Ph), 7.88 (1H, d, J = 7.9 Hz, H Ph), 7.92 (1H, d, J = 9.3 Hz, H Ph),

8.32 (1H, d, J = 8.3 Hz, H Ph), 8.61 (1H, d, J = 9.3 Hz, H Ph) ppm; ¹³C NMR (100 MHz, CDCl₃)

δ

= 63.4

(CHCl₂), 119.8, 122.0 (CH), 125.3 (CH), 127.2, 127.8 (CH), 128.0 (CH), 129.1 (CH), 129.6 (2

×

CH), 130.1

Molecules 2020, 25, 2863

29 of 41

(CH), 130.4 (SC Ph), 134.0 (CCl), 135.4, 136.4 (Cl₂CH

C

), 137.5 (2

×

CH), 138.9 (CNO₂), 147.8 (NC), 149.8

(NCS) ppm; MS m/z (I_rel, %): 448 [M⁺] (28), 413 [M

−

Cl]⁺(7), 364 [M-CHCl₂-NO₂+H]⁺(15), 175 (100),

111 [PhCl]⁺(55); HRMS (ESI⁺) m/z calcd for C₂₀H₁₁N₂O₂Cl₃SNa [M + Na]⁺: 470.9505; found: 470.9504.

Synthesis of 2-(Benzylsulﬁnyl)-4-(dichloromethyl)-3-nitrobenzo[h]quinoline (37a) (General method). To a

solution of quinoline 36a (0.429 g, 1.0 mmol) in chloroform (5 mL) and glacial acetic acid (2 mL) at

0 ^◦C, hydrogen peroxide (1.13 g, 10.0 mmol, 30% aq.) was added dropwise. After 3 h at 0 ^◦C, the

solution was allowed to reach r.t. and stirred additionally for 2 d. The solution was then extracted

with chloroform (3

×

30 mL), washed with water (2

×

50 mL), dried with CaCl₂and dried in vacuo.

Column chromatography was carried out with a solvent ratio of 2: 1 (petroleum ether-ethyl acetate).

Yield 0.396 g (89%), orange solid, m.p. 138–139 ^◦C. IR (ATR)

ν

= 1697, 1533, 1353, 1076, 830, 695

max

1

cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 4.57 (2H, q, J = 12.7 Hz, SCH₂), 7.25–7.31 (6H in all, m, CHCl₂

and 5H Ph overlapped), 7.81–7.92 (2H, m, H Ar), 8.02 (1H, dd, J = 7.5 Hz, J = 1.5 Hz, H Ar), 8.15 (1H, d,

J = 9.4 Hz, H Ar), 8.76 (1H, d, J = 9.4 Hz, H Ar), 9.31 (1H, dd, J = 7.7 Hz, J = 1.0 Hz, H Ar) ppm; ¹³

C

NMR (100 MHz, CDCl₃)

(CH), 128.7 (CH), 128.8 (2

δ

= 62.2 (CH₂), 62.5 (CHCl₂), 122.0 (CH), 123.3, 126.2 (CH), 128.0 (CH), 128.6

CH), 129.5, 130.4 (2 CH), 130.5, 131.1 (CH), 131.9 (CH), 134.0, 135.9, 138.8

O]⁺(5), 360 [M

CH₂Cl₂] (5), 96

×

(CNO₂), 148.3, 153.2 ppm; MS m/z (I_rel, %): 444 [M⁺] (10), 428 [M

−

(100); HRMS (ESI⁺) m/z calcd for C₂₁H₁₄N₂O₃Cl₂SNa [M + Na]⁺: 467.0000; found: 466.9998.

2-[(4-Chlorophenyl)sulﬁnyl]-4-(dichloromethyl)-3-nitrobenzo[h]quinoline (37b). Same procedure as for 37a

,

but starting from 36b (0.450 g, 1.0 mmol). Yield 0.424 g (91%), yellow solid, m.p. 166–168 ^◦C. IR (ATR)

1

ν

= 3082, 1546, 1342, 1092, 828, 750 cm⁻¹. H NMR (400 MHz, CDCl₃)

δ

= 7.20 (1H, s, CHCl₂), 7.50

max

(2H, d, J = 8.6 Hz, H Ar), 7.84–7.91 (2H, m, H Ar), 7.95–8.03 (3H, m, H Ar), 8.12 (1H, d, J = 9.4 Hz, H

Ar), 8.71 (1H, d, J = 9.4 Hz, H Ar), 9.28–9.33 (1H, m, H Ar) ppm; ¹³C NMR (100 MHz, CDCl₃)

