1-Phenyl-1H- and 2-phenyl-2H-1,2,3-triazol derivatives: Design, synthesis and inhibitory effect on alpha-glycosidases

ACCEPTED MANUSCRIPT

Highlights

•

60 non-glycoside triazoles divided into two regioisomers series were obtained.

Series B (2-phenyl-2H-1,2,3-triazoles) contained potent yeast maltase inhibitors.

Most of the active inhibitors are carboxaldehyde derivatives.

Phenylhydrazones, N-methyleneisonicotinamides and oximes also provide active inhibitors.

The new triazoles are promising leads for development as drugs for type 2 Diabetes.

ACCEPTED MANUSCRIPT

1

-phenyl-1H- and 2-phenyl-2H-1,2,3-triazol derivatives: Design, Synthesis and Inhibitory

Effect on alpha-glycosidases

a,1

b,1

a

Daniel Gonzaga , Mario Roberto Senger , Fernando de Carvalho da Silva , Vitor Francisco

a,

b,

Ferreira *, Floriano Paes Silva Junior *

a

Universidade Federal Fluminense, Instituto de Química, Departamento de Química Orgânica,

Campus do Valonguinho, 24210-141, Niterói – RJ, Brazil.

b

Fundação Oswaldo Cruz, Instituto Oswaldo Cruz, Laboratório de Bioquímica de Proteínas e

Peptídeos, 21040-360 - Rio de Janeiro – RJ, Brazil.

*

To whom correspondence should be addressed.

e-mail: floriano@ioc.fiocruz.br. Telephone: + 55 21 3865-8157, Fax: 21 2590-3495

e-mail: cegvito@vm.uff.br. Telephone: + 55 21 2629-2345

1

These authors contributed equally to this work

1

ACCEPTED MANUSCRIPT

Abstract

Due to aging and increasingly overweight in human population, the incidence of non-insulin

dependent diabetes mellitus (NIDDM or Type 2 DM) is increasing considerably. Therefore,

searching for new α-glycosidase inhibitors (GIs) capable of slowing down carbohydrate

assimilation by humans is an important strategy towards control of NIDDM. In this report, we

disclose the search for new easily accessible synthetic triazoles as anti-diabetic compounds. Two

series of non-glycosid triazoles were synthesized (series A and B) and screened against baker's

yeast α-glucosidase (MAL12) and porcine pancreatic α-amylase activity (PPA). Of the 60

compounds tested at 500 µM, were considered hits (≥ 60% inhibition) six triazoles against

MAL12 and three against PPA, with the inhibition reaching up to 99.4% on MAL12 and 88.6%

on PPA. The IC50 values were calculated for both enzymes and ranged from 54-482 µM for

MAL12 and 145 to 282 µM for PPA. These results demonstrated the potential activity of simple

and non-glycosidic triazoles as an important novel class of GIs for the development of drugs to

treat Type 2 DM.

Keywords: Triazole, Diabetes, Amylase, Maltase, Glycosidase Inhibitors, Drug Design.

2

ACCEPTED MANUSCRIPT

1

. Introduction

The interest in 1,2,3-triazoles by the medicinal chemistry community began to increase

after the improvement of Huisgen 1,3-dipolar cycloaddition [1-3] which made easy the

preparation of these heterocycles. Several 1,2,3-triazoles were then screened for important

biological activities, including anti-HIV [4], β-lactamase inhibition [5,6], anti-tubercular [7], α-

glycosidase inhibition [8,9], anti-HSV [10], antiepileptic [11,12], antiplatelet [13], dopamine D2

receptor ligands (related to Schizophrenia) [14], anti-inflammatory [15,16], antimicrobial [17,18]

and antifungal [19,20]. Currently, a few 1,2,3-triazoles are already in the final stages of clinical

trials, the most promising compounds being the anticancer carboxyamidotriazole (CAI, 1) and

the reverse transcriptase inhibitor tert-butyldimethylsilylspiroaminooxathioledioxide (TSAO, 2),

in addition to two antibiotics, tazobactam (3) and cefatrizine (4) [21] (Figure 1).

Due to aging and increasingly overweight in human population, the incidence of non-

insulin dependent diabetes mellitus (NIDDM) is increasing considerably. Therefore, searching

for new α-glycosidase inhibitors (α-GIs) capable of slowing down or halting carbohydrate

metabolism is an important goal in pharmacotherapeutic control of NIDDM. Inhibition of starch

cleavage by α-amylase is the first step towards controlling the enzymatic degradation of

polysaccharides, which is a process essential for carbohydrate assimilation.

Five-membered azaheterocycles, such as imidazole [23,24], 1,2,3-triazole [25,26] and

tetrazole [27] derivatives, exhibit potent GI activity and are thought to achieve this by mimicking

the sugar moieties. The latter can be rationalized by the fact that triazoles can actively participate

in hydrogen bonding and dipole-dipole interactions due to their strong dipole moment, while still

showing excellent stability toward hydrolysis and oxidative/reductive conditions. The triazole

ring can be considered a bioisostere of the amide group because these moieties have a similar H-

bond acceptor capacity, a similar distance between substituents (3.8-3.9 Å in amides and 5.0-5.1

Å in triazoles), and a similar dipolar character (amide 4.0 Debye; triazole 5.0 Debye).

Recently, a series of triazoles were synthesized and had their ability to inhibit α-

glucosidase from bacillus stearothermophilus evaluated, with compound 5 (IC₅₀1.15 µM)

shown in Figure 2, being the most active inhibitor [28]. Also, the compounds 6 (n = 1) and 7 (n =

4

) were moderate inhibitors toward glycosidase of A. niger [29]. Our group has synthesized

several glycoconjugated triazoles that were subsequently assayed against the baker's yeast

maltase (MAL12) and porcine pancreatic alpha-amylase (PPA) in the search for new α-GIs [8,9].

The results revealed that most of them presented a superior inhibitory profile than acarbose (IC₅₀

1

5

09 ± 12 µM), notably the derivatives 8 (IC50 3.8 ± 0.5 µM), 9 (IC50 5.7 ± 0.3 µM) and 10 (IC50

.2 ± 0.9 µM). The pharmacological potential of this triazole series was demonstrated by the

reduction of post-prandial blood glucose levels in normal rats treated with a 50 mg/kg oral dose

of compounds 8 or 9. This result indicates that this triazole series could represent new candidates

for the development of novel drugs for the treatment of metabolic diseases, such as diabetes

(

Figure 2). At that time, we found a modest but interesting inhibitory activity for compound 11

Figure 2), in which the glycoside moiety in ribofuranosyl 1H-1,2,3-triazoles was replaced by an

aryl ring. Since the triazoles reported as having highest activity against α-glycosidases have a

carbohydrate moiety it was surprising to find this slight activity of 11.

Triazoles with α-GI inhibitory ability are natural or synthetic glycosides. Since

carbohydrate groups are known to be more synthetically challenging [30] we decided to

synthesize other small molecules based on the non-glycosidic compound 11 (Scheme 1) by

producing several classical and non-classical bioisoteres through simple interconvertion of

3

ACCEPTED MANUSCRIPT

functional groups (bioisosteres with similar physical or chemical properties) and keeping the

phenyl-1H-1,2,3-triazol framework (12-17) or making simple bioisosteres on ring equivalent 2H-

1

,2,3-triazol (18-23). With this strategy we also tried to circumvent the potential problems

arising from the fact that compound 11 also has an aldehyde group that could form potential

covalent adducts (Schiff base) with many other enzymes. The new triazoles were evaluated

against two α-glycosidases: MAL12 and PPA.

2

. Results

All 1,2,3-triazoles (series A and B) were prepared by known synthetic routes. The

methodology for obtaining the 1H-1,2,3-triazoles (series A) was based on the Huisgen 1,3-

dipolar cycloaddition reaction between propargylic alcohol and aromatic azides, which were

catalyzed by Cu(I) and provided only the 1,4-regioisomers [31]. The aromatic azides were

obtained by a diazotization/substitution sequence with the corresponding anilines [32] The

derivatization reactions were performed using well-established methodologies. The esterified

(13) and etherified (14) derivatives were made from the nucleophilic substitution reaction

between the alcohol (12) and acid chlorides or alkyl bromides in basic medium, respectively. The

partial oxidation of the alcohol (12) in the presence of IBX/DMSO led to formation of 4-

carboxaldehyde-1,2,3-triazoles (15), which served as a synthetic intermediate for 4-vinyl-1H-

1

,2,3-triazoles (16). The 4-vinyl-1H-1,2,3-triazoles (16) were obtained from the Wittig reaction

with methyltriphenylphosphonium bromide in THF/NaH. The hydrazones and oximes (17) were

generated by reaction with aromatic hydrazines or NH OH.HCl.

2

Concurrently, the preparation of the derivatives 2H-1,2,3-triazoles followed the synthetic

sequence for obtaining the Fisher osazone (D-Glucose adduct with substituted phenylhydrazines)

followed by oxidative cyclization by Hudson’s method (refluxed in aqueous solution of CuSO

generating the derivative phenyl-D-glucosotriazole [33-38]. Then, the oxidative cleavage of the

glycotriazole in aqueous NaIO afforded the 3-carboxaldehyde-2H-1,2,3-triazoles (18). The

alditolyl-triazoles (21) were produced by reduction using NaBH . Next, several methods of

4

),

4

derivatization were used as previously described to form 4-vinyl-1H-1,2,3-triazoles (19),

hydrazones or oximes (20), esters 22 and ethers 23. All of the compounds were obtained in good

1

13

yields and were fully characterized by H nuclear magnetic resonance ( H NMR), C NMR,

infrared spectroscopy (FTIR), mass spectroscopy, and elemental analysis (CHN) (see

Experimental Section).

As planned, the triazole moiety has been incorporated into 60 newly synthetized 1H- and

2

H-1,2,3-triazoles and tested on two carbohydrate-active enzymes. It is worthy to note that the

physicochemical properties of the triazole group are favorable for studies involving the discovery

of new bioactive compounds since it acts as a rigid link, in which the substituents attached to the

triazole at positions 1 and 4 are held at a fixed distance of 5.0 Å.

Table 1 summarizes the inhibitory screening of the compounds, which were tested at a

concentration of 500 µM, against yeast MAL12 enzyme. Our results demonstrated that seven

compounds inhibit enzymatic activity more effectively than acarbose, a commercial anti-diabetic

drug. From those, the six compounds exhibiting ≥ 60% inhibition were selected for IC50

determination. Table 2 shows the IC50 and binding efficiency index (BEI) values for these

compounds. BEI is a useful metric for the initial stages of drug development where it is

necessary to optimize hits from initial screening into lead compounds [39,40]. This index reflects

4

ACCEPTED MANUSCRIPT

the necessity to improve binding (as measured by pIC50) without increasing excessively

compound size or MW (which can bring solubility issues, for instance).

Table 3 summarizes the inhibitory screening against PPA activity; the samples were also

tested at 500 µM. Acarbose was the most active inhibitor reaching 99.6% inhibition. Six

compounds presenting ≥ 60% inhibition were considered active and selected for IC₅₀

determination. Table 4 shows the IC and BEI values for these compounds.

5

0

3

. Discussion

The triazoles are important compounds in medicinal chemistry and promising therapeutic

agents for a variety of diseases, including type 2 Diabetes Mellitus. Previously, our group

performed the synthesis and screening for the inhibitory activity of glycoconjugated triazoles

(GCTs) on α-glucosidases, which confirmed them as promising prototype compounds [8,9,41].

Specifically, it was demonstrated that β-D-ribofuranosyl 1H-1,2,3-triazoles (ribofuranosyl

GCTs) inhibiting MAL12 were also able to reduce post-prandial glucose levels in normal rats

[8]. We hypothesized that this hypoglycemiant activity was due to inhibition of mammalian α-

glucosidases involved in sugar metabolism, such as PPA. To test this hypothesis, we

characterized the inhibitory mechanism of GCTs on porcine PA (PPA) [9]. Ribofuranosyl GCTs

significantly inhibited PPA with IC₅₀in the middle to high micromolar range. We also

demonstrated that ribofuranosyl GCTs are reversible noncompetitive inhibitors when we used 2-

chloro-4-nitrophenyl-α-D-maltotrioside as the substrate. Finally, we have assayed the ability of

1

,2,3-triazole glycoconjugates synthesized from D-glucose to inhibit yeast maltase but found that

the latter are far less active than ribofuranosyl GCTs [41].

Following up with the discovery of novel α-GIs bearing a triazole ring, in this paper we

report the design, synthesis and inhibitory activity of non-glycosidic N-phenyl-1H- and N-

phenyl-2H-1,2,3-triazol derivatives on two α-glucosidases: MAL12 and PPA. The sugar moiety

attached to the triazole ring was replaced by several substituted and non-substituted phenyl

moieties, which is a departure from the GCTs previously characterized by our group. The

compounds were divided into two series, depending on the attachment position of the phenyl

ring: the 'A' series, where the phenyl ring is bonded to the N1 atom; and the 'B' series, where the

phenyl ring is linked to the N2 atom. Further variation in each series was obtained by the

conversion of the starting 4-methylalcohol (series A) or 4-carboxaldehyde (series B) derivatives

into the respective aldehyde, alcohol, ester, ether, vinyl, oxime and phenylhydrazone derivatives

by a series of known synthetic reactions.

Screening for α-GI activity against MAL12 and PPA showed a clear trend regarding the

substitution pattern of the triazole core. Regardless of the enzyme tested in the experiment, only

ring bioisosteres 2-phenyl-2H-1,2,3-triazoles showed inhibition above 50% when screened at a

fixed concentration of 500 µM. As expected from previous results with prototype compound 11,

several carboxaldehydes (11, 15a-b and 18a-d) were among the most active α-GIs. Noteworthy,

some N-addition derivatives, such as those containing a phenylhydrazone (20b), oxime (20i) or

N-methyleneisonicotinamide (20h) group also had interesting inhibition profiles.

Among the six compounds for which IC50 values against MAL12 were determined, four

(

18a, 18b, 18d and 20b) presented IC50 values smaller (more potent) than acarbose (IC50=109

8

µM). Compound 18b was the most potent with 54 µM (BEI = 20.6). It is interesting to note that

addition of a chlorine to the 4-position in the 2-phenyl group (18b) results in slight improvement

in IC in relation to 18a but attachment of a fluorine atom to the same position (18e) has a

5

0

5

ACCEPTED MANUSCRIPT

drastic negative effect on inhibitory potency (almost 10-fold increase in IC50 when compared to

1

8b). Despite the lower BEI for the 3,5-dichlorophenylhydrazone 20b (BEI is only 12.4), this

compound is interesting for further consideration because it preserves strong maltase inhibition

IC = 75 µM) while preventing potential issues associated with analogs bearing the aldehyde

(

5

0

group.

When comparing these values for yeast maltase inhibition with the data previously

characterized by our group [8] concerning the GCT series, it was determined that the

carbohydrate moiety attached to N1 in this series can be substituted with a 2-phenyl group, when

the C5 substituent in the 2H-1,2,3-triazoles is either a carboxaldehyde or =N-R group. Among

GCTs, the most potent maltase inhibitors (IC 3-5 µM) utilized bulky aromatic or hydrophobic

5

0

groups, such as cyclohexenyl or phenoxymethyl, as C4 substituents and 1-O-methyl-2,3-O-

isopropylidene-β-D-ribofuranose as the carbohydrate moiety [8].

According to our previous modelling work with MAL12 [8], when binding to the free

enzyme, the triazole ring may interact with the catalytic carboxylate Glu268 while the C4

substituent in 1H-1,2,3-triazole derivatives are involved in hydrophobic contacts at the -1 subsite

of the enzyme. With the 2-phenyl-2H-1,2,3-triazoles synthesized in this work, preliminary

modelling results indicate that the aromatic group may bind in similar fashion as the glycoside

moiety in GCTs (data not shown). Further work is necessary to characterized the inhibition mode

of these compounds thus allowing more accurate molecular modelling studies.

