Chapter-2 N-aryl triazoles via Chan-Lam coupling Chapter 2 Synthesis of N...

Chapter-2 N-aryl triazoles via Chan-Lam coupling

Studies on heterocyclic analogues 63

Chapter 2

Synthesis of N-aryl-1,2,4-triazoles via Chan-Lam coupling reaction

2.1 Introduction

The discovery of the copper catalyzed Chan–Lam coupling reaction with

boronic acids more than ten years ago has great advanced in the carbon–heteroatom

cross-coupling chemistry. The N-arylation of various heterocycles is now a powerful

new synthetic tool. Due to the widespread importance of aryl-N bond formation, many

synthetic methods have emerged over the years. Palladium- and copper-mediated N-

arylations are important tools in organic synthesis.

N-Arylation of azoles was carried out by metal mediated reactions such as the

Ullmann coupling, aromatic nucleophilic substitution and Pd or Cu catalyzed

arylation. Besides the traditional Ullmann1, 2 and Goldberg3-5 procedures, the

palladium-catalyzed reaction discovered by Buchwald6, 7 and Hartwig8, 9 has been a

major breakthrough in this field. More recently, Chan10 and Lam11, 12 introduced the

copper-mediated arylation of N-nucleophiles using stoichiometric copper (II) acetate

and boronic acids (Figure-2.1). The three methods Ullmann–Goldberg, Buchwald–

Hartwig (Figure-2.2) and Chan–Lam have become standard procedures for N-aryl

bond formation, and many examples illustrate their wide application in organic

synthesis.

In general, there are a wide variety of protocols describing the metal-mediated

arylation of amines,13-15 amides,16 imides,16 imidazoles,14,17,18 benzimidazoles,18,19

sulfonamides,16 pyrroles20 and lactams.21 However the Chan-Lam coupling reaction

made even more attractive by the mild conditions required. Significant progress has

been made in expanding the scope and the applications as well as understanding the

mechanism of this reaction.



Figure-2.1

X HNu Nu

X= halide HNu= NHRR',HOArHSR

Cu(I) Cat.

base+

X H2NR NHR

X= halide

PdCl2(dppf) Cat.

baseDioxane, 100oC

+

Ullman-Goldberg Coupling

Buchwald-Hartwig Coupling

Figure-2.2

2.2 Synthetic aspect

2.2.1 C-N bond formation via Chan-Lam cross coupling reaction

The recent development of copper (II)-promoted N and O arylation with

boronic acids has resulted in advances in the carbon–heteroatom cross-coupling

transformation. One reason for its popularity is the mild reaction conditions needed,

e.g. room temperature, weak base, and ambient atmosphere. This approach also takes

advantage of the ready availability of the boronic acids. In the recent years researchers

made considerable progress in expanding this copper-mediated cross-coupling

methodology.

Lam and co-workers11 initially studied a new aryl/heteroaryl C-N bond cross-coupling

reaction via the arylboronic acid/cupric acetate arylation of Pyrazoles. This new

methodology is mild, proceeds at room temperature exposed to air, and works for



many heteroarenes and arylboronic acids providing good yields of N-arylated

heteroarenes (Figure-2.3).

Figure-2.3

Yu, S. and Mederski et al.20,22 was reported that N-arylation proceeded in good yields

with pyrroles and indoles containing a chelating aldehyde, ketone or ester located in a

position alpha to the NH group. Recently, Bekolo et al.23 reported N-arylation of

electron-deficient pyrroles and indoles having no carbonyl group at the C2-position

(2) was developed to give the N-arylated indole (3) in good to excellent yields using

diisopropylethylamine as the base (Figure-2.4). Neither triethylamine nor pyridine

gave the desired product under these conditions.

Figure-2.4

Lam P.Y.S. et al.24 was explored the cross-coupling between 3-pyridylboronic acid

and benzimidazole and obtained only 22% yield. However, changing the boron

reagent to the corresponding propylene glycol boronic ester resulted in a higher yield

of 54% (Figure-2.5).



Figure-2.5

R. A. Joshi et al.24 was reported that the cross-coupling of aminopurines (5) and

aminopyrimidines (7) and (8) with arylboronic acids gave N-arylated products in

moderate to good yields (Figure-2.6).

Figure-2.6

X.-Q. Yu et al.25,26 was developed an efficient and mild method for the direct N-

arylation of nucleosides (10, 11) with arylboronic acids catalyzed by copper(II)

acetate hydrates. The presence of water was important. Replacing copper(II) acetate

with copper(II) acetate monohydrate in the absence of molecular sieves significantly

increased the yield. The mixed solvent methanol–water (4:1) was optimal. In addition,

only N,N,N’,N’-tetramethylethylenediamine as the base gave products (12, 13) in

good yields (Figure-2.7).



NH

N

N

N NH

N

NH2

O

NH2

R

B(OH)2

R

B(OH)2

+

+

NN

O

H2N

N N

NN

H2N

R

R

Reaction and conditionCu(OAc)2 (1 eq), TMEDA (2 eq)MeOH-H2O (4:1), r.t., 45 min

(10)

(11)

(12)

(13)

Figure-2.7

Naoki Matsuda et al.27 was reported a copper-catalyzed amination of arylboronates

with electrophilic aminating reagents, hydroxylamines. In a typical experiment,

treatment of phenyl boronicacid neopentylglycol ester (14) with O-benzoyl-N,N-

diethylhydroxylamine (15) in the presence of 10 mol% [Cu(OAc)2·OH2]/dppbz

(dppbz=1,2-bis(diphenylphosphino)-benzene) and 2.0 equivalents of LiOtBu in THF

at room temperature afforded N,N-diethylaniline (16) in 71% yield (Figure-2.8).