= 62.4

(CHCl₂), 122.0 (CH), 123.3, 125.8 (CH), 127.0 (2 CH), 128.2 (CH), 128.8 (CH), 129.7 (2 CH), 130.5,

δ

×

131.0 (CH), 132.0 (CH), 134.0, 136.0, 138.0 (CNO₂), 138.3, 141.1, 148.2, 153.4 (NCS) ppm; MS m/z (I_rel, %):

464 [M⁺] (2), 418 [M-NO₂]⁺(2), 365 [M-O-CHCl₂]⁺(38), 335 [M-CHCl₂-NO₂]⁺(12), 111 [PhCl]⁺(50),

100 (100); HRMS (ESI⁺) m/z calcd for C₂₀H₁₁N₂O₃Cl₃SNa [M + Na]⁺: 486.9454; found: 486.9454.

Synthesis of 4-(Dichloromethyl)-3-nitro-2-(pyrrolidin-1-yl)benzo[h]quinoline (38). To a solution of quinoline

37a (0.445 g, 1.0 mmol) in toluene (10 mL), pyrrolidine (0.107 g, 1.5 mmol) was added and the mixture

heated to 100 ^◦C for 3 h. After cooling, the crude product was puriﬁed by column chromatography

◦

using petroleum ether - ethyl acetate (10: 1). Yield 0.290 g (77%), red solid, m.p. 169–170 C. IR

1

(ATR) ν_max= 2884, 1584, 1506, 1359, 821, 734 cm⁻¹. H NMR (400 MHz, CDCl₃) δ = 1.99–2.09 (4H, m,

NCCH₂), 3.61–3.71 (4H, m, NCH₂), 7.07 (1H, s, CHCl₂), 7.61–7.71 (3H, m, H Ar), 7.85 (1H, dd, J = 7.6

Hz, J = 1.3 Hz, H Ar), 8.50 (1H, d, J = 9.3 Hz, H Ar), 9.03 (1H, d, J = 7.9 Hz, H Ar) ppm; ¹³C NMR (100

MHz, CDCl₃)

δ

= 25.5 (2

×

NC

C

H₂), 48.1 (2

×

NCH₂), 64.0 (CHCl₂), 113.9, 122.6 (CH), 124.1 (CH), 125.5

(CH), 126.6 (CH), 127.6 (CH), 129.2 (CH), 130.2, 130.4 (CNO₂), 134.3, 135.6, 145.5, 147.5 ppm; MS m/z

(I_rel, %): 375 [M⁺] (100), 358 [M

−

OH]⁺(15), 340 [M

−

Cl]⁺(5), 329 [M

−

NO₂]⁺(12), 259 [M-NO₂-Pyr]⁺

(30); HRMS (ESI⁺) m/z calcd for C₁₈H₁₅N₃O₂Cl₂Na [M + Na]⁺: 398.0439; found: 398.0440.

Synthesis of 2-ethoxy-2-oxoethyl 4,5-dichloro-1,2-thiazole-3-carboxylate (41). To a solution of isothiazole 40

(0.198 g, 1.0 mmol) and ethyl bromoacetate (0.501 g, 3.0 mmol) in EtOH (10 mL), sodium ethanolate

(0.204 g, 3.0 mmol) was added at r.t. The mixture was heated to reﬂux for 3 d. The product was

extracted with chloroform (3

×

10 mL) and puriﬁed through a short column chromatography using

petroleum ether – ethyl acetate (10:1). Yield 0.165 g (58%), yellowish solid, m.p. 31–33 ^◦C. IR (KBr)

1

ν

_max= 2983, 1743, 1427, 1193, 1038, 947 cm⁻¹. H NMR (200 MHz, CDCl₃)

δ

= 1.31 (3H, t, J = 7.1 Hz,

OCH₂CH₃), 4.28 (2H, q, J = 7.1 Hz, OCH₂CH₃), 4.91 (2H, s, OCH₂C=O) ppm; ¹³C NMR (50 MHz,

CDCl₃) = 14.0 (CH₃), 61.7 (O H₂CH_3,O H₂C=O), 126.1 (CCl), 150.8 (SCCl), 153.1 (C=N), 158.2, 166.7;

MS m/z (I_rel, %): 283 [M⁺] (18), 238 [M OEt]⁺(15), 210 [M CO₂Et]⁺(12), 180 [M OCH₂CO₂Et]⁺

(100); HRMS (ESI⁺) m/z calcd for C₈H₇NO₄Cl₂SNa [M + Na]⁺: 305.9371; found: 305.9370.