When compared with MAL12 results, fewer compounds showed significant activity on

the PPA enzyme; this trend has been previously observed for other triazoles [9]. Two

carboxaldehyde-substituted compounds (18c and 18d) and the oxime 20i presented the highest

activity against PPA with IC values ranging from 145 to 282 µM. Compound 18d presented the

5

0

most similar activities against both α-glycosidases; this compound was also only 50% more

potent on inhibition of MAL12 than on the inhibition of PPA. It can be hypothesized that

compound 18d binds to a homologous site shared by the enzymes; both enzymes belong to the

GH13 family of glycoside hydrolases [42].

4

. Conclusion

We have reported syntheses of 60 non-glycoside triazoles divided into two regioisomers

series (ring bioisoteres). Series B, i.e. 2-phenyl-2H-1,2,3-triazoles, contained a number of potent

yeast maltase inhibitors, which presented inhibition efficacy greater than the classical α-

glucosidase inhibitor acarbose. Most of the active inhibitors are carboxaldehyde derivatives and

these act upon both yeast maltase and PPA; aldehyde groups may react with amine groups in the

enzyme polypeptide chain to form Schiff bases. This covalent attachment is usually reversible,

and further work is being conducted by our group to determine the kinetics of the inhibition

mechanism followed by these compounds. We also identified new active α-GI analogs where the

carboxaldehyde group was substituted by phenylhydrazone, N-methyleneisonicotinamide and

oxime groups, which are promising leads for further development of these triazoles as drugs to

treat type 2 Diabetes.

6

ACCEPTED MANUSCRIPT

5

. Experimental Section

.1. Chemistry

Reagents were purchased from Sigma-Aldrich and were used without further purification.

Column chromatography was performed with silica gel 60 (Merck 70-230 mesh). Analytical

thin-layer chromatography was performed with silica gel plates (Merck, TLC silica gel 60 F254),

and the plots were visualized using UV light or aqueous solutions of ammonium sulfate. Yields

refer to chromatographically and spectroscopically homogeneous materials. Melting points were

obtained on a Fischer-Johns apparatus and were uncorrected. Infrared spectra were measured

using KBr pellets on a Perkin-Elmer model 1420 FT-IR Spectrophotometer, calibrated relative to

-1

the 1601.8 cm absorbance of polystyrene. NMR spectra were recorded on a Varian Unity Plus

VXR (500 MHz) instrument in DMSO-d or CDCl solutions. The chemical shift data were

6

3

reported in units of δ (ppm) downfield from tetramethylsilane or the solvent, either of which

were used as an internal standard; coupling constants (J) are reported in Hertz and refer to

apparent peak multiplicities. The high-resolution mass spectra (electrospray ionization) were

obtained using a QTOF Micro (Waters, Manchester, UK) mass spectrometer (HRESIMS).

α-Glucosidase from S. cerevisiae (CAS number: 9001-42-7), p-nitrophenyl-α-D-

glucopyranoside (PNP-G; CAS number: 3767-28-0), α-Amylase type I-A suspension in 2.9 M

NaCl with 3 mM CaCl from porcine pancreas (CAS number: 9000-90-2), 2-chloro-4-

2

nitrophenyl-α-D-maltotrioside (CNPG3; CAS number: 118291-90), acarbose (CAS number:

5

6180-94-0), phosphate buffer, Hepes buffer, sodium chloride and calcium chloride, which were

purchased from Sigma (USA).

Representative 1H and 13C NMR spectra for the compounds obtained in this work are

provided as supplementary material online.

4

.1.1 General procedure for preparation of 12a-d

In a round-bottom flask equipped with a magnetic stirring bar, the substituted aniline (10

mmols) was dissolved in HCl 6M (10 mL) cooled in an ice bath and the temperature was

maintained between 0-5 ºC. Subsequently, NaNO (15 mmols in 25 mL of water) was added

2

dropwise. The reaction mixture was then stirred for 30 minutes at 0-5ºC. Next, sodium azide

solution (40 mmols with 50 mL of water) was added drop-wise. After the addition, the system

was stirred for another hour. Finally, the mixture was extracted with ethyl acetate and the

combined organic extracts were washed with water, dried over anhydrous sodium sulfate, filtered

and concentrated under reduced pressure. The aromatic azides obtained were used directly

without further purification.

To a round-bottom flask equipped with a magnetic stirring bar were added an aromatic

azide (0.83 mmol), propargyl alcohol (0.75 mmol), tert-butanol (0.7 mL), copper sulfate

pentahydrate (0.04 mmol), sodium ascorbate (0.11 mmol) and water (0.7 mL). The reaction

mixture was stirred for 48-72 hours at room temperature. Next, the mixture was extracted with

ethyl acetate and the combined organic extracts were washed with water, dried over anhydrous

sodium sulfate, filtered and concentrated in vacuo. The product was purified via silica-gel

column chromatography, using gradient mixture of hexane-ethyl acetate, to afford the pure

derivatives 12a-d.

7

ACCEPTED MANUSCRIPT

o

4

1

3

7

.1.1.1 (1-phenyl-1H-1,2,3-triazole-4-yl)methanol (12a). White solid, m.p. 110-111 C (m.p lit.

-1

1

09-110ºC [7]); IR ν_m_a_x(cm ): 3202, 1595, 1499, 1240, 1007, 756, 686; H NMR (DMSO-d ,

00.00 MHz) δ: 4.74 (2H, d, J 5.5 Hz, H-6), 5.33 (1H, t, J 5.5, OH), 7.60 (2H, t, J 7.3 Hz, H-4’),

.71 (2H, t, J 7.3 Hz, H-3’ and H-5’), 8.02 (2H, d, J 7.3 Hz, H-3’ and H-5’) 8.78 (1H, s, H-5);

6

1

3

C NMR(DMSO-d , 75.0 MHz APT) δ: 55.0 (C-6), 120.0 (C-4’), 120.9 (C-5), 128.4 (C-3’ and

6

C-5’), 129.8 (C-2’and C-6’), 136.8 (C-1’), 149.1 (C-4).

4

1

6

.1.1.2 (1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-yl)methanol (12b). Brown solid, m.p. 128-

o

-1

29 C (m.p. lit. 127-129 ºC [7]); IR νmax (cm ): 3184, 3116, 3074, 2970, 1608, 1519, 1262,

1

048, 1016, 838; H NMR (DMSO-d

6 3

, 300.00 MHz) δ: 3.94 (OCH ), 4.72 (2H, d, J 5.5 Hz, H-

1

3

), 7.22-7.25 (2H, m, H-3’and H-5’), 7.88-7.92 (2H, m, H-2’ and H-6’), 8.64 (1H, s, H-5); C

NMR(DMSO-d , 75.0 MHz APT) δ: 55.1 (C-6), 55.6 (OCH ), 115.0 (C-3’ and C-5’), 121.0 (C-

6

3

5

), 121.8 (C-2’ and C-6’), 130.3 (C-4’), 148.9 (C-1’), 159.3 (C-4).

o

4

.1.1.3 (1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)methanol (12c). White solid, m.p. 143-144 C

-1

(m.p. lit. 144-145ºC [7]); IR ν

(cm ):3216, 1502, 1242, 1186, 1092, 1062, 1040, 1012, 835,

max

76, 701, 676; H NMR (DMSO-d , 300.00 MHz) δ: 4.63 (2H, d, J 3.3 Hz, H-6), 5.33 (1H, t, J

.3, OH), 7.62 (2H, d, J 9.1 Hz, H-3’ and H-5’), 7.92 (2H, d, J 9.1 Hz, H-2’ and H-6’); 8.66 (1H,

1

7

3

6

1

3

s, H-5); C NMR(DMSO-d

6

, 75.0 MHz APT) δ: 55.0 (C-6), 121.1 (C-5), 121.6 (C-2’ and C-6’),

1

29.9 (C-3’ and C-5’), 132.8 (C-4’), 135.6 (C-1’), 149.4 (C-4).

4

1

.1.1.4 (1-(2,5-dichlorophenyl)-1H-1,2,3-triazole-4-yl)methanol (12d). White solid, m.p. 117-

o

-1

18 C (m.p. lit. 114-116 ºC [7]); IR ν

(cm ):3338, 2361, 1585, 1485, 1445, 1238, 1099,

max

1

037, 871, 819, 644; H NMR (DMSO-d , 300.00 MHz) δ: 4.75 (2H, d, J 3.3 Hz, H-6), 5.47 (1H,

6

t, J 3.3 Hz, OH), 7.84 (1H, dd, J 1.6 and 5.2 Hz), 7.93 (1H, d, J 5.2 Hz, H-3’), 7.99 (1H, d, J 1.6

1

3

Hz, H-6’), 8.55 (1H, s, H-5); C NMR(DMSO-d , 75.0 MHz APT) δ: 54.9 (C-6), 124.9 (C-5),

6

1

27.5 (C-2’), 128.1 (C-6’), 131.3 (C-4’), 132.0 (C-3’), 132.5 (C-5’), 135.6 (C-1’), 148.2 (C-4).

.1.2 General procedure for preparation of 13a-k and 22a-d

4

Into a round-bottom flask were added 5.71 mmols of alditolyl-triazole 12 or 21a in 50 ml

dichloromethane, 0.9 mL of pyridine (2 eq.), 5.71 mmols of acyl chloride and catalytic amount

of DMAP. The mixture was stirred vigorously at room temperature, and the reaction progress

was monitored by thin layer chromatography. Next, the mixture was washed with distilled water

(3 x 100 mL), saturated sodium bicarbonate solution (5 x 100 mL), dried over anhydrous sodium

sulfate, filtered and concentrated under reduced pressure. The product was purified via silica-gel

column chromatography using gradient mixture of hexane-ethyl acetate, to afford the pure

derivatives 13a-k and 22a-d.

4

IR ν

.1.2.1 (1-phenyl-1H-1,2,3-triazole-4-yl)methylbenzoate (13a). White solid, m.p. 110-111 ºC;

-1

(cm ): 3135, 3093, 2965, 2363, 2338, 1722, 1600, 1505, 1451, 1274, 1241, 1106, 1099;

max

1

H NMR (CDCl , 500.00 MHz)δ:5.66 (2H, s, H-6), 7.53-7.59 (1H, m, H-4’), 7.63-7.73 (4H, m,

3

H-3’, H-5’, H-3” and H-5”), 7.77-7.83 (1H, m, H-4”), 8.11-8.16 (4H, m, H-2’, H-6’, H-2” and H-

1

3

6

5

”), 8.34 (1H, s, H-5); C NMR(CDCl

3

, 125.0 MHz APT) δ: 57.9 (C-6), 120.2 (C-4’), 123.0 (C-

), 128.5 (C-3’ and C-5’), 128.8 (C-2’ and C-6’), 129.3, 129.9, 132.8, 133.5 (C-2”, C-3”, C-4”,

8

ACCEPTED MANUSCRIPT

C-5” and C-6”), 129.4 (C-1”), 136.6 (C-1’), 143.1 (C-4), 165.5 (C-8). Anal. Calcd for

C

16

H

13

N

3

O

2

: C, 68.81; H, 4.69; N, 15.05. Found: C, 68.23; H, 4.96; N, 14.68.

4

8

.1.2.2 (1-(2,5-dichlorophenyl)-1H-1,2,3-triazole-4-yl)methylbenzoate (13b). White solid, m.p.

5-86 ºC; IR ν_m_a_x(cm ): 3053, 1731, 1588, 1486, 1449, 1264, 1098, 1038, 733; H NMR

-1

1

(

CDCl , 500.00 MHz) δ: 5.65 (2H, s, H-6); 7.60-7.68 (3H, m, H-3”, H-4” and H-5”), 7.72-7.81

3

(

1H, m, H-6’), 7.85 (1H, dd, J1.8 and 5.4 Hz, H-4’), 7.93 (1H, d, J5.4 Hz, H-3’), 8.05-8.13 (2H,

1

3

m, H-2” and H-6”); 8.86 (1H, s, H-5); C NMR(CDCl , 125.0 MHz APT) δ: 57.6 (C-6), 126.8

3

(

C-5), 127.5 (C-2’ and C-6’), 128.5 (C-3’ and C-5’), 128.8, 129.3, 129.8, 133.1 and 133.5 (C-2”,

C-3”, C-4”, C-5”and C-6”), 130.8 (C-1’), 132.1 (C-4’), 135.4 (C-1”), 143.3 (C-4), 165.5 (C-8).

Anal. Calcd for C16 : C, 55.19; H, 3.18; N, 12.07. Found: C, 55.63; H, 3.21; N, 11.92.

2 3 2

H11Cl N O

4

IR ν

8

.1.2.3 (1-(2,5-dichlorophenyl)-1H-1,2,3-triazole-4-yl)methyl hexanoate (13c). Yellow oil;

-1

(cm ): 3153, 3098, 2932, 2958, 1738, 1589, 1489, 1451, 1240, 1166, 1099, 1042, 1003,

max

1

09; H NMR (CDCl , 500.00 MHz) δ: 0.97 (3H, t, J 6.8 Hz,C-13), 1.36-1.41 (4H, m, H-11 and

3

H-12), 1.67 (2H, p, J 7.3 Hz, H-10), 2.46 (2H, t, J 7.3 Hz, H-9), 5.37 (2H, s, H-6), 7.85 (1H, dd,

J 2.5 and 8.5 Hz, H-4’); 7.93 (1H, d, J 8.5 Hz, H-3’), 8.01 (1H, d, J 2.5 Hz, H-6’), 8.72 (1H, s,

1

3

H-5); C NMR(CDCl , 125.0 MHz APT) δ: 13.6 (C-13), 21.7 (C-12), 24.0 (C-10), 30.5 (C-11),

3

3.3 (C-9), 56.7 (C-6), 126.6 (C-5), 127.4 (C-2’), 128.1 (C-6’), 131.4 (C-4’), 131.9 (C-3’), 132.5

(

C-5’), 135.3 (C-1’), 142.3 (C-4), 172.6 (C-8); Anal. Calcd for C H Cl N O : C, 52.64; H,

1

5

17

2

3

2

5

.01; N, 12.28. Found: C, 52.77; H, 5.11; N, 12.16.

4

.1.2.4 (1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)methylacetate (13d). Brown solid, m.p. 74-75

-1

ºC; IR ν (cm ): 3180, 3074, 2964, 1741, 1581, 1487, 1232, 1097, 1047, 1028, 993, 834, 805;

max

1

H NMR (CDCl , 500.00 MHz) δ: 2.19 (3H, s, H-8), 5.35 (2H, s, H-6), 7.85 (1H, dd, J 1.5 and

3

1

3

4

.8 Hz, H-4’), 7.93(1H, d, J 4.8 Hz, H-3’), 8.03 (1H, d, J 1.5 Hz, H-6’), 8.74 (1H, s, H-5); C

NMR(CDCl , 125.0 MHz APT) δ:20.6 (C-9), 56.8 (C-6), 126.9 (C-5), 127.6 (C-2’), 128.3 (C-

3

6

’), 131.6 (C-4’), 132.0 (C-3’), 132.6 (C-5’), 135.3 (C-1’), 142.3 (C-4), 170.1 (C-8); Anal. Calcd

for C H ClN O : C, 52.50; H, 4.01; N, 16.70. Found: C, 52.59; H, 4.01; N, 16.58.