Figure-2.8

Shiyu Chen et al.28 was carried out N-arylation of amines using phenylboronic acid

could be efficiently promoted in the presence of Cu(OAc)2 and DBU as base under

the microwave (MW) irradiation (Figure-2.9).

(18)(17)

NH

PhB(OH)2+Cu(OAc)2, DBU

MW, 100oC NPh

Figure-2.9



Steven A. Rossi et al.29 was carried out the copper-catalyzed mono alkylation of

primary amides using alkylboronic acids. The key to this reaction is the discovery that

the combination of a mild base (sodium trimethylsilanolate) and di-tert-butyl peroxide

(DTBP) as the oxidant is uniquely effective in promoting the catalytic cross-coupling

reaction of primary amides and primary boronic acids (Figure-2.10).

Figure-2.10

2.2.2 C-O and C-S bond formation via Chan-Lam coupling.

The formation of carbon−sulfur bonds has received less attention. Difficulties

in C−S bond formation can be attributed to the sulfur species rapidly and irreversibly

deactivating the catalyst. So the efficient formation of the C−S bond is a most

important aspect of organic chemistry. Many research groups have made great effort

to overcome this problem in recent years, and several excellent catalytic systems that

used Pd, Cu, Ni, Fe and other metals as catalysts have been found for C−S bond

formation. Hua-Jian Xu et al.30 was developed a general protocol to achieve the

oxidative cross-coupling reactions of diverse boronic acids with thiols using a simple

copper catalyst in environment-friendly solvent at room temperature (Figure-2.11).

Figure-2.11

Manoj Mondal et al31 was reported the Chan–Lam C–O cross coupling methodology

for the synthesis of O-aryloxime ether at room temperature using aryl oxime and aryl

boronic acids as coupling partners in the presence of different bases, solvents, and

copper acetate as a catalyst (Figure-2.12).



Figure-2.12

Arunima Medda et al.32 was developed a convenient protocol for the efficient

synthesis of aryloxycoumarins by Cu-promoted C-O coupling reactions from readily

available hydroxycoumarin derivatives in the presence of the catalytic system

Cu(OAc)2/Et3N. By applying this condition, a series of arylboronic acids have been

successfully reacted to afford the coupled products in fair to good yields (Figure-

2.13).

+

B(OH)2

Cu(OAc)2

O

OH

O

O

O

O

O OCH2Cl2, Et3NRT/ N2 atm.

Figure-2.13

2.2.3 Modification in Chan-Lam Coupling

Collman J. P. et al.33,34 was first introduced catalytic carbon– nitrogen

coupling by using catalytic amount of [Cu(OH).TMEDA]2Cl2 (10 mol%) arylboronic

acids react smoothly with imidazoles (19) in dichloromethane at room temperature to

give a variety of N-arylimidazoles (20) in good to excellent yields. The reaction also

occurs in water in lower yield. N-Arylation of imidazole is faster than O-arylation of

bulk water (Figure-2.14).

Figure-2.14

Raghuvanshi D. et al.35,36 have been developed viable and efficient Ni-catalyzed N-

arylation using the reaction of arylboronic acids with amines, amides, and N-



heterocycles under atmospheric conditions. The method is practical and offers an

alternative to the corresponding Cu-mediated Chan-Lam process for the construction

of the C-N bond (Figure-2.15).

BR OH

OH+ NuH

NiCl2.6H2O2,2'-bipyridyl

DBU, CH3CNRT

NuR

R= H, Me, CF3

NuH- amines, NH-heterocyclesand amides

Figure-2.15

M. Lakshmi Kantam et al.37 have been carried out the coupling of imides with various

arylboronic acids using Cu-Al hydrotalcite in refluxing methanol with continuous

bubbling of air through the mixture without employing base or ligand to afford N-

arylated products in very good yields. Cu-Al hydrotalcite is used for four cycles

successfully with minimal loss of activity (Figure-2.16).

NH

O

O

(HO)2BR

N

O

O

RCu-Al Hydrotalcite

MeOH, Reflux, Air

R= H, OCH3, F, Cl, CH3

+

Figure-2.16

2.2.4 N-Arylation of Triazoles

N-Aryl derivatives of azoles are very important organic compound for an

organic synthesis because of their wide range of biological activity. N-Arylation of

azoles was carried out by metal mediated reactions such as the Ullmann coupling38-40,

aromatic nucleophilic substitution41,42 and Pd or Cu catalyzed43 arylation.

Many reactions are reported for the N-arylation of triazoles using aryl halides and

copper catalyst. Liangbo Zhu et al.44 reported CuI catalyzed N-arylation of triazole

using (S)-pyrrolidinylmethylimidazole (I) as a ligand and Cs2CO3 in good to excellent

yield. Kai Yang et al.45 have used 8-hydroxyquinolin-Noxide (II) ligand and CuBr for

the N-arylation. Copper-diamine catalyzed N-Arylation of triazoles was carried out by



Jon C. Antilla and co-workers.46 In this process (1S,2S)-N,N’-dimethylcyclohexane-

1,2-diamine (III) or N,N’-dimethylethane-1,2-diamine (IV) were used as a ligand,

while DMF and K3PO4 were used for obtaining complete conversion of starting

materials. Both (1S, 2S)-N,N’-dimethylcyclohexane-1,2-diamine and N,N’-

dimethylethane-1,2-diamine were capable ligands for the arylation of triazoles.

Palaniswamy Suresh and Kasi Pitchumani47 reported Per-6-amino-β-cyclodextrin

(per-6-ABCD) (V) acting simultaneously as a supramolecular ligand for CuI and host

for aryl bromides, catalyzes N-arylation of triazoles with aryl bromides under mild

conditions. This simple method proceeds with excellent yield for the coupling of

triazole with various substituted aryl bromides demonstrating good tolerance of other

functionalities. Also solox ligand48 and copper/iron co-catalyzed N-arylation of azoles

are reported49,50 (Figure-2.17).

