Efficient syntheses of 1,2,3-triazoloamide derivatives using solid- and solution-phase synthetic approaches

Article

Efﬁcient Syntheses of 1,2,3-Triazoloamide

Derivatives Using Solid- and Solution-Phase

Synthetic Approaches

Doohyun Lee ¹, Daehun Kim ¹, Seungyeon Lee ¹, Taegeum Kim ¹, Joobin Kim ¹, Sohee Kim ¹,

Kwang-Hyeon Liu ¹, Sangkyu Lee ¹, Jong-Sup Bae ¹, Kyung-Sik Song ¹, Chang-Woo Cho ²,

Youn Kyung Son ³, Dong Jae Baek ^4,* and Taeho Lee ^1,

*

Received: 16 September 2015 ; Accepted: 29 October 2015 ; Published: 5 November 2015

Academic Editors: Wim Dehaen and Derek J. McPhee

1

College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University,

80 Daehak-ro, Buk-gu, Daegu 702-701, Korea; newkiy@hanmail.net (D.L.); eogns1201@nate.com (D.K.);

tmddusj@naver.com (S.L.); eksvnddlv321@naver.com (T.K.); joobin87@naver.com (J.K.);

ksh71051@naver.com (S.K.); dstlkh@knu.ac.kr (K.-H.L.); sangkyu@knu.ac.kr (S.L.);

baejs@knu.ac.kr (J.-S.B.); kssong@knu.ac.kr (K.-S.S.)

2

Department of Chemistry, Kyungpook National University, 80 Daehak-ro, Buk-gu, Daegu 702-701, Korea;

cwcho@knu.ac.kr

3

National Institute of Biological Resources, Hwangyeong-ro 42, Seo-gu, Incheon 404-708, Korea;

sophy004@korea.kr

4

College of Pharmacy, Natural Medicine Research Institute, Mokpo National University, 1666 Youngsan-ro,

Muan-gun, Jeonnam 534-729, Korea

*

Correspondence: dbaek@mokpo.ac.kr (D.J.B.); tlee@knu.ac.kr (T.L.); Tel.: +82-53-950-8573 (T.L.);

Fax: +82-53-950-8557 (T.L.)

Abstract: Efﬁcient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide

derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and

expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide

library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on

amide formation with secondary amines and chloro-acid chlorides; S_N2 reaction with sodium

azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The

target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity

points in excellent overall yields and purities using the reported solid- and solution-phase synthetic

routes, respectively.

Keywords: 1,2,3-triazoloamide; solid-phase synthesis; solution-phase synthesis

1. Introduction

Combinatorial chemistry has emerged as a powerful technique for the synthesis of biologically

active small molecules for the purpose of medicinal chemistry programs within the pharmaceutical

industry [1–5]. Recently, the 1,2,3-triazole moiety, produced by Cu(I)-catalyzed [3 + 2] cycloaddition

reactions, has been used as a scaffold for generating combinatorial libraries [6–10]. 1,2,3-Triazoles can

mimic the topological and electronic features of an amide bond, and this be used as bioisosteres of

the amide moiety. They are particularly stable to reduction, oxidation, and hydrolysis conditions.

Various α-1,2,3-triazoloamide derivatives have been shown to exhibit a wide range of biological

activities [11 –19]. In recent examples, α-1,2,3-triazoloamide related compounds have been developed

and studied as tropomysin receptor kinase A (TrkA) inhibitors [11], as inhibitors of Mycobacterium

tuberculosis [12], as phosphodiesterase 4B (PDE4B) inhibitor for anticancer agents [13], as quorum

Molecules 2015, 20, 19984–20013; doi:10.3390/molecules201119673

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Molecules 2015, 20, 19984–20013

sensing modulators [14], as β-haematin inhibitors for antimalarial agents [15], as γ-secretase

modulators [16], as protein tyrosine phosphatase (PTPs) inhibitors [17], as lymphoid tyrosin

phosphatase (Lyp, PTPN22) inhibitors [18], and as glucokinase (GK) acitvators [19].

Previously, we have reported a solid-phase synthetic protocol for the preparation of secondary

α-1,2,3-triazoloamides 1 (R²= H, Figure 1) [20]. However, an expanded α-1,2,3-triazoloamide

library was needed for our drug discovery project, which includes the secondary and

tertiary 1,2,3-triazoloamides. Herein, we describe the construction of expanded libraries of

secondary α-1,2,3-triazoloamides 1 on solid-phase and of tertiary 1,2,3-triazoloamides 2 in parallel

solution-phase, which is applicable to high-throughput construction of drug-like compound libraries.