1

10

3

2

4

.1.2.5 (1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)methylbenzoate (13e).White solid, m.p. 55-56

-1

ºC; IR νmax (cm ): 3150, 2926, 2869, 1739, 1645, 1554, 1503, 1444, 1381, 1232, 1157, 1093,

1

7

6

047, 988, 820, 773, 741, 696, 651; H NMR (DMSO-d

6

, 500.00 MHz) δ: 5.62 (2H, s, H-6),

.59-7.82 (5H, m, H-1”, H-2”, H-3”, H-4”, H-5”, H-6”), 8.05-8.14 (4H, m, H-2’, H-3’, H-5’, H-

1

3

6

’), 9.08 (1H, s, H-5); C NMR(DMSO-d , 125.0 MHz APT) δ: 57.8 (C-6), 121.9 (C-5), 123.1

(C-3’ and C-5’), 128.5 (C-2’and C-6’), 128.8, 129.3, 129.8, 133.1 and 133,5 ( C-2”, C-3”, C-4”,

C-5”and C-6”), 130.8 (C-1’), 132.1 (C-4’), 135.4 (C-1”), 143.3 (C-4), 165.5 (C-8); Anal. Calcd

for C H ClN O : C, 61.25; H, 3.86; N, 13.39. Found: C, 61.28; H, 3.91; N, 13.14.

1

6

12

3

2

-

1

4

3

5

7

.1.2.6 (1-phenyl-1H-1,2,3-triazole-4-yl)methyl hexanoate (13f). Yellow oil; IR ν_m_a_x(cm ):

1

147, 2957, 2872, 1736, 1597, 1503, 1466, 1239, 1167, 1045, 759, 690; H NMR (DMSO-d ,

6

00.00 MHz) δ: 0.84 (3H, t, J 7,0 Hz, H-13), 1.21-1.31 (4H, m, H-11 and H-12), 1.55 (2H, p, J

.5 Hz, H-10), 2.33 (2H, t, J 7.5 Hz, H-9), 5.23 (2H, s, H-6), 7.50 (1H, t, J 8.0 Hz, H-4’), 7.60

13

(

2H, t, J 8.0 Hz, H-3’ and H-5’), 7.90 (2H, d, J 8.0 Hz, H-2’ and H-6’), 8.82 (1H, s, H-5); C

NMR(DMSO-d , 125.0 MHz APT) δ: 13.7 (C-13), 21.7 (C-12), 24.1 (C-11), 30.6 (C-10), 33.3

C-9), 56.8 (C-6), 120.1 (C-4’), 122.8 (C-5), 128.8 (C-3’ and C-5’), 129.9 (C-2’ and C-6’), 136.6

6

(

9

ACCEPTED MANUSCRIPT

(C-1’), 143.2 (C-4), 172.6 (C-8); Anal. Calcd for C15

19 3 2

H N O : C, 65.91; H, 7.01; N, 15.37.

Found: C, 65.61; H, 7.03; N, 15.52.

4

1

.1.2.7 (1-(2,5-dichlorophenyl)-1H-1,2,3-triazole-4-yl)methylacetate (13g). Brown solid, m.p.

12-113 ºC; IR ν_m_a_x(cm ): 3149, 3110,1738, 1503, 1367, 1254, 1233, 1098, 1056, 1035, 823;

-1

1

H NMR (DMSO-d , 500.00 MHz) δ: 2.18 (3H, s, H-8), 5.33 (2H, s, H-6), 7.78-7.81 (2H, m, H-

6

1

3

’ and H-5’), 8.05-8.07 (2H, m, H-4’ and H-6’), 8.98 (1H, s, H-5); C NMR(DMSO-d , 125.0

6

MHz APT) δ: 20.6 (C-9), 56.9 (C-6), 121.9 (C-5), 123.0 (C-2’ and C-6’), 129.8 (C-3’ and C-5’),

1

3

33.1 (C-1’), 135.3 (C-4’), 143.3 (C-4), 170.0 (C-8). Anal. Calcd for C H Cl N O : C, 46.18; H,

.17; N, 14.69. Found: C, 46.36; H, 3.13; N, 14.45.

11 9 2 3 2

4

5

1

3

.1.2.8 (1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)methyl hexanoate (13h). White solid, m.p. 55-

-1

6 ºC; IR ν_m_a_x(cm ):3150, 2927, 2869, 1739, 1645, 1603, 1554, 1503, 1444, 1382, 1317, 1232,

1

157, 1093, 1047, 988, 820, 773, 741, 696, 651; H NMR (DMSO-d , 500.00 MHz) δ: 0.96 (t,

6

H, J 6.6 Hz, H-13), 1.35-1.41 (m, 4H, H-11 and H-12), 1.62-1.72 (m, 2H), 2.46 (t, 2H, J 7.2 Hz,

H-9), 5.35 (s, 2H, H-6), 7.78 (d, 2H, J 9.0 Hz, H-2’ and H-6’),8.05 (d, 2H, J 9.0 Hz, H-3’ and H-

1

3

5

’), 8.92 (s, 1H, H-5); C NMR(DMSO-d , 125.0 MHz APT) δ: 13.7 (C-13), 21.7 (C-12), 24.1

6

(C-11), 30.6 (C-10), 33.3 (C-9), 56.8 (C-6), 121.8 (C-5), 123.0 (C-3’ and C-5’), 129.9 (C-2’ and

C-6’), 133.1 (C-4’), 135.3 (C-1’), 143.4 (C-4), 172.6 (C-8); Anal. Calcd for C H ClN O : C,

1

5

18

3

2

5

8.54; H, 5.89; N, 13.65. Found: C, 59.21; H, 6.05; N, 13.37.

4

.1.2.9 (1-phenyl-1H-1,2,3-triazole-4-yl)methyl decanoate (13i). Yellow solid, m.p. 45-46 ºC;

-1

1

IR νmax (cm ): 3141, 2919, 2849, 1742, 1506, 1466, 1253, 1223, 1212, 1158, 1052, 757; H

NMR (DMSO-d , 500.00 MHz) δ: 0.83 (t, 3H, J 7.0 Hz, H-17), 1.21-1.24 (m, 12H, H-11, H-12,

6

H-13, H-14, H-15 and H-16), 1.51-1.58 (m, 2H, H-10), 2.34 (t, 2H, J 7.0 Hz, H-9), 5.23 (s, 2H,

H-6), 7.50 (t, 1H, J 8.5 Hz, H-4’), 7.61 (t, 2H, J 8.5 Hz, H-2’ and H-6’), 7.90 (d, 2H, J 8.5 Hz,

1

3

H-3’ and H-5’), 8.81 (s, 1H, H-5); C NMR (DMSO-d , 125.0 MHz APT) δ: 14.0 (C-17), 22.1

6

(C-16), 24.5 (C-10), 28.5 (C-11), 28.7 (C-12), 28.7 (C-14), 28.9 (C-13), 31.3 (C-14), 30.6 (C-9),

5

1

6.9 (C-6), 120.1 (C-4’), 122.9 (C-5), 128.8 (C-3’ and C-5’), 129.9 (C-2’ and C-6’), 136.6 (C-

’), 143.3 (C-4), 172.7 (C-8); Anal. Calcd for C H N O : C, 69.27; H, 8.26; N, 12.76. Found:

1

9

27

3

2

C, 69.19; H, 8.17; N, 12.45.

4

1

.1.2.10 (1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl)methyl decanoate (13j). Yellow solid, m.p.

-1

6-48 ºC; IR νmax (cm ): 3143, 2916, 2851, 1738, 1503, 1470, 1415, 1384, 1350, 1291, 1250,

1

6

229, 1157, 1095, 1048, 991, 930, 827, 785, 743, 715, 678; H NMR (DMSO-d , 500.00 MHz)

δ: 0.83 (3H, t, J 7.0 Hz, H-15), 1.20-1.24 (12H, m, H-9, H-10, H-11, H-12, H-13, and H-14),

.50-1.60 (2H, m, H-9), 2.33 (2H, t, J 7.0 Hz, H-8), 5.20 (2H, s, H-6), 7.67 (2H, d, J 8.5 Hz H-3’

1

3

and H-5’), 7.95 (2H, d, J 8.5 Hz, H-2’ and H-6’), 8.86 (1H, s, H-5); C NMR(DMSO-d , 125.0

6

MHz APT) δ: 11.2 (C-16), 19.3 (C-15), 21.7 (C-9), 25.7 (C-10), 25.9 (C-11), 25.9 (C-13), 26.1

(C-12), 28.5 (C-14), 30.6 (C-8), 54.0 (C-6), 119.1 (C-5), 120.2 (C-3’ and C-5’), 127.1 (C-2’ and

C-6’), 130.4 (C-1’), 132.6 (C-4’), 140.7 (C-4), 169.9 (C-8). Anal. Calcd for C H ClN O : C,

1

9

26

3

2

6

2.71; H, 7.20; N, 11.55. Found: C, 63.12; H, 7.34; N, 11.25.

4

.1.2.11 (1-phenyl-1H-1,2,3-triazole-4-yl)methylacetate (13k).White solid, m.p. 54-55 ºC;

-1

1

IR νmax (cm ): 3146, 3100, 2997, 2965, 1950, 1727, 1599, 1509, 1448, 1238, 1051, 756; H

NMR (DMSO-d , 500.00 MHz) δ: 2.19 (3H, s, CH ), 5.34 (2H, s, H-6), 7.59-7.65 (1H, m, H-4’),

6

3

10

ACCEPTED MANUSCRIPT

13

7

.69-7.76 (2H, m, H-3’ and H-5’); 7.99-8.04 (2H, m, H-2’ and H-6’), 8.42 (1H, s, H-5); C

NMR(DMSO-d , 125.0 MHz APT) δ: 20.7 (C-9), 57.0 (C-6), 120.2 (C-4’), 122.9 (C-5), 128.8

C-3’ and C-5’), 129.9 (C-2’ and C-6’), 136.6 (C-1’), 143.2 (C-4), 170.1 (C-8). Anal. Calcd for

C H N O : C, 60.82; H, 5.10; N, 19.34. Found: C, 60.84; H, 5.21; N, 19.29.

6

(

11

3

2

-1

4

.1.2.12 (2-phenyl-2H-1,2,3-triazole-4-yl)methyl decanoate (22a). Yellow oil; IR ν_m_a_x(cm ):

2

953, 2952, 2852, 1740, 1600, 1500, 1464, 1418, 1352, 1322, 1156, 1112, 1046, 967, 1022, 756;

1

H NMR (DMSO-d , 500.00 MHz) δ: 0.83 (3H, t, J 6.9 Hz), 1.21-1.27 (12H, m, H-10, H-11, H-

6

1

2, H-13, H-14 and H-15), 1.50-1.57 (2H, m, H-9), 2.35 (2H, t, J 6.9 Hz, H-8), 5.72 (2H, s, H-6),

7

8

9

.40-7.46 (1H, m, H-4’), 7.54-7.60 (2H, m, H-2’ and H-6’), 7.97-8.00 (2H, m, H-3’ and H-5’),

1

3

.07 (1H, s, H-4); C NMR (DMSO-d

6

, 125.0 MHz APT) δ: 13.9 (C-16), 22.1 (C-15), 24.4 (C-

), 28.4 (C-10), 28.6 (C-11), 28.7 (C-13), 28.8 (C-12), 31.2 (C-14), 33.3 (C-8), 56.7 (C-6), 118.4

(

1

C-4’), 127.9 (C-3’ and C-5’), 129.7 (C-2’ and C-6’), 135.9 (C-4), 139.1 (C-1’), 145.2 (C-4),

72.6 (C-7); Anal. Calcd for C19 : C, 69.27; H, 8.26; N, 12.76. Found: C, 69.31; H, 8.36;

N, 12.51.

27 3 2

H N O

-

1

4

2

9

.1.2.13 (2-phenyl-2H-1,2,3-triazole-4-yl)methylhexanoate (22b). Yellow oil; IR ν_m_a_x(cm ):

957, 2931, 2872, 2861, 1741, 1599, 1499, 1464, 1353, 1316, 1241, 1161, 1110, 1099, 1046,

67, 756, 690, 669; H NMR (DMSO-d , 500.00 MHz) δ: 0.84 (3H, t, J 5.7 Hz, H-13), 1.23-1.28

1

6

(4H, m, H-11 and H-12), 1.51-1.61 (2H, m, H-10), 2.36 (2H, t, J 7.8 Hz, H-9), 5.30 (2H, s, H-6),

7

8

1

6

.41-7.46 (1H, m, H-4’), 7.55-7.60 (2H, m, H-3’ and H-5’), 8.00-8.03 (m, 2H, H-2’ and H-6’),

1

3

.10 (s, 1H, H-4); C NMR (DMSO-d

1), 30.6 (C-10), 33.3 (C-9), 56.7 (C-6), 118.3 (C-4’), 127.8 (C-3’ and C-5’), 129.6 (C-2’ and C-

’), 135.8 (C-4), 139.1 (C-1’), 145.2 (C-5), 172.6 (C-8); Anal. Calcd for C15 : C, 65.91;

6

, 125.0 MHz APT) δ:13.6 (C-13), 21.7 (C-12), 24.1 (C-

19 3 2

H N O

H, 7.01; N, 15.37. Found: C, 64.93; H, 6.84; N, 14.86.

4

IR ν

.1.2.14 (2-phenyl-2H-1,2,3-triazole-4-yl)methylbenzoate (22c). Brown solid, mp 55-56 ºC;

-1

(cm ): 3465, 3127, 3067, 3025, 2950, 2472, 2159, 1977, 1745, 1597, 1500, 1238, 1062;

max

1

H NMR (CDCl , 500.00 MHz) δ: 5.63 (2H, s, H-6), 7.53-7.59 (1H, m, H-4’), 7.63-7.73 (4H,m,

3

H-3’, H-5’, H-3” and H-5”), 7.77-7.83 (1H, m, H-4”), 8.11-8.16 (4H, m, H-2’, H-6’, H-2” and H-

1

3

6

”), 8.34 (1H, s, H-4); C NMR (CDCl , 125.0 MHz APT) δ: 57.8 (C-6), 118.5 (C-4’), 128.0

3

(

1

C-3’ and C-5’), 128.9 (C-1”), 129.2 (C-3” and C-5”), 129.4 (C-4”), 129.8 (C-2’ and C-6’),

33.6 (C-2” and C-6”), 136.2 (C-4), 139;1 (C-1’), 145.1 (C-5), 165.5 (C-8); Anal. Calcd for

: C, 68.81; H, 4.69; N, 15.05. Found: C, 68.88; H, 4.92; N, 14.93.

16 13 3 2

C H N O

-

1

4

3

1

.1.2.15 (2-phenyl-2H-1,2,3-triazole-4-yl)methylacetate (22d). Brown oil; IR ν_m_a_x(cm ): 3464,

126, 3067, 2025, 2950, 2473, 2159, 1958, 1745, 1597, 1499, 1458, 1412, 1323, 1305, 1237,

174, 1062; H NMR (CDCl , 500.00 MHz) δ: 2.12 (3H, s, CH ), 5.27 (2H, s, H-6), 7.32-7.38

1

3

(

1H, m, H-4), 7.44-7.51 (2H, m, H-3’ and H-5’), 7,81 (1H, s, H-1), 8.03-8.07 (2H, m, H-2’ and

1

3

H-6’); C NMR (CDCl , 125.0 MHz APT) δ: 20.8 (CH ), 57.4 (C-6), 118.8 (C-4’), 127.7 (C-3’

3

and C-5’), 129.2 (C-2’ and C-6’), 135.4 (C-4), 139.6 (C-1’), 144.6 (C-5), 170.6 (C-8); Anal.

Calcd for C H N O : C, 60.82; H, 5.10; N, 19.34 Found: C, 60.84; H, 5.21; N, 19.29.