X

NN

HN N

NN

CuI (5%),Ligand (I) (10%)

Cs2CO3, DMF, 110oC

X= halides

+

Br

NN

HN N

NN

CuI (1 mol%),Ligand (II) (10 mol%)

Cs2CO3, DMSO, 90oC+R

R

NN

HN N

NN

CuI (5 mol%),Ligand (III or IV) (10 mol%)

K3PO4, DMF, 110oC, 24 hrs+

IR R

MeHN NHMe

MeHN NHMe

(III) (IV)

N

PhH2C

N

N

(I)

N

OH O

(II)

Ligands

Per-6-amino-b-cyclodextrin (per-6-ABCD)(V)

Br

NN

HN N

NN

K2CO3, DMSO, 110oC+R

RCuI

8 mol % Per-6- ABCD

Figure-2.17



Chhanda Mukhopadhyay et al.51 was developed a highly efficient and simple protocol

for the N-arylation of some hindered aza-heterocycles in water has with readily

available basic copper carbonate as the catalyst using bis(3,5-dimethyl-1H-pyrazol-1-

yl)methane as ligand (Figure-2.18).

Figure-2.18

Deping Wang et al.52 was reported 6,7-dihydroquinolin-8(5H)-one oxime, one of the

commercially available oximes, as an excellent ligand for the Cu-catalyzed N-

arylation of azoles with aryl iodides, bromides, and electrondeficient chlorides in

water as a green chemistry approach (Figure-2.19).

Figure-2.19

The sonochemical nucleophilic aromatic substitutions on haloarenes with different

amines also have been studied.53,54 Peter magdolen et al.54 was studied the

sonochemical nucleophilic aromatic substitution on 4-flourobenzaldehyde with

different azoles (Figure-2.20).

Figure-2.20

Pilar Lopez-Alvarado et al.55 was carried out treatment of a variety of azoles or their

anions with p-tolyllead triacetate in the presence of copper acetate afforded the

corresponding N-aryl derivatives, normally in excellent yields (Figure-2.21).



Figure-2.21

Chan D. M. T. and Lam P. Y. S. et al.56 have been discovered a new aryl C-N bong

cross coupling reaction via the aryl boronicacid and cupric acetate with NH

containing heterocycles (Figure-2.22).

Figure-2.22



2.3 Current research work

Carbon–nitrogen cross-coupling between aryl and aromatic heterocycles is an

important process. Many reactions for the N-arylation of azoles are reported.57-60 The

advantage of the copper-mediated boronic acid carbon–nitrogen bond formation

reaction is its high tolerance of a wide range of functional groups and its high success

rate on a broad spectrum of substrates because of the mildness and efficiency of the

reaction conditions.

In current research work a series of N-substituted triazoles was prepared by Chan-

Lam cross coupling reaction. Initially two triazole motifs were synthesized via heating

of corresponding thioamide with formic acid and hydrazine hydrate. These triazoles

were further reacted with different aryl boronic acids in presence of copper acetate

and triethyl amine under oxygen environment. The newly synthesized N-substituted

triazoles were purified by column chromatography and characterized by IR, Mass, 1H

NMR, 13C NMR spectroscopy and elemental analysis.



2.4 Results and discussion

Scheme-2.1 Synthesis of N-aryl triazoles

Scheme-2.2

Scheme-2.3

Scheme-2.4



N-aryl triazoles were synthesize by reaction of triazoles with aryl boronicacids

and copper acetate using triethyl amine as a base in dichloromethane at room

temperature for 16-24 hours. The required triazoles Int-1 and Int-2 were directly

prepared from corresponding thioamide by heating at 80oC with formic acid and

hydrazine hydrates for 2-3 hours. All the synthesized compounds are required to

purify by column chromatography using mixture of ethyl acetate and hexane.

The structures of SPG-2a-t were established on the basis of their elemental analysis

and spectral data (MS, IR, 1H NMR and 13C NMR). Some representative examples for

each step are described here.

The structure of SPG-2a supported by its mass (m/z 347), which agrees with its

molecular formula C18H16F3N3O. The 1H NMR spectrum shows signals at δ= 1.325

ppm (d, 6H, 2 x iPrCH3, j=6.0 Hz), δ=4.657 ppm (m, 1H, iPrCH), δ=7.111 ppm (s,

1H, Ar-H), δ=7.359 ppm (tt, 1H, Ar-H j=1.2, 7.6 Hz), δ=7.474 ppm (t, 2H, Ar-H, j=2,

7.6 Hz), δ=7.690 ppm (dt, 2H, Ar-H, j=1.2, 7.6 Hz) δ=7.823ppm (s, 1H, Ar-H),

δ=7.971 ppm (s, 1H, Ar-H), δ=8.525 ppm (s, 1H, CH-triazole).

The structure of SPG-2p supported by its mass (m/z 394.35), which agrees with its

molecular formula C21H13F3N4O. The 1H NMR spectrum shows signals at δ=7.325

ppm (t, 1H, Ar-H), δ=7.399 ppm (t, 3H, Ar-H), δ=7.675 ppm (q, 1H, Ar-H), δ=7.961

ppm (m, 2H, Ar-H), δ=7.851 ppm (m, 1H, Ar-H), δ=8.091 ppm (t, 2H, Ar-H),

δ=8.571 ppm (s, 1H, Ar-H), δ=9.504 ppm (s, 1H, CH-triazole), δ=10.498 ppm (s, 1H,

-CONH).