Figure 1. Structure and use of 1,2,3-triazoloamides 1 and 2.

2. Results and Discussion

The synthetic sequence for secondary α-1,2,3-triazoloamides 1 (R²= H) is shown in

Scheme 1 [20]. According to the solid-phase synthetic approach with the polymer-bound amines 3,

which were prepared by reductive amination reaction from Acid sensitive Methoxy Benzaldehyde

(AMEBA) [20 ,21] resin 4 and primary amines 5 (the ﬁrst diversity element R¹; Figure 2),

polymer-bound chloroamides 7 can be easily prepared by the reaction of amine resin 3 with

chloro-acid chloride 6 (the second diversity element A; Figure 3) and triethylamine in CH₂Cl₂at

room temperature. Treatment of solid supported chloroamides 7 (R = Cl, A = CH₂or CHCH₃) with

sodium azide in DMF at room temperature, provides the α-azidoamide resin 8 (R = N₃).

Scheme 1. Solid-phase synthesis of secondary α-1,2,3-triazoloamide derivatives 1.

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Molecules 2015, 20, 19984–20013

Figure 2. Diversity reagents 5 for secondary α-1,2,3-triazoloamides 1.

Figure 3. Diversity reagents 6 for 1,2,3-triazoloamides 1 and 2.

In the case of β-chloroamide 7ac, which was prepared by the reaction of amine resin 3a and

3-chloropropionyl chloride (6c), the S_N2 reaction with sodium azide gave the undesired acrylamide

12 because of an elimination of β-chloroamide (Scheme 2). The reaction was conﬁrmed by ATR-FTIR

analysis of resin 11 and the cleavage of the resin 11 under 30% TFA in CH₂Cl₂at room temperature

provided an N-phenylacrylamide (12) [22,23] as a major product.

Scheme 2. Reaction of amine resin 3a and 3-chloropropionyl chloride (6c).

The selective [3 + 2] Hüisgen cycloaddition [24 –29] was performed with α-azidoamide resin 8

and terminal acetylene 9 (the third diversity element R³; Figure 4) according to optimized reaction

condition (3 equiv. CuI, 3 equiv. sodium ascorbate, DMF/piperidine (4:1), room temperature) [20].

The well-known methods for the synthesis of 1,2,3-triazoles (catalytic CuSO₄/sodium ascorbate

or CuI/diisopropylethylamine as reagents and H₂O/t-BuOH, EtOH, or THF as solvent) were not

very efﬁcient. Under the general cleavage conditions of AMEBA resin (30% TFA, CH₂Cl₂, room

temperature), the resulting polymer-bound product 10aaa gave the desired α-1,2,3-triazoloamide

1aaa (44%) and by-product 13 (30%), while unreacted resin 10aaa remained as was conﬁrmed by

ATR-FTIR analysis (Scheme 3).

Figure 4. Diversity reagents 9 for 1,2,3-triazoloamides 1 and 2.

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Scheme 3. Cleavage of α-1,2,3-triazoloamide resin 10aaa.

Finally, the α-1,2,3-triazoloamide resin 10aaa was cleaved from the solid support under 30% TFA

˝

in CH₂Cl₂at 45 C to provide the desired α-1,2,3-triazoloamide 1aaa [24,27,30] (93% over six steps,

from Merriﬁeld resin) without formation of by-product 13.

The reaction progress on solid-phase was monitored by ATR-FTIR (Figure 5). The progress of

reductive amination of AMEBA resin 4 and amine 5a (R¹= Ph) was checked by the appearance of the

´1

weak NH stretching band at 3424 cm and the disappearance of the aldehyde stretching band at

1678 cm^´1. The progression of amide formation for 7aa (R¹= Ph, A = CH₂) was monitored by

´1

ATR-FTIR which displayed the disappearance of the characteristic NH band at 3424 cm

and

appearance of the amide carbonyl stretching band at 1666 cm^´1. The S_N2 reaction of 7aa (R¹= Ph,

A = CH₂) with sodium azide was monitored by the appearance of the azide stretching band at

2101 cm^´1. The completion of selective [3 + 2] Hüisgen cycloaddition of 7aa and 9a was conﬁrmed

by the disappearance of the azide stretching band.