1

11

3

2

4

.1.3 General procedure for preparation of 14a-g and 23a-b

11

ACCEPTED MANUSCRIPT

Into a round bottom flask was added 5.71 mmols of triazole type 12 or 21a in 50 mL of

dry THF, 17.13 mmols of sodium hydride and 57.1 mmols of alkyl bromide. The mixture was

heated to reflux, and reaction progress was monitored by TLC. Subsequently, the solvent was

evaporated and the mixture was extracted with ethyl acetate, washed with distilled water (3 x 100

mL) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced

pressure, and the product was purified via silica-gel column chromatography using a gradient

mixture of hexane-ethyl acetate, to afford the pure derivatives 14a-g and 23a-b.

-

1

4

3

.1.3.1 4-(ethoxymethyl)-1-phenyl-1H-1,2,3-triazole (14a). Yellow oil; IR ν_m_a_x(cm ): 3140,

1

065, 2963, 2929, 2859, 2359, 1653, 1599, 1503, 1465, 1388, 1231, 1099, 1044, 758, 690; H

6 3

NMR (DMSO-d , 500.00 MHz) δ: 1.28 (3H, t, J 7.0 Hz,CH ), 3.67 (2H, q, J 7.0 Hz,H-8), 4.71

(

2H, s, H-6), 7.61 (1H, t, J7.5 Hz, H-4’), 7.72 (2H, t, J7.5 Hz H-3’ and H-5’), 7.61 (2H, d, J7.0

13

Hz, H-2’ and H-6’), 8.90 (1H, s, H-3); C NMR (CDCl

3

, 125.0 MHz APT) δ: 15.0 (C-9), 63.0

C-6), 65.0 (C-8), 120.0 (C-4’), 122.0 (C-5), 128.5 (C-3’ and C-5’), 129.8 (C-2’ and C-6’), 136.7

C-1’), 145.4 (C-4); Anal. Calcd for C11 O: C, 65.01; H, 6.45; N, 20.68. Found: C, 65.21;

(

13 3

H N

H, 6.41; N, 20.04.

-1

4

.1.3.2 4-(butoxymethyl)-1-phenyl-1H-1,2,3-triazole (14b). Yellow oil; IR ν_m_a_x(cm ): 3105,

3

073, 2957, 2926, 2859, 2365, 1599, 1504, 1466, 1340, 1296, 1231, 1191, 1098, 1042, 759, 699;

1

H NMR (CDCl , 500.00 MHz) δ: 0.98 (3H, t, J 7,5 Hz, CH ), 1.38-1.50 (2H, m, H-10), 1.58-

3

1

7

.68 (2H, m, H-10), 3.60 (2H, t, J 6,3 Hz, H-8), 4.70 (2H, s, H-6), 7.57-7.63 (1H, m, H-4’), 7.68-

1

3

.74 (2H, m, H-3’ and H-5’), 7.99-8.03 (2H, m, H-2’ and H-6’), 8.87 (1H, s, H-3); C NMR

, 125.0 MHz APT) δ: 13.8 (C-11), 18.9 (C-10), 31.3 (C-9), 63.3 (C-6), 69.5 (C-8), 120.0

C-4’), 122.0 (C-5), 128.6 (C-3’ and C-5’), 129.9 (C-2’ and C-6’), 136.8 (C-1’); 145.5 (C-4);

O: C, 67.51; H, 7.41; N, 18.17. Found: C, 68.34; H, 7.73; N, 16.45.

(CDCl

3

(

17 3

Anal. Calcd for C13H N

4

.1.3.3 1-(4-chlorophenyl)-4-(ethoxymethyl)-1H-1,2,3-triazole (14c). Brown solid, m.p. 90-91

-1

ºC; IR ν_m_a_x(cm ): 3141, 3101, 2925, 2855, 2359, 1563, 1504, 1461, 1438, 1376, 1343, 1232,

1

096, 1052, 1029, 1011, 824; H NMR (CDCl , 500.00 MHz) δ: 1.27 (3H, t, J 7.0 Hz, CH ), 3.67

3

(

2H, q, J 7.0 Hz, H-8), 4.70 (2H, s, H-6), 7.78-7.80 (2H, m, H-3’ and H-5’), 8.06-8.09 (2H, m,

1

3

H-2’ and H-6’), 8.93 (1H, s, H-3); C NMR (CDCl , 125.0 MHz APT) δ: 13.8 (C-9),62.9 (C-

3

6

1

5

),65.1 (C-8),121.7 (C-5),122,1 (C-3’ and C-5’), 129.8 (C-2’ and C-6’), 132.8(C-4’), 135.5 (C-

’), 145.5 (C-4); Anal. Calcd for C H ClN O: C, 55.59; H, 5.09; N, 17.68. Found: C, 56.01; H,

.00; N, 20.45.

1

12

3

4

.1.3.4 1-(4-chlorophenyl)-4-(butoxymethyl)-1H-1,2,3-triazole (14d). Brown solid, m.p. 63-64

-1

1

ºC; IR ν_m_a_x(cm ): 2157, 2960, 2931, 2867, 1504, 1350, 1230, 1096, 1048, 992, 838, 814; H

NMR (DMSO-d , 500.00 MHz) δ: 0.87 (3H, t, J 6.9 Hz, H-11), 1.27-1.39 (2H, m, H-10), 1.47-

6

1

5

.56 (2H, m, H-9), 3.49 (2H, t, J 6.6 Hz, H-8), 4.58 (2H, s, H-6), 7.65-7.69 (2H, m, H-3’ and H-

1

3

’), 7.93-7.98 (2H, m, H-2’ and H-6’), 8.80 (1H, s, H-3); C NMR (DMSO-d , 125.0 MHz

6

APT) δ: 13.7 (C-11), 18.8 (C-10), 31.2 (C-9), 63.2 (C-6), 69.4 (C-8), 121.7 (C-5), 122.0 (C-3’

and C-5’), 129.8 (C-2’ and C-6’), 132.9 (C-4’), 135.5 (C-1’), 145.5 (C-4). Anal. Calcd for

C H ClN O: C, 58.76; H, 6.07; N, 15.81. Found: C, 60.08; H, 6.41; N, 15.04.

13

16

3

-

4

)

.1.3.5 1-(4-methoxyphenyl)-4-(ethoxymethyl)-1H-1,2,3-triazole (14e).Yellow oil; IR νmax (cm

1

: 3139, 2973, 2865, 1611, 1518, 1461, 1379, 1303, 1253, 1191, 1096, 1042, 893, 832, 765, 695,

12

ACCEPTED MANUSCRIPT

1

6

7

1

5

1

60 ; H NMR (DMSO-d

), 3.96 (s, 1H, CH

6

, 500.00 MHz) δ: 1.27 (3H, t, J 7.0 Hz, H-8), 3.66 (q, 2H, J 7.0 Hz, H-

3

), 4.68 (s, 2H, H-6), 7.25 (d, 2H, J 9.0 Hz), 7.92 (d, J 9.0 Hz, 1H), 8.78 (d,

1

3

H, J 2.5 Hz, H-6’), 8.63 (s, 1H, H-5); C NMR (DMSO-d , 125.0 MHz APT) δ:15.0 (C-9),

5.6 (CH ), 63.0 (C-6), 65.0 (C-8), 114.9 (C-5), 116.1 (C-2’ and C-6’),121.8 (C-3’ and C-5’),

30.2 (C-1’), 145.1 (C-4’), 159.3 (C-4). Anal. Calcd for C H ClN O: C, 48.55; H, 4.07; N,

5.44. Found: C, 48.65; H, 4.01; N, 15.04.

6

3

1

11

3

4

.1.3.6 1-(2,5-dichlorophenyl)-4-(butoxymethyl)-1H-1,2,3-triazole (14f). Yellow oil; IR ν

max

-1

(

cm ): 3139, 2932, 2863, 1719, 1586, 1475, 1443, 1371, 1229, 1091, 1040, 1003, 852, 810, 666;

1

H NMR (DMSO-d

6

, 500.00 MHz) δ: 0.99 (3H, t, J 6.9 Hz, H-11), 1.40-1.48 (2H, m, H-10),

1

.60-1.66 (2H, m, H-9), 3.61 (2H, t, J 6.9 Hz, H-8), 4.71 (2H, s, H-6), 7.84 (1H, dd, J 3.0 and 9.0

13

Hz, H-4’), 7.92 (1H, d, J 9.0 Hz, H-3’), 8.01 (1H, d, J 3.0 Hz, H-6’), 8.66 (1H, s, H-5); C NMR

DMSO-d , 125.0 MHz APT) δ: 13.6 (C-11), 18.8 (C-10), 31.2 (C-9), 63.0 (C-6), 69.4 (C-8),

25.8 (C-5), 127.4 (C-2’), 128.1 (C-6’), 131.3 (C-4’), 131.9(C-3’), 132.4 (C-5’), 135.5 (C-1’),

(

6

1

4

44.4 (C-4). Anal. Calcd for C13

.47; N, 13.63.

2 3

H15Cl N O: C, 52.01; H, 5.04; N, 14.00. Found: C, 51.52; H,

4

.1.3.7 1-(2,5-dichlorophenyl)-4-(ethoxymethyl)-1H-1,2,3-triazole (14g). Yellow oil; IR ν

max

-1

(cm ): 3141, 2975, 2868, 1732, 1588, 1487, 1448, 1376, 1231, 1097, 1038, 874, 809, 698, 671,

1

6

8

51; H NMR (DMSO-d , 500.00 MHz) δ: 1.27 (3H, t, J 3.9 Hz, H-9), 3.67 (2H, q, J3.9 Hz, H-

6

), 4.70 (s, 2H, H-6), 7.84 (1H, dd, J 1.5 and 5.4Hz), 7.92 (1H, d, J 5.4 Hz), 8.02 (1H, d, J 1.5

1

3

Hz, H-6’), 8.63 (1H, s, H-5); C NMR (CDCl

3

, 125.0 MHz APT) δ: 14.9 (C-9), 62.8 (C-6), 65.0

(C-8), 125.8 (C-5), 127.4 (C-2’), 128.0 (C-6’), 131.2 (C-4’), 131.8(C-3’), 132.4 (C-5’), 135.5 (C-

1

4

’), 144,4 (C-4). Anal. Calcd for C11

.24; N, 13.74.

2 3

H11Cl N O: C, 48.55; H, 4.07; N, 15.41. Found: C, 48.46; H,

-

1

4

3

1

.1.3.8 4-(ethoxymethyl)-2-phenyl-2H-1,2,3-triazole (23a). Yellow oil; IR ν_m_a_x(cm ): 3142,

066, 3052, 2976, 2930, 2870, 2455, 1949, 1878, 1741, 1599, 1499, 1463, 1415, 1370, 1352,

312, 1261, 1230, 1170, 1102, 1040, 966, 911, 850, 756; H NMR (CDCl , 500.00 MHz) δ: 1.19

1

3

(

7

3H, t, J 7.0 Hz, CH ), 3.55 (2H, q, J 7.0 Hz, H-8), 4.61 (2H, s, H-6), 7.24-7.29 (1H, m, H-4’),

.36-7.43 (2H, m, H-3’ and H-5’), 7.73 (1H, s, H-4), 7.96-8.00 (2H, m, H-2’ and H-6’); C

3

1

3

NMR (CDCl , 125.0 MHz APT) δ: 15.0 (C-9), 63.7 (C-6), 66.1 (C-8), 118.7 (C-4’), 127.3 (C-3’

3

and C-5’), 129.1 (C-2’ and C-6’), 134.8 (C-4), 139.7 (C-1’), 146.8 (C-4). Anal. Calcd for

C H N O: C, 65.01; H, 6.45; N, 20.68. Found: C, 63.81; H, 6.25; N, 20.12.

11 13 3

1

4

3

1

5

3

.1.3.9 4-(butoxymethyl)-2-phenyl-2H-1,2,3-triazole (23b); Yellow oil; IR ν_m_a_x(cm- ): 3125,

078, 3066, 3053, 2959, 2933, 2871, 2454, 1949, 1876, 1742, 1599, 1500, 1464, 1415, 1355,

313, 1261, 1231, 1168, 1155, 1102, 1038, 966, 849, 756, 703, 691, 666; H NMR (DMSO-d ,

00.00 MHz) δ: 0.93 (3H, t, J 7.3 Hz,CH ), 1.34-1.36 (2H, m, H-10), 1.57-1.67 (2H, m, H-9),

.55 (2H, t, J 6.6 Hz, H-8), 4.68 (2H, s, H-6), 7.30-7.36 (1H, m, H-4’), 7.43-7.50 (2H, m, H-3’

1

6

3

1

3

and H-5’), 7.79 (1H, s, H-4), 8.03-8.07 (2H, m, H-2’ and H-6’); C NMR (DMSO-d , 125.0

6

MHz APT) δ: 13.8 (C-11), 19.2 (C-10), 31.6 (C-9), 63.9 (C-6), 70.6 (C-8), 118.7 (C-4’), 127.3

(C-3’ and C-5’), 129.1 (C-2’ and C-6’), 134.7 (C-4), 139.7 (C-1’), 147.0 (C-5). Anal. Calcd for

C H N O: C, 67.51; H, 7.41; N, 18.17 Found: C, 66.98; H, 7.61; N, 17.65.

13

17

3

4

.1.4 General procedure for preparation of 15a-b

13

ACCEPTED MANUSCRIPT

Into a round-bottom flask equipped with a magnetic stirring bar already containing a

solution of 10 mmols of 1,2,3-triazoles type 12 in 27.5 mL of DMSO was added 11 mmols of

IBX. This mixture was stirred at room temperature for 4 h. Next, distilled water (20 mL) was

added, and stirring was continued for 15 minutes at room temperature. Subsequently, the mixture

was filtered, extracted with ethyl acetate and dried over with MgSO . The product was purified

4

via silica-gel column chromatography using gradient mixture of hexane-ethyl acetate to afford

the pure derivatives 11 and 15a-b.

o

4

9

.1.4.1 1-Phenyl-1H-1,2,3-triazole-4-carbaldehyde (11). White solid, m.p. 96-98 C (m.p. lit. 95-

-1

1

6 ºC [7]); IR νmax (cm ): 3431, 3131, 1691, 1529, 1209, 1168, 990, 853, 782, 761, 683; H

, 500.00 MHz) δ: 7.65-7.70 (1H, m, H-4’), 7.73-7.79 (2H, m, H-3’ and H-5’),

.02-8.12 (2H, m, H-2’ and H-6’), 9.66 (1H, s, H-5), 10.24 (1H, s, H-6); C NMR (DMSO-d ,

6

NMR (DMSO-d

6

13

8

1

25.0 MHz APT) δ: 120.7 (C-2’ and C-6’), 126.1 (C-5), 129.5 (C-3’ and C-5’), 129.9 (C-4’),

36.0 (C-1’), 147.6 (C-4), 184.8 (C-6).

4

1

7

1

5

.1.4.2 1-(4-Chlorophenyl)-1H-1,2,3-triazole-4-carbaldehyde (15a). Yellow solid, m.p. 159-

o

1

60 C (m.p. lit. 159-160 ºC [7]); IR ν

499, 1355, 1254, 1216, 1099, 1053, 989, 877, 828, 773; H NMR (DMSO-d , 500.00 MHz) δ:

(cm- ): 3096, 3041, 2844, 2360, 1905, 1705, 1531,

max

1

6

.71 (2H, d, J 5.4 Hz, H-3’ and H-5’), 8.02 (2H, d, J 5.4 Hz, H-2” and H-6”), 9.56 (1H, s, H-5),

1

3

0.12 (1H, s, H-6); C NMR (DMSO-d , 125.0 MHz APT) δ: 122.5 (C-2’ and C-6’), 126.3 (C-

6

), 129.9 (C-3’ and C-5’), 133.9 (C-4), 134.8 (C-4’), 147.6 (C-4), 184.9 (C-6).