δ

C

−

Molecules 2020, 25, 2863

30 of 41

Synthesis of 2,2,2-Triﬂuoroethyl 4,5-dichloro-1,2-thiazole-3-carboxylate (43). A solution of isothiazole 42

(0.217 g, 1.0 mmol) and 2,2,2-triﬂuoroethanol (0.300 g, 4.0 mmol) in 20 mL dry THF was reﬂuxed for

4 d. After cooling to r.t., the solution was concentrated, diluted with water (20 mL), extracted with

hexane (3

×

20 mL), and washed with water (2

×

20 mL). Subsequently, the product was puriﬁed by

column chromatography (hexane). Yield 0.179 g (64%), white solid, m.p. 51–52 ^◦C. IR (KBr)

ν

=

max

cm⁻¹: 1741, 1430, 1358, 1167, 1091, 745. H NMR (200 MHz, CDCl₃)

δ = 4.61 (2H, q, J = 8.2 Hz, OCH₂);

1

¹³C NMR (50 MHz, CDCl₃)

δ = 61.3 (J_C,F= 37.1 Hz, CH₂), 122.6 (J_C,F= 276.0 Hz, CF₃), 126.3 (CCl),

151.3 (C=N), 152.3 (SCCl), 157.3 (C=O) ppm; MS m/z (I_rel, %): 279 [M⁺] (15), 244 [M

−

Cl]⁺(2), 197

[M-CH₂CF₃+H]⁺(12), 180 [M-OCH₂CF₃]⁺(100), 153 [M-CO₂CH₂CF₃+H]⁺(40); HRMS (ESI⁺) m/z

calcd for C₆H₂NO₂Cl₂SF₃Na [M + Na]⁺: 301.9033; found: 301.9035.

Synthesis of 4,5-Dichloro-N’-phenyl-1,2-thiazole-3-carbohydrazide (44a) (General method). To a suspension of

phenylhydrazine (0.324 g, 3.0 mmol) in dry THF (10 mL), the isothiazole 42 (0.216 g, 1.0 mmol) was

added at r.t. The mixture was stirred for 1 d. After removal of the solvent, the residue was treated with

cold HCl (10%) and the resulting precipitate ﬁltered oﬀ. Subsequently, it was washed with cold water

(3

×

5 mL) and Et₂O (2

×

3 mL). The product was dried in vacuo. Yield 0.216 g (75%), light brown solid,

1

m.p. 145–147 ^◦C. IR (KBr)

ν

= 3254, 1678, 1605, 1351, 884, 746 cm⁻¹. H NMR (200 MHz, CDCl₃)

δ

max

= 6.88–6.96 (3H, m, H Ph), 7.20–7.26 (3H, m, NH, 2H Ph), 8.81 (1H, s, NH) ppm; ¹³C NMR (50 MHz,

CDCl₃)

δ

= 113.8 (2

×

CH), 121.6 (CH), 125.3 (CCl), 129.2 (2

×

CH), 147.3, 150.9 (SCCl), 155.3, 158.9

ppm; MS m/z (I_rel, %): 287 [M⁺] (14), 180 [M-CONHNHPh]⁺(5), 107 [PhNHNH]⁺(100); HRMS (ESI⁺)

m/z calcd for C₁₀H₇N₃OCl₂SNa [M + Na]⁺: 309.9585; found: 309.9585.

4,5-Dichloro-N’-[3-(triﬂuoromethyl)phenyl]-1,2-thiazole-3-carbohydrazide (44b). Same procedure as for 44a

,

but using 3-triﬂuoromethylphenylhydrazine (0.370 g, 2.1 mmol) and stirring the mixture at reﬂux for 4

h. Yield 0.338 g (95%), yellowish solid, m.p. 152–153 ^◦C. IR (KBr)

ν

_max= 3300, 1691, 1497, 1340, 1161,

1

798 cm⁻¹. H NMR (200 MHz, DMSO-d₆)

δ

= 7.03–7.09 (3H, m, H Ar), 7.34–7.49 (1H, m, H Ar), 8.57

= 108.2 (J_C,F= 3.9 Hz, CH), 115.2

CF₃),

(1H, s, NH), 10.79 (1H, s, NH) ppm; ¹³C NMR (50 MHz, DMSO-d₆)