Figure 5. ATR-FTIR spectra of resins 3, 4, 7, 8 and 10 (R¹= R²= Ph, A = CH₂).

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Following the optimized solid-phase synthetic route, the secondary α-1,2,3-triazoloamide

derivatives 1 were prepared starting from Merriﬁeld resin and appropriate primary amines 5

(R¹NH₂; Figure 2), α-chloroacetyl chlorides 6a and 6b (Cl-A-COCl; Figure 3), and terminal

acetylenes 9 (R³C”CH; Figure 4) and the products displayed in Table 1. In most cases, secondary

α-1,2,3-triazoloamide derivatives 1 (80 examples) were obtained with high yields (94%–75%) and

high purities, >95% as judged from LC-MS traces (integration of 200–400 nm diode array traces).

Table 1. Prepared secondary α-1,2,3-triazoloamide derivatives 1 ^a.

Yield

(%) ^b

Yield

(%) ^b

Entry Products R¹

A

R³

Entry Products

R¹

A

R³

1

2

3

4

5

6

7

8

1aaa

1aab

1aac

1aad

1aae

1aaf

Ph

CH₂

Ph

4-MeO-Ph

4-CN-Ph

3-thiophenyl 82

2-pyridyl

n-Bu

Ph

4-MeO-Ph

4-CN-Ph

93

91

83

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

1dan

1dao

1eaa

1eab

1eac

1ead

1eae

1eaf

1faa

1fab

1fac

1fad

1fae

1faf

1dba

1dbb

1dbc

1dbd

1dbe

1dbg

1dbh

1dbi

1dbj

1dbk

1dbl

1dbm

1dbn

1dbo

1eba

1ebb

1ebc

1ebd

1ebe

1ebf

1fba

1fbb

1fbc

1fbd

1fbe

1fbf

2-MeO-Ph

n-Bu

i-Pr

CH₂

2,4-di-F-Ph

Bn

94

88

81

88

83

80

89

79

87

75

77

84

83

88

91

87

80

83

94

89

94

83

74

82

87

92

86

83

81

79

78

84

81

88

83

78

75

81

82

Ph

4-MeO-Ph

4-CN-Ph

3-thiophenyl

2-pyridyl

n-Bu

85

92

94

89

1baa 4-MeO-Ph CH₂

1bab 4-MeO-Ph CH₂

1bac 4-MeO-Ph CH₂

1bad 4-MeO-Ph CH₂

1bag 4-MeO-Ph CH₂

1baj 4-MeO-Ph CH₂

1bak 4-MeO-Ph CH₂

1bal 4-MeO-Ph CH₂

1bam 4-MeO-Ph CH₂

1ban 4-MeO-Ph CH₂

1bao 4-MeO-Ph CH₂

1caa 3-MeO-Ph CH₂

1cab 3-MeO-Ph CH₂

1cac 3-MeO-Ph CH₂

1cad 3-MeO-Ph CH₂

1cae 3-MeO-Ph CH₂

1cah 3-MeO-Ph CH₂

1caj 3-MeO-Ph CH₂

1cak 3-MeO-Ph CH₂

1cal 3-MeO-Ph CH₂

1cam 3-MeO-Ph CH₂

1can 3-MeO-Ph CH₂

1cao 3-MeO-Ph CH₂

1daa 2-MeO-Ph CH₂

1dab 2-MeO-Ph CH₂

1dac 2-MeO-Ph CH₂

1dad 2-MeO-Ph CH₂

1dae 2-MeO-Ph CH₂

1dag 2-MeO-Ph CH₂

1dah 2-MeO-Ph CH₂

1dai 2-MeO-Ph CH₂

1daj 2-MeO-Ph CH₂

1dal 2-MeO-Ph CH₂

1dam 2-MeO-Ph CH₂

9

Ph

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

3-thiophenyl 85

4-MeO-Ph

4-CN-Ph

3-thiophenyl

2-pyridyl

n-Bu

3-MeO-Ph

3-Me-Ph

2-Me-Ph

4-NMe₂-Ph

4-PhO-Ph

2,4-di-F-Ph

Bn

Ph

4-MeO-Ph

4-CN-Ph

87

89

84

79

92

87

85

91

90

87

i-Pr

2-MeO-Ph CHCH₃

Ph

2-MeO-Ph CHCH₃4-MeO-Ph

2-MeO-Ph CHCH₃4-CN-Ph

2-MeO-Ph CHCH₃3-thiophenyl

2-MeO-Ph CHCH₃2-pyridyl

2-MeO-Ph CHCH₃3-MeO-Ph

2-MeO-Ph CHCH₃2-MeO-Ph

2-MeO-Ph CHCH₃

2-MeO-Ph CHCH₃4-NMe₂-Ph

2-MeO-Ph CHCH₃4-PhO-Ph

2-MeO-Ph CHCH₃2,4-di-F-Ph

3-thiophenyl 76

2-pyridyl

2-MeO-Ph

3-Me-Ph

2-Me-Ph

4-NMe₂-Ph

4-PhO-Ph

2,4-di-F-Ph

Bn

81

83

93

90

91

92

88

94

90

86

4-Me-Ph