4

1

.1.4.3 1-(2,5-Dichlorophenyl)-1H-1,2,3-triazole-4-carbaldehyde (15b). White solid, m.p. 160-

o

-1

61 C (m.p. lit. 163-164 ºC [7]); IR ν

(cm ): 3138, 3092, 2860, 1704, 1573, 1529, 1487,

max

1

456, 1402, 1371, 1261, 1199, 1170, 1142, 1100,1075, 1042, 982, 857, 816, 765, 698, 649; H

NMR (DMSO-d , 500.00 MHz) δ: 8.03-8.05 (1H, m, H-4’), 8.10-8.11 (1H, m, H-3’), 8.28 (1H,

6

1

3

s, H-6’), 9.62 (1H, s, H-5), 10.38 (1H, s, H-6); C NMR (DMSO-d , 125.0 MHz APT) δ: 127.8

6

(

C-2’), 128.4 (C-6’), 130.6 (C-5), 132.0 (C-4’), 132.1 (C-3’), 132.6 (C-5’), 134.7 (C-1’), 146.7

C-4), 184.7 (C-6).

4

.1.5 General Procedure for preparation of 16a and 19a

In a round-bottom flask equipped with a magnetic stirring bar already containing a suspension of

anhydrous THF (50 mL) and NaH (2.0 equiv.) was added methyltriphenylphosphonium bromide

(2.90 mmols) under argon atmosphere. The mixture was stirred during 15 minutes in ultrasound

bath and acquired an intense yellow color. The agitation was maintained for 2 hours at room

temperature before the triazole-substituted aldehyde (1.45 mmols) was added. After 1-2 hours,

the reaction mixture was poured into distilled water at 0 °C. This mixture was extracted with

ethyl acetate (3 x 50 mL). The organic phases were combined and washed with distilled water (2

x 50 mL) and dried over with anhydrous sodium sulfate. The product was purified via flash

column chromatography using gradient mixture of hexane-ethyl acetate.

o

4

[

.1.5.1 1-phenyl-4-vinyl-1H-1,2,3-triazole (16a). White solid, m.p. 83-85 C (m.p. lit 85-87 ºC

-1

1

7]); IR ν_m_a_x(cm ):3134, 1597, 1500, 1465, 1236, 1043, 996, 926, 827, 757, 687; H NMR

(

CDCl , 300.00 MHz) δ: 5.42 (1H, dd, J 1.2and 11.0 Hz, H-6), 6.02 (1H, dd, J 1.2 and 17.8Hz,

3

H-7a), 6.80 (1H, dd, J 11.0 and 17.6 Hz, H-7), 7.41-7.75 (5H, m,H-2’, H-3’, H-4’, H-5’ and H-

14

ACCEPTED MANUSCRIPT

1

3

6

2

4

3

’), 7.95 (1H, s, H-5); C NMR (CDCl , 75.0 MHz APT) δ: 116.4 (C-7), 120.1 (C-5), 125.7 (C-

’and C-6’), 128.7 (C-3’and C-5’ or C-4’), 129.9 (C-3’and C-5’ or C-4’), 136.6 (C-6), 146.3 (C-

).

-

1

4

1

.1.5.2 2-phenyl-4-vinyl-2H-1,2,3-triazole (19a). Yellow oil; IR ν

(cm ): 2923, 2857, 2359,

max

1

599, 1502, 1461, 1375, 1313, 955, 915, 753; H NMR (CDCl , 300.00 MHz)δ:5.49 (1H, dd,

3

J1.2 and 11.3 Hz, H-6), 5.96 (1H, dd, J 1.2 and 17.7Hz, H-7a), 6.82 (1H, dd, J 11.3 and 17.7 Hz,

H-7b), 7.31-7.37 (1H,m, H-4’), 7.45-7.51 (2H, m, H-3’ and H-5’), 7.85 (1H, s, H-4), 8.05-8.08

1

3

(

1H, m, H-2’ and H-3’); C NMR (CDCl , 75.0 MHz APT) δ: 117.9 (C-1’ and C-7), 118.6 (C-

3

6

), 125.4 (C-3’ and C-5’), 127.2 (C-2’ and C-6’), 129.1 (C-4’), 132.7 (C-4), 147.6 (C-5); Anal.

Calcd for C10 : C, 70.16; H, 5.30; N, 24.54. Found: C, 70.26; H, 5.25; N, 24.12.

9 3

H N

4

.1.6 General Procedure for preparation of 17a-l and 20a-i

Into a round-bottom flask equipped with a magnetic stirring bar already containing a solution of

.89 mmols of aldehyde triazole 11, 15a-b or 18a-e in 50 mL of ethanol were added

2

phenylhydrazine hydrochloride (2.89 mmols) or hydroxylamine hydrochloride (20 mmols) and a

few drops of sulfuric acid. After 24 hours of stirring at room temperature, water was added, and

the product was collected via vacuum filtration.

4

1

5

.1.6.2 (E)-1-phenyl-4-((2-phenylhydrazono)methyl)-1H-1,2,3-triazole (17a). Brown solid, m.p.

-

1

24-125 ºC; IR νmax (cm ): 3276, 3144, 3042, 1599, 1531, 1496, 1370, 1270, 1173, 1107, 1067,

1

046, 907, 888, 867, 737, 693; H NMR (DMSO-d

6

, 500.00 MHz) δ: 7.16-7.19 (3H, m, H-3’, H-

’ and H-6), 7.24-7.29 (2H, m, H-2” and H-6”), 7.32-7.38 (1H, m, H-4’), 7.46-7.52 (2H, m, H-3’

1

3

and H-5’), 7.80 (1H, s, H-4), 8.01-8.05 (2H, m, H-2’ and H-6’), 11.06 (1H, s, H-8); C NMR

DMSO-d , 125.0 MHz APT) δ: 112.7 (C-5), 120.1, 120.7, 121.8, 122.9, 129.2, 129.4 (C-2’, C-

(

6

3

1

2

’, C-4’, C-5’, C-6’, C-2”, C-3”, C-4”, C-5” and C-6”), 130.0 (C-7), 136.2 (C-1’), 143.0 (C-1”),

44.7 (C-4); Anal. Calcd for C H N : C, 68.42; H, 4.98; N, 25.55. Found: C, 68.04; H, 5.21; N,

6.27.

1

3

13

5

4

.1.6.2 (E)-4-((2-(2,5-dichlorophenyl)hydrazono)methyl)-1-phenyl-1H-1,2,3-triazole (17b).

-1

Brown solid, m.p. 164-165 ºC; IR νmax (cm ): 3412, 3238, 2361, 1596, 1533, 1494, 1453, 1403,

1

3

1

367, 1262, 1197, 1137, 1097, 1082, 1042, 847, 823, 753, 684, 626; H NMR (DMSO-d

6

,

00.00 MHz) δ: 7.03-7.06 (1H, m, H-4”), 7.59 (2H, d, J 5.4 Hz, H-4” and H-6”), 7.67-7.71 (2H,

m, H-3” and H-4”), 7.74-7.80 (2H, m, H-3’ and H-5’), 8.09-8.13 (2H, m, H-2’ and H-6’), 8,40

1

3

(

1

1H, s, H-5), 9.30 (1H, s, H-6), 12.12 (1H, s, H-7); C NMR (DMSO-d

6

, 75.0 MHz APT) δ:

17.0 (C-5), 118.6 (C-6”), 122.8 (C-4”), 128.2 (C-3”), 129.7 (C-2’ and C-6’), 129.8 (C-2”),

30.0 (C-3’ and C-5’), 134.7 (C-4’), 137.7 (C-5”), 138.8 (C-1’), 139.5 (C-6), 144.3 (C-1”), 145.4

(

C-4); Anal. Calcd for C H Cl N : C, 54.23; H, 3.34; N, 21.08. Found: C, 54.21; H, 2.92; N,

17 15 2 5

2

0.76

.1.6.3 (E)-4-((2-(4-fluorophenyl)hydrazono)methyl)-1-phenyl-1H-1,2,3-triazole (17c). Yellow

4

-1

solid, m.p. 206-207 ºC; IR ν

1

(cm ): 3275, 3149, 1605, 1592, 1502, 1369, 1209, 1210, 1110,

max

1

047,829, 759, 691; H NMR (DMSO-d

6

, 300.00 MHz) δ: 7.18-7.27 (2H, m, H-3” and H-5”),

15

ACCEPTED MANUSCRIPT

7

.32-7.37 (2H, m, H-2” and H-6”), 7.32-7.38 (1H, m, H-4’), 7.45 (1H, s, H-5), 7.46-7.52 (2H, m,

1

3

H-3’ and H-5’), 8.01-8.05 (2H, m, H-2’ and H-6’), 9.26 (1H, s, H-6), 11.06 (1H, s, H-8); C

NMR (DMSO-d , 75.0 MHz APT) δ: 113.9 (d, J 7,74 Hz, C-3” and C-5”), 115.6, 115.9, 120.1,

6

1

22.1, 122.9, 128.8, 129.4 (C-2’, C-3’, C-4’, C-5’, C-6’, C-2”, C-6”), 120.8 (C-5), 130.1 (C-6),

1

36.2 (C-1’), 141.4 (C-1”), 141.7 (C-4), 144.4 (d, J 213.4 Hz, C-4”); Anal. Calcd for C H FN :

1

5

12

5

C, 64.05; H, 4.30; N, 24.90. Found: C, 64.11; H, 4.25; N, 24.85.

4

.1.6.4 (E)-4-((2-(4-Chlorophenyl)hydrazono)methyl)-1-phenyl-1H-1,2,3-triazole (17d). Yellow

-1

solid, m.p. 143-145 ºC; IR ν

(cm ): 3266, 1598, 1527, 1490, 1367, 1263, 1172, 1075, 1045,

max

1

9

6

7

1

2

06, 865, 822, 758, 688; H NMR (DMSO-d

6

, 500.00 MHz) δ: 7.20 (1H, d, J 5.4 Hz, H-2” or H-

”), 7.34-7.39 (2H, m, H-3” and H-5”), 7.43 (1H, d,J 5.4 Hz, H-2” or H-6”), 7.49 (1H, s, H-5),

.61-7.80 (3H, m, H-3’, H-4’ and H-5’), 8.07-8.14 (2H, m, H-2’, H-3’ and H-6’), 8.40 (H-6),

1

3

0.70 (H-8); C NMR (DMSO-d

6

, 125.0 MHz APT) δ: 113.5, 114.3, 120.1, 120.7, 122.8, 128.8,

29.0, 129.9 (C-2’, C-3’, C-4’, C-5’, C-6’, C-2”, C-3”, C-5” and C-6”), 123.5 (C-5), 130.1 (C-6),

36.2 (C-1’), 142.8 (C-1”), 145.6 (C-4); Anal. Calcd for C15

3.52. Found: C, 60.48; H, 4.02; N, 22.91.

H12ClN5: C, 60.51; H, 4.06; N,

4

.1.6.5 (E)-4-((2-(4-bromophenyl)hydrazono)methyl)-1-phenyl-1H-1,2,3-triazole (17e). Yellow

-1

solid, m.p. 228-229 ºC; IR ν

(cm ): 3267, 3145, 1593, 1529, 1489, 1368, 1264, 1068, 1047,

max

1

8

22, 760; H NMR (DMSO-d , 500.00 MHz) δ: 7.28-7.33 (2H, m, H-3” and H-5”), 7.50 (1H, s,

6

H-5), 7.52-7.58 (2H, m, H-2” and H-6”), 7.68-7.88 (3H, m, H-3’, H-4’ and H-5’), 8.07-8.10

1

3

(

2H, m, H-2’ and H-6’), 9.30 (1H, s, H-6), 11.28 (1H, s, H-8); C NMR (DMSO-d

APT) δ: 111.0 (C-4”), 114.8 (C-5), 123.1 (C-2” and C-6”), 129.4 (C-3’, C-4’ and C-5’), 130.0

C-2’ and C-6’), 131.9 (C-6), 136.2 (C-1’), 142.7 (C-1”), 144.1 (C-4); Anal. Calcd for

: C, 52.65; H, 3.53; N, 20.47. Found: C, 52.31; H, 3.68; N, 20.13.

6

, 125.0 MHz

(

15 5

C H12BrN

4

.1.6.6 (E)-4-((2-(2,5-dimethylphenyl)hydrazono)methyl)-1-phenyl-1H-1,2,3-triazole (17f).

-1

Yellow solid, m.p. 109-111 ºC; IR ν

7

(cm ): 3268, 1597, 1489, 1293, 1264, 1068, 1047, 821,

max

1

57, 689; H NMR (CDCl , 500.00 MHz)δ: 2.20 (2 x CH ), 6.72 (1H, d, J 8.5 Hz, H-4”), 7.14

3

(

1H, d, H-3”), 7.44 (s, 1H, H-6”), 7.47 (1H, s, H-5), 7.63-7.69 (m, 3H, H-3’, H-4’ and H-5’),

1

3

8

1

4

5

2

.08-8.13 (m, 2H, H-2’ and H-6’), 9.25 (s, 1H, H-5), 11.56 (1H, s, H-7); C NMR (CDCl ,

3

25.0 MHz APT) δ: 16.6 (CH ), 21.1 (CH ), 112.0 (C-6”), 117.4 (C-2”), 120.3 (C-5), 120.6 (C-

3

”), 121.5 (C-2’ and C-6’), 122.7 (C-2”), 129.3 (C-3’ and C-5’ and C-4’), 130.2 (C-6), 135.9 (C-

”), 136.2 (C-1’), 142.3 (C-1”), 143.5 (C-4); Anal. Calcd for C17

4.04. Found: C, 69.66; H, 5.89; N, 23.34

17 5

H N : C, 70.08; H, 5.88; N,

4

.1.6.7

(E)-4-((2-(2,4-dinitrophenyl)hydrazono)methyl)-1-phenyl-1H-1,2,3-triazole

(17g).

-1

Orange solid, m.p. 190-192 ºC; IR ν_m_a_x(cm ): 3282, 3147, 3112, 2973, 1619, 1586, 1513, 1500,

1

418, 1334, 1311, 1220, 1136, 1087, 1045, 830, 768; H NMR (CDCl , 500.00 MHz) δ: 7.67

3

(1H, t, J 7.8 Hz, H-4’), 7.77 (2H, t, J 7.8 Hz, H-3’ and H-5’), 8.12 (2H, d, J7.8 Hz, H-2” and H-

6

”), 8.23 (1H, d, J 9.8 Hz, H-2”), 8.50 (1H, dd, J 2.7 and 9.8 Hz, H-3”), 8.71 (1H, s, H-4), 8.98

1

3

(1H, d, J 2.7 Hz, H-5”), 9.03 (1H, s, H-8); C NMR (CDCl , 125.0 MHz APT) δ: 116.8 (C-2”),

3

1

2

20.3 (C-5), 121.9 (C-2’ and C-6’), 123.0 (C-3”), 129.1 (C-3’ and C-5’), 129.5(C-4’), 129.8 (C-

”), 130.0 (C-5”), 136.3 (C-1’), 137.6 (C-4”), 140.8 (C-6), 144.1 (C-1”), 144.6 (C-4); Anal.