Table 2.1 Synthesis of N-aryl triazoles

Entry R Time h Yield % mp oC

2a H 20 82 70-72

2b 4-F 18 84 78-80

2c 3-OCH3 19 78 72-74

2d 4-Br 22 75 76-78

2e 4-CH2CH3 20 70 70-72

2f 3-Cl, 4-CF3 24 72 80-82

2g 4-CF3 21 80 66-68

2h 3-CH3 22 86 72-74

2i 3-N(CH3)2 25 65 78-80

2j 4-Cl 24 87 82-84

2k 4-CN 26 76 76-78

2l 3-F 21 82 64-66

2m 2-F 20 80 68-70

2n 2-CF3 26 84 70-72

2o 2-CN 24 68 82-84

2p 3-F 25 30 210-212

2q 3-morpholine 28 25 230-232

2r 3-CH3 26 15 216-218

2s 2-F 29 25 196-198

2t 4-F 28 24 190-192



In the proposed general mechanism for Chan-Lam coupling reaction (Figure-

2.23), the arylboronic acid initially undergoes transmetalation with copper complex 1

to generate boric acid and intermediate 2, which then coordinates the NH-triazole

substrate, forming complex 3. In the presence of dioxygen, complex 3 has been

proposed to undergo oxidation, forming a putative Cu(III) intermediate 4, which

undergoes reductive elimination, yielding the coupling product 5.

AcOCu

OAc

L LII

Ar-B(OH)2

Transmetalation

ArCu

OAc

L LIIN

NHN

Coordination/deprotonation

ArCu

N

L LII

NN

O2 Oxidation

ArCu

N

L L

NN

III

NN

NAr

-Cuo

-CuI

Reductiveelimination

1

2

3

4

5

Figure-2.23 Proposed general mechanism for Chan-Lam coupling reaction.



2.5 Conclusion

In summary, we have synthesized a library of N-aryl substituted triazole

derivatives using Chan-Lam cross coupling reaction. Usually in Chan-Lam coupling

reaction major problem arise of low yield. In current work one of the triazole motifs

(Int-1) gave N-aryl triazoles (SPG-2a-o) with excellent yield, while other one (Int-2)

gave poor yield. This procedure offers a good scope for the N-arylation of triazole

ring with moderate to good yield.



2.6 Experimental section

Thin-layer chromatography was accomplished on 0.2-mm precoated plates of

silica gel G60 F254 (Merck). Visualization was made with UV light (254 and 365nm)

or with an iodine vapor. IR spectra were recorded on a FTIR-8400 spectrophotometer

using DRS prob. 1H (400 MHz), 13C (100 MHz) NMR spectra were recorded on a

Bruker AVANCE II spectrometer in CDCl3 and DMSO. Chemical shifts are

expressed in δ ppm downfield from TMS as an internal standard. Mass spectra were

determined using direct inlet probe on a GCMS-QP 2010 mass spectrometer

(Shimadzu). Solvents were evaporated with a BUCHI rotary evaporator. Melting

points were measured in open capillaries and are uncorrected.

General synthesis of NH-triazoles Int-1 and Int-2.

Add formic acid to the hydrazine hydrate at 0oC and stirred for 5 min. To this

mixture corresponding thioamide was added portion wise at room temperature, than

heated up to 80oC for 2-3 hours. After the completion of the reaction mixture was

poured in to cooled water. The separated solid was filtered and washed with water to

obtained analytically pure product (yield Int-1= 95%, Int-2= 90%).

General synthesis of N-aryl triazoles SPG-2a-t.

Dry dichloromethane (10 vol) and dry molecular sieves were taken in RBF.

Triazole (5 mmol), triethyl amine (20 mmol), boronic acid (6 mmol), and copper (II)

acetate (6 mmol) were added to this solution. The suspension then stirred for 2 days

under air. The calcium chloride guard tube was used to protect the reaction from

moisture. The reaction was monitored by TLC using Ethyl acetate: Hexane as a

mobile phase. The suspension was diluted with dichloromethane, filtered and washed

with water and brine. The organic phase was dried (Na2SO4) and the solvent

removed under reduced pressure.



Spectral data of the synthesized compounds

4-fluoro-N-(4-fluoro-3-(1H-1,2,4-triazol-3-yl)phenyl)benzamide (Int-2): white

solid; Rf 0.35 (4:6 hexane-EtOAc); mp 230-232°C; IR (KBr): 3292, 3185, 3068, 2939,

1643, 1556, 1504, 1384, 1325, 1242, 1159, 1082, 1006, 912, 844, 746, 678, 617, 499

cm-1; 1H NMR: δ 767-7.411 (m, 3H, Ar-H), 7.908 (s, 1H, Ar-H), 8.059-8.094 (dd, 2H,

Ar-H), 8.471-8.481 (d, 1H, Ar-H), 8.694 (s, 1H, -CH triazole), 10.460 (s, 1H, -NH

amide), 14.250 (s, 1H, -NH triazole); 13C NMR (100 MHz, DMSO): 115.23, 115.45,

116.41, 116.63, 121.34, 122.87, 130.35, 130.44, 130.99, 135.51, 154.12, 156.58,

162.87, 164.36, 165.35; MS (m/z): 300 (M+); Anal. Calcd for: C15H10F2N4O: C, 60.00;

H, 3.36; N, 18.66; Found: C, 60.12; H, 3.27; N, 18.71.

3-(3-fluoro-5-isopropoxyphenyl)-1-phenyl-1H-1,2,4-triazole (SPG-2a): white


1512, 1431, 1342, 1295, 1228, 1116, 977, 891, 759, 698 cm-1; 1H NMR: δ 1.319-

1.334 (d, 6H, (-CH3)2, j= 8.4 Hz), 4.626-4.687 (m, 1H, -CH), 7.111 (s, 1H, Ar-H),

7.354-7.363 (tt, 1H, Ar-H, j=1.2, 7.6 Hz), 7.471-7.480 (t, 2H, Ar-H, j=2, 7.6 Hz),

7.679-7.703 (dt, 2H, Ar-H, j=1.2, 7.6 Hz), 7.823 (s, 1H, Ar-H), 7.971 (s, 1H, Ar-H),

8.525 (s, 1H, Ar-H); 13C NMR (100 MHz, DMSO): 21.94, 70.74, 114.16, 115.41,

116.24, 119.91, 125.52, 128.30, 129.65, 132.74, 136.92, 136.92, 141.64, 158.42, 162;

MS (m/z): 297 (M+); Anal. Calcd for: C17H16FN3O: C, 68.67; H, 5.42; N, 14.13;

Found: C, 68.45; H, 5.51; N, 14.07..