3-Me-Ph

2-Me-Ph

2-MeO-Ph CHCH₃

Bn

Ph

n-Bu

i-Pr

CHCH₃

Ph

4-MeO-Ph

4-CN-Ph

CHCH₃4-MeO-Ph

CHCH₃4-CN-Ph

CHCH₃3-thiophenyl

CHCH₃

CHCH₃4-MeO-Ph

CHCH₃4-CN-Ph

CHCH₃3-thiophenyl

CHCH₃

3-thiophenyl 91

2-pyridyl

n-Bu

2-pyridyl

3-MeO-Ph

2-MeO-Ph

4-Me-Ph

3-Me-Ph

4-NMe₂-Ph

4-PhO-Ph

84

86

80

78

85

88

92

Ph

2-pyridyl

n-Bu

i-Pr

a

All reactions were performed on 150–200 mg scale of resin 10 and the purities of compounds 1 were over

95% as judged from LC-MS traces (integration of diode array 200–400 nm traces); ^bSix-step overall yield from

Merriﬁeld resin (loading capacity = 0.94 mmol/g).

With a successful synthetic route for secondary α-1,2,3-triazoloamides 1, the stage progressed to

the tertiary 1,2,3-triazoloamides 2 (R²“ H) (Scheme 4). The chloroamides 15 [31–37] were prepared

from the reaction of secondary amines 14 (the ﬁrst diversity elements R¹and R²; Figure 6) and

chloro-acid chlorides 6a and 6c (the second diversity element A; see Figure 3) with triethylamine

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Molecules 2015, 20, 19984–20013

in CH₂Cl₂at room temperature (99%–92% yields). Followed by S_N2 reaction of tertiary amides

15 with sodium azide to generated the corresponding azidoamides 16 [15,17,38–41] in high yields

(99%–94% yields) (Figure 7). In contrast to the solid-phase synthesis of secondary 1,2,3-triazoloamides

1, treatment of tertiary β-chloroamide 15ac with sodium azide in DMF at room temperature, provided

the corresponding β-azidoamide 16ac in high yield (94% yield) without formation of the undesired

acrylamide. Under the general conditions [6–10,24–28] of the Cu-catalyzed 1,3-dipolar cycloaddition

(catalytic CuSO₄/sodium ascorbate) of azidoamide 16aa and terminal acetylene 9a in H₂O/t-BuOH,

the desired tertiary 1,2,3-triazoloamide 2aaa is generated in high yield (96%).

O

R¹

Et₃N

R¹

R

Cl

+

NH

R²

N

R²

A

Cl

A

CH₂Cl₂, rt

14

6

15

(R = Cl)

NaN₃, MeCN, rt

R³

16 (R = N₃)

O

N

5 mol% CuSO₄

R¹

N

9

R³

N

R²

A

10 mol% Na-ascorbate

t-BuOH, H₂O, rt

2

A

(

= CH₂, CH₂CH₂)

Scheme 4. Solution-phase synthesis of tertiary 1,2,3-triazoloamide derivatives 2.

Figure 6. Diversity reagents 14 for tertiary 1,2,3-triazoloamides 2.

Figure 7. Prepared tertiary amides 15 and sodium azidoamide 16.

By using the parallel solution-phase synthetic route, we were able to prepare a number of tertiary

1,2,3-triazoloamide derivatives 2 displayed in Table 2 starting from appropriate secondary amines 14

(R¹R²NH; Figure 6), chloro-acid chlorides 6a and 6c (Cl-A-COCl; Figure 3), and terminal acetylenes

9 (R³C”CH; Figure 4). In most cases, tertiary 1,2,3-triazoloamide derivatives 1T (80 examples) were

obtained with high yields (99%–84%) from azidoamide 16 and in high purities, >95% as judged from

LC-MS traces (integration of 200–400 nm diode array traces).