Calcd for C H N O : C, 50.99; H, 3.14; N, 27.75. Found: C, 50.79; H, 3.11; N, 27.36

1

5

11

7

4

16

ACCEPTED MANUSCRIPT

4

.1.6.8 (E)-N’-((1-phenyl-1H-1,2,3-triazol-4-yl)methylene)isonicotinohydrazide [7] (17h). White

-1

solid, m.p. 212-213 ºC (m.p. lit. 212-213 ºC); IR ν

1

(cm ): 3436, 2980, 2861, 1672, 1585,

max

1

552, 1499, 1300, 1056, 763, 753, 681; H NMR (DMSO-d , 500.00 MHz) δ: 7.64 (t, 1H, J 7.5

6

Hz, H-4’), 7.74 (t, 2H, J 7.5 Hz, H-3’ and H-5’), 7.96 (d, 2H, J 6.0 Hz, H-2” and H-5”), 8.13 (d,

2

1

H, J 7.5 Hz, H-2’ and H-6’), 8.77 (s, 1H, H-5), 8.92 (d, 2H, J 6.0 Hz, H-3” and H-4”), 9.43 (s,

1

3

H, H-6), 12.2 (s, 1H, H-7); C NMR (DMSO-d , 125.0 MHz APT) δ: 120.4 (C-4), 121.7 (C-2’

6

and C-6’), 129.2 (C-2” and C-6”), 130.0 (C-3’, C-4’ and C-5’), 136.4 (C-1’), 140.4 (C-1”), 141.0

C-3” and C-4”), 144.1 (C-4), 150.5 (C-6), 161,8 (C-8).

(

4

.1.6.9 (E)-1-(4-chlorophenyl)-4-((2-phenylhydrazono)methyl)-1H-1,2,3-triazole (17i). White

-1

solid, m.p. 211-213 ºC; IR νmax (cm ): 3272, 1596, 1526, 1487, 1368, 1265, 1170, 1092, 1042,

1

014, 986, 864, 834, 803, 754, 683; H NMR (DMSO-d , 500.00 MHz) δ: 6.98 (1H, t, J 4.5 Hz,

6

H-4”), 7.32 (2H, d, J 4.5 Hz, H-3” and H-5”), 7.40 (2H, t, J 4.5 Hz, H-2” and H-6”), 7.45 (1H, s,

H-5), 7.85-7.87 (2H, m, H-2” and H-6”), 8.12-8.15 (2H, m, H-3” and H-5”), 9.29 (1H, s, H-6),

1

3

1

4

1.30 (1H, s, H-7); C NMR (DMSO-d , 125.0 MHz APT) δ: 118.4 (C-5), 125.8, 127.4, 128.1,

6

28.2, 128.6, 134,9 (C-2’, C-3’, C-5’, C-6’, C-2”, C-3”, C-4”, C-5” and C-6”), 135.7 (C-6),

39.4 (C-4’), 140.7 (C-1’), 148.7 (C-1”), 150,3 (C-4); Anal. Calcd for C H ClN : C, 60.51; H,

.07; N, 23.52. Found: C, 60.58; H, 4.02; N, 22.35.

1

5

12

5

4

.1.6.10 (E)-4-((2-(4-bromophenyl)hydrazono)methyl)-1-(4-chlorophenyl)-1H-1,2,3-triazole

-1

(17j). White solid, m.p. 205-206 ºC; IR νmax (cm ): 3429, 3267, 3144, 1593, 1527, 1486, 1291,

1

7

1

6

261, 1171, 1100, 1069, 1045, 987, 905, 863, 818, 703; H NMR (DMSO-d , 500.00 MHz) δ:

.30 (d, 2H, J 8,8 Hz, H-2” e H-6”), 7.49 (s, 1H, H-5), 7.54 (d, 2H, J 8.8 Hz, H-3”and H-5”),

.84-7.86 (m, 2H, H-2’ and H-6’), 8.12-8.14 (m, 2H, H-3’and H-5’), 9.31 (s, 1H, H-6), 11.32 (s,

1

3

H, H-7); C NMR (DMSO-d , 125.0 MHz APT) δ: 113.5 (C-5), 114.2, 121.7, 122.3, 122.6,

6

23.0, 128.9 (C-2’, C-3’, C-5’, C-6’, C-2”, C-3”, C-5”, C-6”), 123.4 (C-4”), 129.9 (C-6), 133.7

(

C-4’), 134.9 (C-1’), 142,7 (C-1”), 143.6 (C-4). Anal. Calcd for C H BrClN : C, 47.83; H,

13 11 5

2

.94; N, 18.59. Found: C, 48.31; H, 3.11; N, 18.36.

4

.1.6.11 (E)-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde oxime (17k). White solid, m.p. 97-99

-1

ºC; IR νmax (cm ): 3411, 3214, 3187, 3156, 3091, 3021, 2989, 2929, 2882, 2801, 2361, 2348,

1

661, 1599, 1501, 1466, 1250, 1236, 1121, 1161, 1051, 987; H NMR (DMSO-d

6

, 500.00 MHz)

δ: 7.48-7.54 (1H, m, H-4’), 7.58-7.63 (2H, m, H-3’ and H-5’), 7.92-7.96 (2H, m, H-2’ and H-6’),

1

3

8

4

.24 (1H, s, H-5), 9.04 (1H, s, H-6); C NMR (DMSO-d

6

, 125.0 MHz APT) δ: 120.5 (C-

’),120.8 (C-5), 129.1 (C-3’ and C-5’), 130.1 (C-2’ and C-6’), 136.6 (C-1’), 140.2 (C-6), 142.4

(

C-4); Anal. Calcd for C H N O: C, 57.4; H, 4.3; N, 29.8. Found: C, 57.8; H, 4.7; N, 30.3

9 8 4

4

6

8

5

1

.1.6.12 (E)-1-(4-chlorophenyl)-1H-1,2,3-triazole-4-carbaldehyde oxime (17l). White solid, m.p.

-1

5-66 ºC; IR ν (cm ): 3101, 3028, 2930, 2821, 1503, 1345, 1269, 1235, 1098, 1039, 982, 924,

max

1

21, 699; H NMR (CDCl , 500.00 MHz) δ: 7.77-7.83 (2H, m, H-3’ and H-5’), 7.91 (1H, s, H-

3

1

3

), 8.09-8.17 (2H, m, H-2’ and H-6’), 9.36 (1H, s, H-6), 12.20 (1H, s, OH); C NMR (CDCl ,

3

25.0 MHz APT) δ: 122.3 (C-5), 129.8 (C-3’ and C-5’), 133.3 (C-4’), 135.2 (C-1’), 137.3 (C-2’

and C-6’), 138.5 (C-4), 142.5 (C-6); Anal. Calcd for C

Found: C, 47.83; H, 3.41; N, 24.45

9 7 4

H ClN O: C, 48.55; H, 3.17; N, 25.17.

17

ACCEPTED MANUSCRIPT

4

.1.6.13 (E)-2-phenyl-4-((2-phenylhydrazono)methyl)-2H-1,2,3-triazole (20a). Brown solid,

-1

m.p. 111-112 ºC; IR ν_m_a_x(cm ): 3271, 3114, 3028, 2963, 2924, 2854, 1599, 1575, 1497, 1399,

1

5

7

340, 1309, 1262, 1122, 1066, 1036, 966, 909, 865, 792, 753, 687, 654; H NMR (CDCl ,

3

00.00 MHz) δ: 7.16-7.19 (3H, m, H-3’, H-5’ and H-6), 7.24-7.29 (2H, m, H-2” and H-6”), 7.32-

.38 (1H, m, H-4’), 7.46-7.52 (2H, m, H-3’ and H-5’), 7.80 (1H, s, H-4), 8.01-8.05 (2H, m, H-2’

1

3

and H-6’), 11.06 (1H, s, H-8); C NMR (CDCl , 75.0 MHz APT) δ: 112.9 (C-4), 118.4, 119.4,

3

1

4

20.6, 127.6, 128.9, 129.1 (C-2’, C-3’, C-4’, C-5’, C-6’, C-2”, C-3”, C-4”, C-5” and C-6”),

34.8 (C-7), 138.8 (C-1’), 143.0 (C-5), 143.8 (C-1”); Anal. Calcd for C H N : C, 68.42; H,

.98; N, 25.55. Found: C, 68.22; H, 4.88; N, 26.60.

1

3

13

5

4

.1.6.14 (E)-4-((2-(2,5-dichlorophenyl)hydrazono)methyl)-2-phenyl-2H-1,2,3-triazole (20b).

-1

Brown solid, m.p. 164-165 ºC; IR ν_m_a_x(cm ): 3260, 2939, 1591, 1498, 1461, 1342, 1263, 1136,

1

2

1

096, 1043, 973, 873, 836, 814, 754, 662; H NMR (DMSO-d , 500.00 MHz) δ: 7.10 (dd, 1H, J

6

.7 and 8.5 Hz, H-4”), 7.61-7.66 (m, H-6”), 7.73-7.81 (m, 3H, H-2”, H-3” and H-4’), 7,80 (s, 1H,

H-5), 8.24-8.27 (m, 2H, J H-3’ and H-5’), 8.24-8.27 (m, 2H, H-2’ and H-6’), 8.60 (s, 1H, H-6),

1

3

1

1.53 (s, 1H, H-7); C NMR (DMSO-d , 125.0 MHz APT) δ: 113.0 (C-4), 115.2 (C-2”), 130.8,

6

29.9, 129.7, 128.5, 125.0, 120.6, 119.1 and 118.5 (C-2”, C-4”, C-6”, C-2’, C-3’, C-4’, C-5’ and

C-6’), 133.1 (C-5”), 137.3 (C-6), 138.5 (C-1’), 141.4 (C-1”), 142.4 (C-4); Anal. Calcd for

C H Cl N : C, 54.23; H, 3.34; N, 21.08. Found: C, 54.14; H, 3.51; N, 21.12.

15

11

2

5

4

.1.6.15 (E)-4-((2-(4-fluorophenyl)hydrazono)methyl)-2-phenyl-2H-1,2,3-triazole (20c). Brown

-1

solid, m.p. 113-115 ºC; IR νmax (cm ): 3260, 1683, 1592, 1499, 1352, 1264, 1212, 1152, 969,

8

7

1

21, 755, 687, 656; H NMR (DMSO-d

6

, 500.00 MHz) δ: 7.20 (2H, d, J 2.0 Hz, H-2” and H-6”);

.23 (1H, s, H-4), 7.51-7.57 (1H, m, H-3” or H-5”), 7.49-7.60 (3H, m, H-3” or H-5”, H-2’ and

1

3

H-6’), 8.12-8.15 (3H, m, H-3’, H-4’ and H-5’), 8.49 (1H, s, H-6), 10.75 (H-8); C NMR

(

DMSO-d , 125.0 MHz APT) δ: 113.3 (d, J 7.4 Hz, C-3” or C-5”), 115.5 (C-2” and C-6”), 115.6

6

(C-2’ and C-6’), 118.2 (C-5), 126.7 (C-3’ and C-5’), 127.6 (C-4’), 129.7 (C-6), 139.1 (C-1”),

1

4

41.3 (C-1’), 147.0 (C-5), 156.3 (d, J 234.4 Hz, C-4”); Anal. Calcd for C H FN : C, 64.05; H,

.30; N, 24.90. Found: C, 63.72; H, 4.31; N, 23.24

15 12 5

4

.1.6.16 (E)-4-((2-(4-chlorophenyl)hydrazono)methyl)-2-phenyl-2H-1,2,3-triazole (20d). Yellow

-1

solid, m.p. 143-145 ºC; IR νmax (cm ): 3266, 1598, 1527, 1490, 1367, 1263, 1172, 1075, 1045,

9

6

1

06, 865, 822, 758, 688; H NMR (DMSO-d

6

, 500.00 MHz) δ: 7.21-7.25 (2H, m, H-2” and H-

”), 7.38-7.42 (2H, m, H-3” and H-5”), 7.46 (1H, s, H-4), 7.52-7.57 (1H, m, H-4), 7.67-7.73 (2H,

1

3

m, H-3’and H-5’), 8.12-8.16 (2H, m, H-2’ and H-6’), 8.50 (H-6), 10.88 (H-8); C NMR

DMSO-d , 125.0 MHz APT) δ:113.7 (C-4), 114.9, 118.2, 118.9, 127.6, 129.0 (C-2’, C-3’, C-4’,

(

6

C-5’, C-6’, C-2”, C-3”, C-4”, C-5” and C-6”), 129.7 (C-7), 122.8 (C-1’), 139.0 (C-1”), 144,7 (C-

4

); Anal. Calcd for C H ClN5: C, 60.51; H, 4.06; N, 23.52. Found: C, 60.58; H, 4.02; N, 23.35.

15 12

4

.1.6.17 (E)-4-((2-(4-bromophenyl)hydrazono)methyl)-2-phenyl-2H-1,2,3-triazole (20e). Yellow

-1

solid, m.p. 117-118 ºC; IR ν_m_a_x(cm ): 3313, 2360, 2339, 1595, 1495, 1401, 1273, 1255, 1152,

1

2

8

1

098, 1070, 962, 890, 825, 761, 658; H NMR (DMSO-d , 500.00 MHz) δ: 7.16-7.20 (2H, m, H-

6

” and H-6”), 7.49-7.60 (3H, m, H-3”, H-5” and H-4’), 7.66-7.73 (2H, m, H-3’ and H-5’), 8.12-

1

3

6

.14 (2H, m, H-2’ and H-6’), 8.16 (1H, s, H-4), 8.50 (H-6), 10.90 (H-8); C NMR (DMSO-d ,

25.0 MHz APT) δ: 110.4 (C-4”), 114.2 (C-2” and C-6”), 115.3 (C-2’ and C-6’), 118.2 (C-4),

27.6 (C-3’, C-4’ and C-5’), 129.7 (C-3” and C-5”), 131.8 (C-6), 139.0 (C-1’), 144.0 (C-1”),

18

ACCEPTED MANUSCRIPT

1

46.8 (C-5); Anal. Calcd for C15

5

H12BrN : C, 60.51; H, 3.53; N, 20.47. Found: C, 52.52; H, 3.61;

N, 19.63

4

.1.6.18 (E)-4-((2-(2,4-dimethylphenyl)hydrazono)methyl)-2-phenyl-2H-1,2,3-triazole (20f).

-1

Yellow solid, m.p. 174-175 ºC; IR ν_m_a_x(cm ): 3299, 3129, 3039, 2965, 2915, 2853, 2359, 1865,

1

598, 1582, 1534, 1501, 1486, 1403, 1373, 1287, 1272, 1143, 1039, 952, 866, 802, 757; H

NMR (CDCl , 500.00 MHz) δ: 2.41 (3H, s, CH ), 2.49 (3H, s, CH ), 6.78 (1H, dd, J 1.2 and 7.6

3

Hz, H-3”), 7.18 (1H, d, J 7.6, H-5”), 7.50 (1H, d, J 1.2 Hz, H-5”), 7.60 (1H,s, H-6), 7.73-7.80

(

2H, m, H-3’ and H-5’), 8.19-8.23 (2H, m, H-2” and H-6”), 8.60 (1H,s, H-4), 10.98 (1H, s, H-8);

1

3

C NMR (CDCl , 125.0 MHz APT) δ: 112.2 (C-4), 117.6 (C-6”), 118.6, 121.1, 121.2, 128.3,

1

6

29.9, 130.3, 136.2 (C-2’, C-3’, C-4’, C-5’, C-6’, C-2”, C-3” and C-5”), 136.8 (C-4”), 138.8 (C-

”), 141.8 (C-1’), 143.1 (C-5); Anal. Calcd for C17

9.53; H, 5.86; N, 23.46.