3-(3-fluoro-5-isopropoxyphenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole (SPG-2b):

white solid; Rf 0.43 (7:3 hexane-EtOAc); mp 78-80°C; IR (KBr): 3090, 2982, 2924,

1790, 1608, 1521, 1437, 1350, 1309, 1226, 1161, 1109, 976, 895, 837, 700, 623, 507

cm-1; 1H NMR: δ 1.320-1.335 (d, 6H, (-CH3)2, j= 12 Hz), 4.623-4.684 (m, 1H, -CH),

7.114 (s, 1H, Ar-H), 7.151-7.194 (t, 2H, Ar-H, j=4.4, 8.4 Hz), 7.652-7.686 (dd, 2H,

Ar-H, j=4.4, 8.8 Hz), 7.807 (s, 1H, Ar-H), 7.807 (s, 1H, Ar-H), 7.953 (s, 1H, Ar-H),

8.469 (s, 1H, Ar-H); 13C NMR (100 MHz, DMSO): 21.72, 70.56, 114.23, 115.34,

116.26, 116.91, 121.97, 125.22, 132.51, 133.23, 141.68, 158.43, 162.11, 163.32; MS

(m/z): 315 (M+); Anal. Calcd for: C17H15F2N3O: C, 64.75; H, 4.79; N, 13.33; Found:

C, 64.68; H, 4.82; N, 13.41.

3-(3-fluoro-5-isopropoxyphenyl)-1-(3-methoxyphenyl)-1H-1,2,4-triazole (SPG-

2c): white solid; Rf 0.41 (7:3 hexane-EtOAc); mp 72-74°C; IR (KBr): 3134, 2983,



2928, 2837, 1739, 1604, 1508, 1442, 1307, 1220, 1161, 1112, 1035, 977, 850, 765,

690, 580 cm-1; 1H NMR: δ 1.319-1.334 (d, 6H, (-CH3)2, j= 8.4 Hz), 3.848 (s, 3H, -

OCH3), 4.623-4.684 (m, 1H, -CH), 6.876-6.905 (dd, 1H, Ar-H, j=2.4, 8.4 Hz), 7.112

(s, 1H, Ar-H),7.213-7.240 (dd, 1H, Ar-H, j=2, 8 Hz), 7.265-7.276 (t, 1H, Ar-H),

7.341-7.382 (t, 1H, Ar-H), 7.821 (s, 1H, Ar-H), 7.971 (s, 1H, Ar-H), 8.514 (s, 1H, Ar-

H); 13C NMR (100 MHz, DMSO): 21.94, 55.70, 70.57, 111.77, 114.27, 115.48,

116.26, 125.23, 130.65, 132.49, 137.94, 141.78, 158.42, 160.55, 161.89; MS (m/z):

327 (M+); Anal. Calcd for: C18H18FN3O2: C, 66.04; H, 5.54; N, 12.84; Found: C,

66.13; H, 5.47; N, 12.79.

1-(4-bromophenyl)-3-(3-fluoro-5-isopropoxyphenyl)-1H-1,2,4-triazole (SPG-2d):


2823, 1745, 1612, 1514, 1457, 1312, 1235, 1173, 1127, 1041, 981, 845, 771, 681, 575

cm-1; MS (m/z): 376 (M+); Anal. Calcd for: C17H15BrFN3O: C, 54.27; H, 4.02; N,

11.17; Found: C, 54.32; H, 3.94; N, 11.22.

1-(4-ethylphenyl)-3-(3-fluoro-5-isopropoxyphenyl)-1H-1,2,4-triazole (SPG-2e):


1905, 1786, 1606, 1527, 1438, 1309, 1259, 1114, 977, 895, 839, 759, 700, 605, 528

cm-1; 1H NMR: δ 1.192-1.230 (t, 3H, -CH3), 1.313-1.328 (d, 6H, (-CH3)2, j= 6 Hz),

2.628-2.685 (q, 2H, -CH2), 4.619-4.680 (m, 1H, -CH), 7.104 (s, 1H, Ar-H), 7.273-

7.294 (d, 2H, Ar-H, j=8.4 Hz), 7.569-7.590 (d, 2H, Ar-H, j= 8.4 Hz), 7.816 (s, 1H, Ar-

H), 7.965 (s, 1H, Ar-H), 8.479 (s, 1H, triazole -CH); 13C NMR (100 MHz, DMSO):

15.98, 21.94, 28.48, 70.54, 114.20, 115.17, 115.40, 120.05, 125.26, 128.87, 132.14,

134.76, 141.59, 144.80, 158.41, 161.82; MS (m/z): 325 (M+); Anal. Calcd for:

C19H20FN3O: C, 70.13; H, 6.20; N, 12.91;Found: C, 70.21; H, 6.17; N, 12.82.

1-(3-chloro-4-(trifluoromethyl)phenyl)-3-(3-fluoro-5-isopropoxyphenyl)-1H-

1,2,4-triazole (SPG-2f): white solid; Rf 0.38 (7:3 hexane-EtOAc); mp 80-82°C; IR

(KBr): 3082, 2981, 2931, 1914, 1776, 1614, 1532, 1441, 1321, 1264, 1127, 975, 886,

841, 747, 716, 629, 536 cm-1; MS (m/z): 399 (M+); Anal. Calcd for: C18H14ClF4N3O:

C, 54.08; H, 3.53; N, 10.51; Found: C, 54.12; H, 3.47; N, 10.43.