(J_C,F= 4.0 Hz, CH), 116.1 (CH), 124.6 (J_C,F= 271.5 Hz, CF₃), 123.0 (CCl), 129.7 (J_C,F= 31.3 Hz,

δ

C

130.2 (CH), 149.5 (CCl), 149.9, 157.8, 160.1 (C=O) ppm; MS m/z (I_rel, %): 355 [M⁺] (25), 336 [M-F]⁺(2),

180 [M-CF₃-Ph-NHNH]⁺(60), 175 [CF₃-Ph-NHNH]⁺(100), 152 [M-CONHNH-Ph-CF₃]⁺(10); HRMS

(ESI⁺) m/z calcd for C₁₁H₆N₃OCl₂SF₃Na [M + Na]⁺: 377.9458; found: 377.9459.

4,5-Dichloro-N-(4-cyano-2,5-diﬂuorophenyl)-1,2-thiazole-3-carboxamide (44c). Same procedure as for 44a

,

but using 4-cyano-2,5-diﬂuoro-aniline (0.354 g, 2.3 mmol) and stirring the mixture at reﬂux for 6 h.

Yield 0.227 g (68%), white solid, m.p. 164–166 ^◦C. IR (KBr)

ν

_max= 3361, 2237 (CN), 1715, 1528, 1190,

1

673 cm⁻¹. H NMR (200 MHz, CDCl₃)

δ = 7.41 (1H, dd, J = 9.8 Hz, J = 5.4 Hz, H Ar), 8.57 (1H, dd,

J = 10.6 Hz, J = 6.2 Hz, H Ar), 9.49 (1H, s, NH) ppm; ¹³C NMR (50 MHz, CDCl₃)

18.8 Hz, 9.6 Hz, (CN)), 108.6 (J_C,F= 28.7 Hz, 1.5 Hz, CH), 112.9 (J_C,F= 2.3 Hz, C( N)), 118.3 (J_C,F

δ

= 95.6 (J_C,F

=

C

=

24.5 Hz, 2.3 Hz, CH), 125.7 (CCl), 131.7 (J_C,F= 11.9 Hz, NC Ph), 147.5 (J_C,F= 244.0 Hz, 2.8 Hz, CF),

152.1 (CCl), 154.6, 156.3 (C=O), 160.1 (J_C,F= 255.3 Hz, 2.3 Hz, CF) ppm; MS m/z (I_rel, %): 333 [M⁺]

(22), 180 [M-NH-Ph-F₂-(CN)]⁺(100), 152 [M-CONH-Ph-F₂-(CN)]⁺(15); HRMS (ESI⁺) m/z calcd for

C₁₁H₃N₃OCl₂SF₂Na [M + Na]⁺: 355.9240; found: 355.9241.

4,5-Dichloro-N-[2-(1H-indol-3-yl)ethyl]-1,2-thiazole-3-carboxamide (44d). Same procedure as for 44a, but

using tryptamine (0.352 g, 2.2 mmol) and triethylamine (0.223 g, 2.1 mmol). Yield 0.265 g (78%), white

1

solid, m.p. 183–185 ^◦C. IR (KBr)

ν

= 3302, 1650, 1537, 1349, 946, 738 cm⁻¹. H NMR (200 MHz,

max

CDCl₃)

(3H, m, 2H Ar, NCH), 7.37 (1H, d, J = 7.7 Hz, H Ar), 7.63 (1H, d, J = 7.7 Hz, H Ar), 8.15 (1H, s, NH)

ppm; ¹³C NMR (50 MHz, CDCl₃)

= 25.3 (CH₂), 39.6 (CH₂), 111.2 (CH), 112.6, 118.7 (CH), 119.5 (CH),

δ = 3.08 (2H, t, J = 8.1 Hz, Ind-CH₂), 3.72–3.82 (2H, m, NCH₂), 7.07 (1H, s, NHC=O), 7.11–7.25

δ

122.1 (CH, CCl), 122.2 (CH), 127.2, 136.4, 150.4 (CCl), 156.7, 159.0 (C=O) ppm; MS m/z (I_rel, %): 339

[M⁺] (4), 180 [M-NHCH₂-ind]⁺(5), 143 [ind-CHCH₂]⁺(100), 130 [ind-CH₂]⁺(91); HRMS (ESI⁺) m/z

calcd for C₁₄H₁₁N₃OCl₂SNa [M + Na]⁺: 361.9900; found: 361.9898.

Article Doi

Polyhalonitrobutadienes as versatile building blocks for the biotargeted synthesis of substituted N-heterocyclic compounds

DOI: 10.3390/molecules25122863

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