17 5

H N : C, 70.08; H, 5.88; N, 24.04. Found: C,

4

.1.6.19 (E)-4-((2-(2,4-dinitrophenyl)hydrazono)methyl)-2-phenyl-2H-1,2,3-triazole [43] (20g).

o

-1

Orange solid, m.p. 189-190 ºC (m.p. lit. 198-200 C); IR ν

1

5

(cm ): 3286, 3131, 1620, 1587,

max

1

517, 1497, 1425, 1366, 1335, 1312, 1294, 1270, 1220, 1145, 1075, 961, 757; H NMR (CDCl ,

3

00.00 MHz) δ: 7.56-7.61 (1H, m, H-4’), 7.69-7.78 (2H, m, H-3’ and H-5’), 8.11-8.18 (2H, m,

H-2” and H-6”), 8.25 (1H, d, J 9.8 Hz, H-2”), 8.50 (1H, dd, J 2.7 and 9.8 Hz, H-3”), 8.71 (1H, s,

1

3

H-4), 8.98 (1H, d, J 2.7 Hz, H-5”), 9.03 (1H, s, H-8); C NMR (CDCl , 125.0 MHz APT) δ:

3

1

4

17.0 (C-2”), 118.5 (C-5), 118.8 (C-2’ and C-6’), 122.8 (C-3”), 128.2 (C-3’ and C-5’), 128.7(C-

’), 130.0 (C-2”), 134.7 (C-5”), 137.6 (C-1’), 138.8 (C-4”), 139.5 (C-6), 144.2 (C-1”), 145.4 (C-

); Anal. Calcd for C15

11 7 4

H N O : C, 50.99; H, 3.14; N, 27.75. Found: C, 50.73; H, 3.11; N, 26.88.

4

.1.6.20 (E)-N’-((2-phenyl-2H-1,2,3-triazol-4-yl)methylene)isonicotinohydrazide (20h). Brown

-1

solid, m.p. 210-211 ºC; IR ν_m_a_x(cm ): 3405, 3178, 3038, 3004, 2847, 1673, 1653, 1598, 1567,

1

503, 1408, 1385, 1357, 1328, 1303, 1226, 1155, 1071, 968, 842, 797, 753, 688, 680, 665; H

NMR (DMSO-d , 300.00 MHz) δ: 7.60 (t, 1H, J=7.5 Hz, H-4’), 7.72 (t, 2H, J 7.5 Hz, H-3” and

6

H-5”), 7.97 (s, 3H, H-2” and H-5”), 8.18 (d, 2H, J 7.5 Hz, H-2’ and H-6’), 8.61 (s, 1H, H-4),

1

3

8

7

.79 (s, 1H, H-6), 11.53 (s, 1H, H-7), 8.93-9.13 (m, 2H, H-3” and H-4”); C NMR (DMSO-d ,

6

5.0 MHz APT) δ: 118.7 (C-4), 128.4 (C-2’ and C-6’), 130.0 (C-2” and C-6”), 134.7 (C-3’, C-4’

and C-5’), 139.0 (C-1’), 139.9 (C-3” and C-4”), 140.3 (C-1”), 145.4 (C-4), 150.5 (C-6), 162.0

(

C-8); Anal. Calcd for C H N O: C, 61.64; H, 4.14; N, 28.75. Found: C, 60.35; H, 4.11; N,

15 12 6

2

7.87

.1.6.21 (E)-2-phenyl-2H-1,2,3-triazole-4-carbaldehyde oxime (20i). White solid, m.p. 111-112

4

-1

ºC; IR ν_m_a_x(cm ): 3253, 3042, 2937, 2823, 1596, 1496, 1445, 1330, 1032, 969, 930, 849, 823,

7

1

55, 671; H NMR (CDCl , 500.00 MHz) δ: 7.35-7.46 (1H, m, H-4’), 7.47-7.54 (2H, m, H-3’

3

1

3

and H-5’), 8.06-8.09 (2H, m, H-2’ and H-6’), 8.14 (1H, s, H-4), 8.35 (1H, s, H-6); C NMR

CDCl , 125.0 MHz APT) δ: 121.5 (C-4’), 121.8, 130.5, 130.8, 131.9 (C-2’, C-3’, C-4’, C-5’ and

(

3

C-6’), 136.1 (C-4), 142.2 (C-1’), 145.3 (C-6); Anal. Calcd for C H N O: C, 57.4; H, 4.3; N, 29.8.

9

8

4

Found: C, 57.4; H, 4.4; N, 31.2.

.1.7 General Procedure for preparation of 18a-e

4

19

ACCEPTED MANUSCRIPT

Into a round-bottom flask containing a suspension of 5 g of glucose (27.8 mmols) in 50 mL of

water were added 83.3 mmols of the appropriate hydrazine, 14 g of sodium acetate, 150 mL of

water and 2 drops of acetic acid. After reaction was complete, the osazone was collected by

vacuum filtration.

Next, the osazone (24.7 mmols) was mixed with 8.8 g of copper sulfate pentahydrate in 185 mL

of water. The reaction was heated to reflux for 2 hours. Next, the reaction was filtered hot to

remove the copper salts and the product was crystallized at room temperature.

Finally, some of the D-arabino triazole-1,2-fenilosotriazole (56 mmols) was dissolved in 80 mL

of water and 19 mmols of sodium metaperiodate was added. The reaction medium was

vigorously stirred for 24 hours at room temperature. Upon completion of the reaction, the

reaction medium was vacuum filtered.

4

6

8

.1.7.1 2-phenyl-2H-1,2,3-triazole-4-carbaldehyde (18a). Brown solid, m.p. 67-68 ºC (m.p. lit.

o

-1

8-69 C [44]); IR νmax (cm ): 3129, 2868, 1694, 1595, 1492, 1313, 1215, 1184, 1069, 1030, 964,

1

6

75, 760, 666; H NMR (DMSO-d , 300.00 MHz) δ: 7.62-7.68 (1H, m, H-4’), 7.73-7.79 (2H, m,

1

3

H-3’ and H-5’), 8.20-8.24 (2H, m, H-2’ and H-6’), 8.77 (1H, s, H-5), 10.29 (1H, s, H-6); C

NMR (DMSO-d , 75.0 MHz APT) δ: 119.4 (C-3’ and C-5’), 129.3 (C-2’ and C-6’), 129.8 (C-4’),

6

1

30.1 (C-4), 147.7 (C-5), 185.0 (C-6).

4

.1.7.2 2-(4-chlorophenyl)-2H-1,2,3-triazole-4-carbaldehyde (18b). Brown solid, m.p. 86-87 ºC;

-1

1

IR ν_m_a_x(cm ): 1708, 1490, 1313, 1099, 967, 888, 831, 763,674; H NMR (DMSO-d , 500.00

6

MHz) δ: 7.80 (d, 1H, J 8.7 Hz, H-2’and H-6’), 8.23 (d, 1H, J 8.7 Hz, H-3’ and H-5’), 8.77 (s,

1

3

1

H, H-5), 10.30 (s, 1H, H-6); C NMR (DMSO-d

29.8 (C-3’ and C-5’),133.5 (C-1’), 136.8 (C-4), 137.3 (C-4’), 147.7 (C-5), 184.5 (C-6); Anal.

ClN O: C, 52.07; H, 2.91; N, 20.24. Found: C, 52.5; H, 2.72; N, 20.6

6

, 125.0 MHz APT) δ: 120.7 (C-2’ and C-6’),

Calcd for C

9

H

6

3

4

.1.7.3 2-(2,5-dimethylphenyl)-2H-1,2,3-triazole-4-carbaldehyde (18c). Brown solid, m.p. 33-34

-1

1

ºC; IR ν_m_a_x(cm ): 3133, 2852, 1707, 1513, 1494, 1447, 1312, 1032, 878, 803, 770; H NMR

(

7

DMSO-d , 300.00 MHz) δ: 2.38 (3H, s, CH ), 2.49 (3H, s, CH ), 7.43 (1H, d, J 7.5 Hz, H-4’),

.49 (1H, d, J 7.5 Hz, H-3’), 7.57 (1H, s, H-6’), 8.73 (1H, s, H-5), 10.29 (1H, s, H-6); C NMR

6 3 3

1

3

(

DMSO-d , 75.0 MHz APT) δ: 17.6 (CH ), 20.3 (CH ), 125.6 (C-6’), 129.4 (C-5’), 130.7 (C-3’),

6 3 3

1

31.7 (C-4’), 136.0 (C-4), 136.8 (C-2’), 138.6 (C-1’), 147.5 (C-5), 185.0 (C-6). Anal. Calcd for

C H N O: C, 65.66; H, 5.51; N, 20.88. Found: C, 62.69; H, 5.25; N, 18.85

11

3

4

1

.1.7.4 2-(2,5-dichlorophenyl)-2H-1,2,3-triazole-4-carbaldehyde (18d). Brown solid, m.p. 114-

15 ºC; IR ν_m_a_x(cm ): 3048, 2892, 2768, 1674, 1573, 1444, 1265, 1211, 1111, 1044, 805; H

-1

1

NMR (DMSO-d , 300.00 MHz) δ: 7.45 (1H, d, J 7.5 Hz, H-4’), 7.50 (1H, d, J 7.5 Hz, H-3’),

6

1

3

7

.58 (1H, s, H-6’), 8.74 (1H, s, H-5), 10.30 (1H, s, H-6); C NMR (DMSO-d , 75.0 MHz APT)

6

δ: 125.3 (C-6’), 129.1 (C-5’), 130.4 (C-3’), 131.4 (C-4’), 135.7 (C-4), 136.4 (C-2’), 138.3 (C-1’),

1

4

47.1 (C-5), 184.7 (C-6); Anal. Calcd for C H Cl N O: C, 44.66; H, 2.08; N, 17.36. Found: C,

10 8 2 3

4.81; H, 2.13; N, 17.45

.1.7.5 2-(4-fluorophenyl)-2H-1,2,3-triazole-4-carbaldehyde (18e). Brown solid, m.p. 77-78 ºC;

4

-1

1

6

IR νmax (cm ): 1699,1511, 1313, 1219, 1032, 967, 839, 758, 675,640; H NMR (DMSO-d ,

5

1

00.00 MHz) δ: 7.58-7.61 (m, 2H, H-2’ and H-6’), 8.24-8.27 (m, 2H, H-3’ and H-5’), 8.78 (s,

H, H-5), 10.30 (s, 1H, H-6); C NMR (DMSO-d , 125.0 MHz APT) δ: 117.0 (d, J 23.5 Hz, C-

6

1

3

20

ACCEPTED MANUSCRIPT

3

’ and C-5’), 122.0 (d, J 8.8 Hz, C-2’ and C-6’), 135.5 (C-1’), 137.1 (C-4), 147.9 (C-5), 162.3 (d,

9 6 3

J 247.5 Hz, H-4’), 185.0 (C-6); Anal. Calcd for C H FN O: C, 56.55; H, 3.16; N, 21.98. Found:

C, 56.50; H, 3.12; N, 21.6.

4

.1.8 General Procedure for preparation of 21a

Into a round-bottom flask already containing a solution of 5.8 mmols of triazole-carbaldehyde

8a in 50 mL of methanol was added 17 mmols of sodium borohydride in an ice bath. Next, the

1

methanol was evaporated under reduced pressure, and the product was extracted with ethyl

acetate, washed with water (3 x 100 mL), dried over with anhydrous sodium sulfate and filtered.

The solvent was evaporated under reduced pressure to give 21a.

o

4

6

9

7

.1.8.1 2-(2-phenyl-2H-1,2,3-triazole-4-yl)methanol (21a). Brown solid, m.p. 64-65 C (m.p. lit.

-1

4-65 ºC [45]); IR νmax (cm ): 3309, 3229, 2939, 2876, 1594, 1493, 1410, 1352, 1048, 1014,

3

, 500.00 MHz) δ: 4.77 (2H, s, H-6), 7.49-7.55 (1H, m, H-4’), 7.64-

.71 (2H, m, H-3’ and H-5’), 8.09-8.13 (2H, m, H-2’and H-6’), 8.14 (1H, s, H-4); C NMR

1

62, 759; H NMR (CDCl

13

(

CDCl , 125.0 MHz APT) δ: 54.9 (C-6), 118.2 (C-4’), 127.4 (C-3’ and C-5’), 129.7 (C-2’ and C-

3

6

4

’), 135.0 (C-4), 150.8 (C-5).

.2. Biological assays

.2.1 Enzyme activity assays

S. cerevisiae maltase assay (MAL12): α-Glucosidase activity was determined in a manner

analogous to previous studies [8]. A reaction mixture with a final volume of 200 ꢀL, containing

o

5

0 mM phosphate buffer, 100 mM NaCl and 1 mM PNP-G pH 7.0, was pre-incubated at 37 C

for 5 min. The reaction was then initiated by the addition of 25 ꢀL [100 µg/mL] of α-

glucosidase. The absorbance observed at 405 nm, corresponding to the liberated p-nitrophenol,

was measured using a FlexStation 3 Benchtop Multi-Mode Microplate Reader (Molecular

Devices, Sunnyvale, CA). All the experiments were repeated at least twice, each experiment

using samples in triplicate.

4

.2.2 Porcine pancreatic α-amylase (PPA) assay: α-amylase activity was determined in a

manner analogous to previous reports [9]. A reaction mixture with a final volume of 200 ꢀL,

containing 50 mM Hepes buffer, 5 mM CaCl , 100 mM NaCl and 1 mM CNPG3 pH 7.0, was

2

o

pre-incubated at 37 C for 5 min before the reaction was initiated by the addition of 20 ꢀL of

PPA 1.5-2 units. The absorbance observed at 405 nm, which corresponds to the liberated 2-

chloro-4-nitrophenol, was measured using a FlexStation 3 Benchtop Multi-Mode Microplate

Reader (Molecular Devices, Sunnyvale, CA). All the experiments were repeated at least two

times, each experiment using samples in triplicate.

4

.2.3 Inhibitor Screening and IC50 determination: The triazoles were stored in 100% DMSO

and diluted in Milli-Q water (Millipore Corporation) before the experiments. DMSO (1-5 %) was

unable to significantly inhibit both enzymatic activities (data not shown), and a maximum of 1 %

DMSO was utilized for further assays. All compounds were screened for glucosidase and

amylase inhibition at 500 ꢀM in the reaction medium described above. For the determination of

the inhibitor concentration at which 50 % inhibition of enzyme activity occurs (IC50), the assay

was performed as above except that the compound concentrations were varied from 1-1000 µM.

21

ACCEPTED MANUSCRIPT

IC50 values were calculated using Sigmaplot 12.0 software (Systat software Inc, USA) by fitting

residual activity data and inhibitor concentration to the four-parameter logistic equation: Res.

Activity = min + (max-min) / (1 + ([I]/EC50) ^ (-Hillslope)).

Acknowledgment

This work was supported by Fundação de Amparo à Pesquisa do Rio de Janeiro (FAPERJ),

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho

Nacional de Desenvolvimento Científico e Tecnológico (CNPq). DTGG, VFF, FPS-Jr and FCS

thank CNPq by the fellowships. MRS was the recipient of a fellowship PAPDRJ –

CAPES/FAPERJ.

22

ACCEPTED MANUSCRIPT

References

[

1] H.C. Kolb, M.G. Finn, K.B. Sharpless, Click Chemistry: Diverse Chemical Function

from a Few Good Reactions, Angew. Chem. Int. Ed. 40 (2001) 2004-2021.

2] R. Huisgen, 1.3-Dipolare Cycloadditionen Rückschau und Ausblick, Angew Chem. 75

(1963) 604-637.

3] R. Huisgen, Kinetics and Mechanism of 1,3-Dipolar Cycloadditions, Angew. Chem. Int.

Ed. 75 (1963) 633-645.

4] F.C. da Silva, M.C.B.V. de Souza, I.C.P.P. Frugulhetti, H.C. Castro, S.L.O. Souza,

T.M.L. de Souza, D.Q. Rodrigues, A.M.T. Souza, P.A. Abreu, F. Passamani, C.R.

Rodrigues, V.F. Ferreira, Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-

1H-1,2,3-triazole derivatives of carbohydrates, Eur. J. Med. Chem. 44 (2009) 373-383.

[

5] R.G. Micetich, S.N. Maiti, P. Spevak, T.W. Hall, S. Yamabe, N. Ishida, M. Tanaka, T.