3-(3-fluoro-5-isopropoxyphenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazole

(SPG-2g): white solid; Rf 0.43 (7:3 hexane-EtOAc); mp 66-68°C; IR (KBr): 3079,

2973, 2942, 1923, 1768, 1619, 1548, 1457, 1315, 1274, 1131, 982, 891, 852, 758,



722, 632, 541 cm-1; MS (m/z): 365 (M+); Anal. Calcd for: C18H15F4N3O: C, 59.18; H,

4.14; N, 11.50; Found: C, 59.27; H, 4.09; N, 11.46.

3-(3-fluoro-5-isopropoxyphenyl)-1-(m-tolyl)-1H-1,2,4-triazole (SPG-2h): white


1773, 1624, 1561, 1448, 1307, 1252, 1128, 993, 879, 852, 749, 756, 641, 561 cm-1;

MS (m/z): 311 (M+); Anal. Calcd for: C18H18FN3O: C, 69.44; H, 5.83; N, 13.50;

Found: C, 69.51; H, 5.78; N, 13.47.

3-(3-(3-fluoro-5-isopropoxyphenyl)-1H-1,2,4-triazol-1-yl)-N,N-dimethylaniline

(SPG-2i): white solid; Rf 0.37 (7:3 hexane-EtOAc); mp 78-80°C; IR (KBr): 3087,

2975, 2964, 1941, 1781, 1606, 1569, 1458, 1319, 1269, 1132, 981, 883, 843, 769,

776, 659, 531 cm-1; MS (m/z): 340 (M+); Anal. Calcd for: C19H21FN4O: C, 67.04; H,

6.22; N, 16.46; Found: C, 67.21; H, 6.13; N, 16.37.

1-(4-chlorophenyl)-3-(3-fluoro-5-isopropoxyphenyl)-1H-1,2,4-triazole (SPG-2j):


1965, 1764, 1636, 1572, 1449, 1326, 1247, 1123, 978, 876, 857, 775, 789, 669, 521

cm-1; MS (m/z): 331 (M+); Anal. Calcd for: C17H15ClFN3O: C, 61.54; H, 4.56; N,

12.67; Found: C, 61.67; H, 4.42; N, 12.71.

4-(3-(3-fluoro-5-isopropoxyphenyl)-1H-1,2,4-triazol-1-yl)benzonitrile (SPG-2k):


1974, 1748, 1639, 1558, 1453, 1334, 1252, 1131, 963, 861, 866, 781, 754, 683, 535

cm-1; MS (m/z): 322 (M+); Anal. Calcd for: C18H15FN4O: C, 67.07; H, 4.69; N, 17.38;

Found: C, 66.98; H, 4.76; N, 17.29.

3-(3-fluoro-5-isopropoxyphenyl)-1-(3-fluorophenyl)-1H-1,2,4-triazole (SPG-2l):


1978, 1758, 1631, 1563, 1462, 1321, 1264, 1142, 967, 873, 861, 798, 761, 639, 519

cm-1; MS (m/z): 315 (M+); Anal. Calcd for: C17H15F2N3O: C, 64.75; H, 4.79; N,

13.33; Found: C, 64.84; H, 4.67; N, 13.41.

3-(3-fluoro-5-isopropoxyphenyl)-1-(2-fluorophenyl)-1H-1,2,4-triazole (SPG-2m):


1987, 1767, 1627, 1559, 1476, 1309, 1268, 1151, 976, 889, 852, 783, 746, 648, 545



cm-1; MS (m/z): 315 (M+); Anal. Calcd for: C17H15F2N3O: C, 64.75; H, 4.79; N,

13.33; Found: C, 64.81; H, 4.64; N, 13.51.

3-(3-fluoro-5-isopropoxyphenyl)-1-(2-(trifluoromethyl)phenyl)-1H-1,2,4-triazole

(SPG-2n): white solid; Rf 0.42 (7:3 hexane-EtOAc); mp 70-72°C; IR (KBr): 3087,

2974, 2978, 1975, 1781, 1634, 1563, 1483, 1312, 1274, 1159, 984, 872, 861, 773,

768, 657, 534 cm-1; MS (m/z): 365 (M+); Anal. Calcd for: C18H15F4N3O: C, 59.18; H,

4.14; N, 11.50; Found: C, 59.27; H, 4.21; N, 11.38.

2-(3-(3-fluoro-5-isopropoxyphenyl)-1H-1,2,4-triazol-1-yl)benzonitrile (SPG-2o):


1968, 1776, 1642, 1574, 1494, 1321, 1267, 1148, 973, 891, 875, 784, 739, 675, 527

cm-1; MS (m/z): 322 (M+); Anal. Calcd for: C18H15FN4O: C, 67.07; H, 4.69; N, 17.38;

Found: C, 67.17; H, 4.56; N, 17.41.

4-fluoro-N-(4-fluoro-3-(1-(3-fluorophenyl)-1H-1,2,4-triazol-3-yl)phenyl)

benzamide (SPG-2p): white solid; Rf 0.43 (4:6 hexane-EtOAc); mp 210-212°C; IR

(KBr): 3078, 2946, 1651, 1547, 1513, 1376, 1331, 1237, 1146, 1079, 1012, 950, 924,

857, 759, 712, 683, 648, 604, 513 cm-1; 1H NMR: δ 7.306-7.347 (t, 1H, Ar-H), 7.378-

7.420 (t, 3H, Ar-H), 7.638-7.694 (q, 1H, Ar-H), 7.816-7.877 (q, 2H, Ar-H), 7.941-

7.961 (d, 1H, Ar-H, j=8.0 Hz), 8.071-8.104 (t, 2H, Ar-H), 8.560-8.571 (d, 1H, Ar-H,

j=4.4 Hz), 9.504 (s, 1H, -CH triazole), 10.498 (s, 1H, -NH amide); MS (m/z): 394

(M+); Anal. Calcd for: C21H13F3N4O: C, 63.96; H, 3.32; N, 14.21; Found: C, 64.04; H,

3.26; N, 14.18.