Yamazaki, A. Nakai, K. Ogawa, Synthesis and beta-lactamase inhibitory properties of 2

beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam-3 alpha-carboxylic acid 1,1-

dioxide and related triazolyl derivatives, J. Med. Chem. 30 (1987) 1469-1474.

6] T. Weide, S.A. Saldanha, D. Minond, T.P. Spicer, J.R. Fotsing, M. Spaargaren, J.M.

Frère, C. Bebrone, K.B. Sharpless, P.S. Hodder, V.V. Fokin, NH-1,2,3-Triazole

Inhibitors of the VIM-2 Metallo-β-Lactamase. ACS Med. Chem. Lett. 1 (2010) 150-

154.

7] N. Boechat, V.F. Ferreira, S.B. Ferreira, M.L.G. Ferreira, F.C. da Silva, M.M. Bastos,

M.S. Costa, M.C.S. Lourenço, A.C. Pinto, A.U. Krettli, A.C. Aguiar, B.M. Teixeira,

N.V. da Silva, P.R.C. Martins, F.A.F.M. Bezerra, A.L.S. Camilo, G.P. da Silva, C.C.P.

Costa, Novel 1,2,3-triazole derivatives for use against Mycobacterium tuberculosis

H37Rv (ATCC 27294) strains, J. Med. Chem. 54 (2011) 5988-5999.

[

8] S.B. Ferreira, A.C.R. Sodero, M.F.C. Cardoso, E.S. Lima, C.R. Kaiser, F.P. Silva, V.F.

Ferreira, Synthesis, Biological Activity, and Molecular Modeling Studies of 1,2,3-

Triazole Derivatives of Carbohydrates as alfa-Glucosidases Inhibitors, J. Med. Chem.

53 (2010) 2364-2375.

[

9] M.R. Senger, L.C.A. Gomes, S.B. Ferreira, C.R. Kaiser, V.F. Ferreira, F. Paes-Silva Jr,

Kinetics Studies on the Inhibition Mechanism of Pancreatic alpha-Amylase by

Glycoconjugated 1H-1,2,3-Triazoles: A New Class of Inhibitors with Hypoglycemiant

Activity, ChemBioCem 13 (2012) 1584-1593.

[

10] A.K. Jordão, V.F. Ferreira, T.M.L. Souza, G.G.S. Faria, V. Machado, J.L. Abrantes,

M.C.B. V. Souza, A.C. Cunha, Synthesis and anti-HSV-1 activity of new 1,2,3-triazole

derivatives, Bioorg. Med. Chem. 19 (2011) 1860-1865.

[11] P.K. Kadaba, Triazolines 14. 1,2,3-Triazolines and triazoles, a new class of

anticonvulsants. Drug design and structure-activity relationships, J. Med. Chem. 31

(1988) 196-203.

[12] M.A. Rogawski, Diverse Mechanisms of Antiepileptic Drugs in the Development

Pipeline. Epilepsy Res. 69 (2006) 273-294.

[

13] A.C. Cunha, J.M. Figueiredo, J.L.M. Tributino, A.L.P. Miranda, H.C. Castro, R.B.

Zingali, C.A.M. Fraga, M.C.B.V. de Souza, V.F. Ferreira, E.J. Barreiro, Antiplatelet

properties of novel N-substitutedphenyl-1,2,3-triazole-4-acylhydrazone derivatives,

Bioorg. Med. Chem. 11 (2003) 2051-2059.

23

ACCEPTED MANUSCRIPT

[

14] R. Menegatti, A.C. Cunha, V.F. Ferreira, E.F.R. Perreira, A. El-Nabawi, A.T. Eldefrawi,

E.X. Albuquerque, G. Neves, S.M.K. Rates, C.A.M. Fraga, E.J. Barreiro, Design,

Synthesis and Pharmacological Profile of Novel Dopamine D2 Receptor Ligands,

Bioorg. Med. Chem. 11 (2003) 4807-4813.

[15] R.T. Buckler, H.E. Hartzler, E. Kurchacova, G. Nichols, B.M. Phillips, Synthesis and

antiinflammatory activity of some 1,2,3- and 1,2,4-triazolepropionic, J. Med Chem. 21

(1978) 1254-1260.

[

16] S. Shafi, M.M. Alam, N. Mulakayala, C. Mulakayala, G. Vanja, A.M. Kalle, R. Pallu,

M.S. Alam, Synthesis of novel 2-mercapto benzothiazole and 1,2,3-triazole based bis-

heterocycles: Their anti-inflammatory and anti-nociceptive activities, Eur. J. Med.

Chem. 49 (2012) 324-333.

[17] A.H. Banday, S.A. Shameem, B. Ganai, Antimicrobial studies of unsymmetrical bis-

1,2,3-triazoles, Org. Med. Chem. Lett. 2 (2012) 13-17.

[18] V. Sumangala, B. Poojary, N. Chidananda, J. Fernandes, N.S. Kumari, Synthesis and

antimicrobial activity of 1,2,3-triazoles containing quinoline moiety, Arch. Pharm Res.

33 (2010) 1911-1918.

[

19] R.G. Lima-Neto, N.N.M. Cavalcante, R.M. Srivastava, F.J.B. Mendonça, A.G.

Wanderley, R.P. Neves, J.V. dos Anjos, Synthesis of 1,2,3-triazole derivatives and in

vitro antifungal evaluation on Candida Strains., Molecules 17 (2012) 5882-5892.

20] I.F. da Silva, P.R.C. Martins, E.G. da Silva, S.B. Ferreira, V.F. Ferreira, K.R.C. da

Costa, M.C. de Vasconcellos, E.S. Lima, F.C. da Silva, Synthesis of 1H-1,2,3-triazoles

and Study of their Antifungal and Cytotoxicity Activities. Med. Chem. 9 (2013) In

Press.

[

21] C. Therin, R.C. Levesque, Molecular basis of antibiotic resistance and β-lactamase

inhibition by mechanism-based inactivators: perspectives and future directions, FEMS

Microbiol. Rev. 24 (2000) 251-262.

[22] S.G. Agalave, S.R. Maujan, V.S. Pore, Click Chemistry: 1,2,3-Triazoles as

Pharmacophores, Chem. Asian J. 6 (2011) 2696-2718.

[

23] T. Tschamber, F. Gessier, E. Dubost, J. Newsome, C. Tarnus, J. Kohler, M. Neuburger,

J. Streith, Carbohydrate transition state mimics: synthesis of imidazolo-Pyrrolidinoses

as potential nectrisine surrogates, Bioorg. Med. Chem. 11 (2003) 3559-3568.

24] T. Granier, N. Panday, A. Vasella, Structure-Activity Relations for Imidazo-pyridine-

Type Inhibitors of β-D-Glucosidases, Helv. Chim. Acta 80 (1997) 979-987.

25] T.M. Krulle, C. de la Fuente, L. Pickering, R.T. Aplin, K.E. Tsisanou, S.E. Zographos,

N.G. Oinkomakos, R.J. Nash, R.C. Griffiths, G.W.J. Fleet, Triazole carboxylic acids as

anionic sugar mimics? Inhibition of glycogen phosphorylase by a d-glucotriazole

carboxylate, Tetrahedron: Asymmetry 8 (1997) 3807-3820.

[

26] R. Périon, V. Ferriéres, M.I. García-Moreno, C.O. Mellet, R. Duval, J.M.G. Fernández,

D. Plusquellec, 1,2,3-Triazoles and related glycolconjugates as new glycosidase

inhibitors, Tetrahedron 61 (2005) 9118-9128.

[

27] B.G. Davis, T.W. Brandstetter, L. Hackett, B.G. Winchester, R.J. Nash, A.A. Watson,

R.C. Griffiths, C. Smith, Fleet, G.W.J. Tetrazoles of manno- and rhamno-pyranoses:

Contrasting inhibition of mannosidases by [4.3.0] but of rhamnosidase by [3.3.0]

bicyclic tetrazoles. Tetrahedron 55 (1999) 4489-4500.

[28] Y. Zhou, Y. Zhao, K.M.O. Boyle, P.V. Murphy, Hybrid angiogenesis inhibitors:

Synthesis and biological evaluation of bifunctional compounds based on 1-

24

ACCEPTED MANUSCRIPT

deoxynojirimycin and aryl-1,2,3-triazoles, Bioorg. Med. Chem. Lett. 18 (2008) 954-

958.

[29] J. Diot, M. Garcia-Moreno, S. Gouin, O. Mellet, K. Kovensky, Multivalent iminosugars

to modulate affinity and selectivity for glycosidases, Org. and Biomol. Chem. 7 (2009)

357-363,

[

30] T.J. Boltje, T. Buskas, G.J. Boons, Opportunities and challenges in synthetic

oligosaccharide and glycoconjugate research. Nat. Chem. 1 (2009), 611–622.

31] V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, A Stepwise

Huisgencycloaddition process: copper(I)-catalyzed regioselective “ligation” of azides

and terminal alkynes. Angew. Chem. Int. Ed. 41 (2002) 2596-2599.

[

32] S.K. Richardson, A. Jeganathan, R.S. Mani, B.E. Haley, D.S. Watt, L.R. Trusal,

Synthesis and biological activity of C-4 and C-15 aryl azide derivatives of anguidine,

Tetrahedron 43 (1987) 2925-2934.

[

33] A. Jonas, H.V. Pechmann, Untersuchungen über Osotriazole: Das Methyl-n-

phenylosotriazol und seine Derivate, Justus Liebigs Ann. Chem. 262 (1891) 277.

34] H. El Khaden, M.H. Meshreki, G.H. Lalib, The scope and mechanism of carbohydrate

osotriazole formation. Part XII. Anhydro- and other triazole derivatives, J. Chem. Soc.

[

(1964) 2306-2309.

[

35] J.L. Riebsomer, G. Sumrell, 2-Phenyl-2,1,3-triazole-4-carboxaldehyde and derivatives.

J. Org. Chem. 13 (1948) 807-814.

36] W.D. Maclay, C.S. Hudson, R.M. Hann, Volemitol heptaacetate, J. Org. Chem. 9 (1944)

293-297.

37] C.S. Hudson, R.M. Hann, The action of copper sulfate on phenylosazones of the sugars.

phenyl-D-glucosotriazole, J. Am. Chem. Soc. 66 (1944) 735-738.

38] C.S. Hudson, R.M. Hann, W.T. Haskins, The action of copper sulfate on the phenyl

osazones of the sugars. II. Some new osotriazoles, J. Am. Chem. Soc. 67 (1945) 939-

941.

[39] C. Abad-Zapatero, Ligand efficiency indices for effective drug discovery, Ex. Opin.

Drug Discov. 2 (2007) 469-488.

[

40] C. Abad-Zapatero, O. Perišić, J. Wass, A.P. Bento, J. Overington, B. Al-Lazikani, M.E.

Johnson, Ligand efficiency indices for an effective mapping of chemico-biological

space: the concept of an atlas-like representation, Drug Discov. Today 15 (2010) 804-

811.

[

41] D. R. da Rocha, W. C. Santos, E.S. Lima, V.F. Ferreira, Synthesis of 1,2,3-triazole

glycoconjugates as inhibitors of α-glucosidases. Carbohydr. Res. 350 (2012) 14-19.

42] B. Henrissat, G.J. Davies, Structural and sequence-based classification of glycoside

hydrolases. Curr. Opion. Struct. Biol. 7 (1997) 637-644.

43] Riebsomer, J. L.; Sumrell, G.; 2-phenyl-2,1,3-triazole-4-carboxaldehyde. J. org. chem.

13(6), 807-814

44] Hann, R. M.; Hudson, C. S.; The action of copper sulfate on phenylosazones of the

sugars. Phenyl-D-glucosotriazole. J. am. Chem. Soc. 1944, 66, 735-738

45] da Silva Junior, R. C.; Ferreira, V. F.; Pinheiro, S.; The stereoselective synthesis of

nopinone based triazole ketones. Tetrahedron: Asymmetry. 2004, 15, 3719-3722

25

ACCEPTED MANUSCRIPT

TABLES

Table 1

Inhibitory screening of the compounds at 500 µM on yeast α-glucosidase activity.

Compounds

Control

Acarbose

A series

Substituents

V ± SD (mAU/min) % inhibition

o

-

388.3 ± 11.6

177.0 ± 11.9

-

52.8

1

2

3

1

2a

R = R = R = H

380.3 ± 57.6

332.4 ± 33.2

2.1

1

3

R = R = H

1

2b

2

14.4

R = OCH

3

1

3

R = R = H

1

2c

2

322.8 ± 40.1

384.0 ± 34.5

16.9

1.1

R = Cl

1

3

R = R = Cl

1

2d

2

R = H

1

2

3

R = R = R = H

13a

4

355.9 ± 4.5

8.4

6 5

R = C H

1

3

R = R = Cl

2

1

3b

R = H

323.6 ± 11.7

16.7

4

R = C

6

H

5

1

3

R = R = Cl

2

1

3c

R = H

337.2 ± 2.5

344.4 ± 1.0

13.2

11.3

4

R = (CH ) CH

2

4

3

1

3

R = R = H

2

1

3d

R = Cl

4

R = CH

3

1

3

R = R = H

2

1

3e

3f

3g

R = Cl

352.3 ± 31.3

355.7 ± 5.7

363.5 ± 4.1

9.3

8.4

6.4

4

R = C H

6

5

1

2

3

R = R = R = H

1

4

2 4 3

R = (CH ) CH

1

3

R = R = Cl

2

1

R = H

4

R = CH

3

1

3

R = R = H

2

1

3h

R = Cl

371.2 ± 29.2

4.4

4

R = (CH ) CH

2

4

3

26

ACCEPTED MANUSCRIPT

1

2

3

R = R = R = H

1

3i

3j

4

364.9 ± 12.8

381.9 ± 9.2

398.5 ± 30.3

6.0

1.7

R = (CH

2

)

8

CH

3

1

3

R = R = H

2

1

R = Cl

4

R = (CH ) CH

2

8

3

1

2

3

R = R = R = H

1

3k

4

-2.6

R = CH

3

1

2

3

R = R = R = H

1

4a

4b

4c

4

387.3 ± 2.0

389.0 ± 4.8

0.3

2 5

R = C H

1

2

3

R = R = R = H

1

4

-0.2

2 3 3

R = (CH ) CH

1

3

R = R = H

2

1

R = Cl

387.7 ± 11.8

386.3 ± 23.1

342.5 ± 10.8

333.5 ± 17.9

350.1 ± 11.3

0.2

0.5

4

R = C H

2

5

1

3

R = R = H

2

1

4d

R = Cl

4

R = (CH ) CH

2

3

1

3

R = R = H

2

1

4e

R = OCH

R = C H

3

11.8

14.1

9.8

4

2

5

1

3

R = R = Cl

2

1

4f

R = H

4

R = (CH ) CH

2

3

1

3

R = R = Cl

2

14g

R = H

4

R = C

2

H

5

1

2

3

1

R = R = R = H

346.9 ± 14.9

338.6 ± 3.2

10.7

12.8

1

3

R = R = H

15a

2

R = Cl

1

3

R = R = Cl

1

5b

2

345.2 ± 26.0

11.1

R = H

1

2

3

16a

R = R = R = H

370.8 ± 31.4

4.5

27

Article Doi

1-Phenyl-1H- and 2-phenyl-2H-1,2,3-triazol derivatives: Design, synthesis and inhibitory effect on alpha-glycosidases

DOI: 10.1016/j.ejmech.2013.12.039

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.ejmech.2013.12.039

Full text of DOI:10.1016/j.ejmech.2013.12.039

Products guided by the article

R&D Labs maybe for 7650-45-5

Relevant to this article

Hot Product