4-fluoro-N-(4-fluoro-3-(1-(3-morpholinophenyl)-1H-1,2,4-triazol-3-yl)phenyl)

benzamide (SPG-2q): white solid; Rf 0.39 (4:6 hexane-EtOAc); mp 230-232°C; IR

(KBr): 3081, 2952, 1643, 1558, 1521, 1384, 1324, 1241, 1153, 1084, 1009, 974, 937,

863, 761, 711, 679, 639, 612, 521 cm-1; MS (m/z): 461 (M+); Anal. Calcd for:

C25H21F2N5O2: C, 65.07; H, 4.59; N, 15.18; Found: C, 65.14; H, 4.43; N, 15.21.

4-fluoro-N-(4-fluoro-3-(1-(m-tolyl)-1H-1,2,4-triazol-3-yl)phenyl)benzamide

(SPG-2r): white solid; Rf 0.45 (4:6 hexane-EtOAc); mp 216-218°C; IR (KBr): 3077,

2945, 1649, 1542, 1532, 1391, 1317, 1238, 1167, 1093, 1017, 983, 945, 871, 784,

741, 659, 631, 557, 511 cm-1; MS (m/z): 390 (M+); Anal. Calcd for: C22H16F2N4O: C,

67.69; H, 4.13; N, 14.35; Found: C, 67.73; H, 4.04; N, 14.41.




benzamide (SPG-2s): white solid; Rf 0.41 (4:6 hexane-EtOAc); mp 196-198°C; IR

(KBr): 3088, 2955, 1650, 1554, 1528, 1387, 1320, 1242, 1174, 1078, 1006, 979, 942,


C21H13F3N4O: C, 63.96; H, 3.32; N, 14.21; Found: C, 64.07; H, 3.27; N, 14.18.


benzamide (SPG-2t): white solid; Rf 0.43 (4:6 hexane-EtOAc); mp 190-192°C; IR

(KBr): 3093, 2939, 1664, 1547, 1541, 1365, 1334, 1251, 1180, 1087, 1024, 984, 951,


C21H13F3N4O: C, 63.96; H, 3.32; N, 14.21; Found: C, 63.89; H, 3.41; N, 14.16.



1H NMR spectrum of Int-2

Expanded 1H NMR spectrum of Int-2



D2O exchange spectrum of Int-2

1H NMR spectrum of SPG-2p



1H NMR spectrum of SPG-2a

Expanded 1H NMR spectrum of SPG-2a



1H NMR spectrum of SPG-2b

Expanded 1H NMR spectrum of SPG-2b



1H NMR spectrum of SPG-2c

Expanded 1H NMR spectrum of SPG-2c



1H NMR spectrum of SPG-2e

Expanded 1H NMR spectrum of SPG-2e



13C NMR spectrum of Int-2

13C NMR spectrum of SPG-2a



13C NMR spectrum of SPG-2b

13C NMR spectrum of SPG-2c



13C NMR spectrum of SPG-2e

Mass spectrum of Int-1



Mass spectrum of Int-2

Mass spectrum of SPG-2a



Mass spectrum of SPG-2b

Mass spectrum of SPG-2c



Mass spectrum of SPG-2e

Mass spectrum of SPG-2p



Mass spectrum of SPG-2q

Mass spectrum of SPG-2r



LCMS spectrum of SPG-2r



IR spectrum of Int-2

IR spectrum of SPG-2a



IR spectrum of SPG-2b

IR spectrum of SPG-2c



2.7 References

1. Ullmann, F.; Ber. Dtsch. Chem. Ges. 1903, 36, 2382.

2. Ullmann, F.; Illgen, E.; Ber. Dtsch. Chem. Ges. 1914, 47, 380.

3. Goldberg, I.; Ber. Dtsch. Chem. Ges. 1907, 40, 4541.

4. Monnier, F.; Taillefer, M.; Angew. Chem., Int. Ed. 2009, 48, 6954.

5. Goldberg, I.; Ber. Dtsch. Chem. Ges. 1906, 39, 1691.

6. Muci, A. R.; Buchwald, S. L.; Top. Curr. Chem. 2002, 219, 131.

7. Guram, A. S.; Rennels, R. A.; Buchwald, S. L.; Angew. Chem., Int. Ed. 1995, 34, 1348.

8. Hartwig, J. F.; Angew. Chem., Int. Ed. 1998, 37, 2046.

9. Louie, J.; Hartwig, J. F.; Tetrahedron Lett. 1995, 36, 3609.

10. Chan, D. M. T.; Monaco, K. L.; Wang, R.P.; Winters, M. P.; Tetrahedron Lett. 1998, 39,

2933.

11. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;

Combs, A.; Tetrahedron Lett. 1998, 39, 2941.

12. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Averill, K. M.; Chan, D. M. T.;

Combs, A.; Synlett 2000, 674.

13. Wolfe, J. P.; Buchwald, S. L.; J. Org. Chem. 2000, 65, 1144.

14. Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R.-G.; Chem. Commun. 2004, 188.

15. Liu, Y.; Bai, Y.; Zhang, J.; Li, Y.; Jiao, J.; Qi, X.; Eur. J. Org. Chem. 2007, 6084.

16. Lan, J.-B.; Zhang, G.-L.; Yu, X.-Q.; You, J.-S.; Chen, L.; Yan, M.; Xie, R.-G. Synlett 2004,

1095–1097.

17. Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S.; J. Org. Chem. 2001, 66, 1528.

18. Wentzel, M. T.; Hewgley, J. B.; Kamble, R. M.; Wall, P. D.; Kozlowski, M. C.; Adv.

Synth. Catal. 2009, 351, 931.

19. Nishiura, K.; Urawa, Y.; Soda, S.; Adv. Synth. Catal. 2004, 346, 1679.

20. Yu, S.; Saenz, J.; Srirangam, J. K.; J. Org. Chem. 2002, 67, 1699.

21. Browning, R. G.; Badarinarayana, V.; Mahmud, H.; Lovely, C. J; Tetrahedron 2004, 60, 359.

22. Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D.; Tetrahedron 1999, , 55, 12757.

23. Bekolo, H.; Can. J. Chem. 2007, 85, 42.

24. Joshi, R. A.; Patil, P. S.; Muthukrishnan, M.; Ramana, C. V.; Gurjar, M. K.; Tetrahedron Lett.

2004, 45, 195.

25. Tao, L.; Yue, Y.; Zhang, J.; Chen, S.-Y.; Yu, X.-Q.; Helv. Chim. Acta 2008, 91, 1008.

26. Yue, Y.; Zheng, Z.-G.; Wu, B.; Xia, C.-Q.; Yu, X.-Q.; Eur. J. Org. Chem. 2005, 5154.

27. Matsuda N.; Hirano K.; Satoh T.; Miura M.; Angew. Chem. Int. Ed. 2012, 51, 3642.

28. Chen S.; Huang H.; Liu X.; Shen J.; Jiang H.,; Liu H.,; J. Comb. Chem. 2008, 10, 358.

29. Rossi S. A.; Shimkin K. W.; Xu Q.; Mori-Quiroz L. M.; Watson D. A.; Org. Lett. 2013, 15,

2314.

30. Xu H. J.; Zhao Y. Q.; Feng T.; Feng Y. S.; J. Org. Chem. 2012, 77, 2878.

31. Mondal M.; Sarmah G.; Gogoi K.; Bora U.; Tetrahedron Lett. 2012 53, 6219.



32. Medda A.; Pal G.; Singha R.; Hossain T.; Saha A.; Das A.; Synthetic Communications

2013, 43, 169.

33. Collman, J. P.; Zhong, M.; Org. Lett. 2000, 2, 1233.

34. Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S.; J. Org. Chem. 2001, 66, 7892.

35. Raghuvanshi D.; Gupta A.; Singh K.; Org. Lett., 2012, 14, 4326.

36. Raghuvanshi D.; Gupta A.; Singh K.; Org. Lett., 2012, 14, 5167.

37. Kantam, M. L.; Prakash, B. V.; Reddy, C. V.; J. Mol. Catal. A: Chem. 2005, 241, 162.

38. Kuwabara, Y.; Ogawa, H.; Inada, H.; Noma, N.; Shirota,Y.; Adv. Mater. 1994, 6, 677.

39. Hu, N.X.; Xie, S.; Popovic, Z.; Ong, B.; Hor, A. M.; J. Am. Chem. Soc.1999, 121, 5097.

40. Kiyomori, A.; Marcoux, J.F.; Buchwald, S. L.; Tetrahedron Lett. 1999, 40, 2657.

41. Maiorana, S.; Baldoli, C.; Buttero, P. D.; Ciolo, M.D.; Papagni, A.; Synthesis 1998, 2, 735.

42. Smith, W. J.; Sawyer, J. S.; Tetrahedron Lett. 1996, 37, 299.

43. Beletskaya, I. P.; Davydov, D. V.; Moreno-Manas, M.; Tetrahedron Lett. 1998, 39, 5617.

44. Zhu L.; Cheng L.; Zhang Y.; Xie R.; You J.; J. Org. Chem., 2007, 72, 2737.

45. Yang K.; Qiu Y.; Li Z.; Wang Z.; Jiang S.; J. Org. Chem., 2011, 76, 3151.

46. Antilla J. C.; Baskin J. M.; Barder T. E.; Buchwald S. L.; J. Org. Chem., 2004, 69,

5578.

47. Palaniswamy S.; Kasi P.; J. Org. Chem., 2008, 73, 9121–9124.

48. Cristau H. J.; Cellier P. P.; Spindler J. F.; Taillefer M.; Chem. Eur. J., 2004, 10, 5607.

49. Taillefer M.; Xia N.; Ouali A.; Angew. Chem. Int. Ed., 2007, 46, 934.

50. Song R. J.; Deng C. L.; Xie Y. X.; Li J. H.; Tetrahedron Lett., 2007, 48, 7845.

51. Mukhopadhyay C.; Tapaswi P. K.; Synthetic Communications, 2012, 42, 2217.

52. Wang D.; Zhang F.; Kuang D.; Yu J.; Lia J.; Green Chem., 2012, 14, 1268.

53. Meciarova M.; Toma S.; Magdolen P.; Ultrasonics Sonochemistry, 2003, 10, 265.

54. Magdolen P.; Meciarova M.; Toma S.; Tetrahedron Letters, 2001, 57, 4781.

55. Lopez-Alvarado P.; Avendaiio C.; Menkndez J. C.; J. Org. Chem., 1995, 60, 5678.

56. Lam P. Y. S.; Clark C. G.; Saubern S.; Adams J.; Winters M. P.; Chan D. M. T.; Combs A.;

Tetrahedron Letters, 1998, 39, 2941.

57. Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Juan, L.; Iovanna, J. L.; Peng,

L.; Helv. Chim. Acta 2009, 92, 1503.

58. Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X.; Tetrahedron Lett. 2007, 48,

3525.

59. Guillou, S.; Bonhomme, F. J.; Janin, Y. L.; Tetrahedron, 2009, 65, 2660.

60. Benard, S.; Neuville, L.; Zhu, J.; J. Org. Chem., 2008, 73, 6441.

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