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a

Table 2. Prepared tertiary 1,2,3-triazoloamide derivatives 2.

Yield

(%) ^b

Yield

(%) ^b

Entry Products NR¹R²

A

R³

Entry Products NR¹R²

A

R³

1

2

3

4

5

6

7

8

2aaa

2aab

2aac

2aad

2aae

2aag

2aah

2aai

morpholine CH₂

piperidine CH₂

pyrrolidine CH₂

Ph

4-MeO-Ph

4-CN-Ph

91

88

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

2can

2cao

2daa

2dab

2dac

2dad

2dae

2dag

2dah

2dai

2daj

2dak

2dal

2dam

2dan

2dao

2eaa

2eab

2eac

2ead

2eae

2eag

2eah

2eai

pyrrolidine

azepine

NPhMe

CH₂

2,4-di-F-Ph

Bn

Ph

4-MeO-Ph

4-CN-Ph

86

81

87

78

88

3-thiophenyl 87

2-pyridyl

3-MeO-Ph

2-MeO-Ph

4-Me-Ph

3-Me-Ph

2-Me-Ph

4-NMe₂-Ph 81

4-PhO-Ph 94

2,4-di-F-Ph 87

80

89

88

86

89

88

3-thiophenyl 89

2-pyridyl

3-MeO-Ph

2-MeO-Ph

4-Me-Ph

3-Me-Ph

2-Me-Ph

4-NMe₂-Ph

4-PhO-Ph

2,4-di-F-Ph

Bn

78

84

80

88

83

78

82

90

89

86

95

9

2aaj

2aak

2aal

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

2aam

2aan

2aao

2baa

2bab

2bac

2bad

2bae

2bag

2bah

2bai

2baj

2bak

2bal

2bam

2ban

2bao

2caa

2cab

2cac

2cad

2cae

2cag

2cah

2cai

Bn

Ph

89

93

80

92

4-MeO-Ph

4-CN-Ph

3-thiophenyl 93

Ph

4-MeO-Ph

4-CN-Ph

2-pyridyl

3-MeO-Ph

2-MeO-Ph

4-Me-Ph

3-Me-Ph

2-Me-Ph

4-NMe₂-Ph 84

4-PhO-Ph 93

2,4-di-F-Ph 93

95

97

88

97

93

86

3-thiophenyl 85

2-pyridyl

3-MeO-Ph

2-MeO-Ph

4-Me-Ph

3-Me-Ph

2-Me-Ph

Ph

95

89

90

95

93

94

84

80

2eaj

2eak

2aca

2acb

2acc

2acd

2ace

2acg

2ach

2aci

2acj

2ack

2acl

2acm

2acn

2aco

morpholine CH₂CH₂

morpholine CH₂CH₂4-MeO-Ph

morpholine CH₂CH₂4-CN-Ph

Bn

Ph

89

81

77

81

4-MeO-Ph

4-CN-Ph

3-thiophenyl 76

2-pyridyl

3-MeO-Ph

2-MeO-Ph

4-Me-Ph

3-Me-Ph

2-Me-Ph

morpholine CH₂CH₂3-thiophenyl 88

morpholine CH₂CH₂2-pyridyl

morpholine CH₂CH₂3-MeO-Ph

morpholine CH₂CH₂2-MeO-Ph

morpholine CH₂CH₂4-Me-Ph

morpholine CH₂CH₂3-Me-Ph

morpholine CH₂CH₂2-Me-Ph

morpholine CH₂CH₂4-NMe₂-Ph

morpholine CH₂CH₂4-PhO-Ph

morpholine CH₂CH₂2,4-di-F-Ph

79

88

83

88

80

88

82

88

75

80

77

83

79

2caj

2cak

2cal

4-NMe₂-Ph 81

4-PhO-Ph 86

2cam

morpholine CH₂CH₂

Bn

a

All reactions were performed on 0.1 mmol scale of 16 and the purities of compounds 2 were over 95% as

b

judged from LC-MS traces (integration of diode array 200–400 nm traces); Three-step overall yield from

secondary amine 14.

3. Experimental Section

3.1. General

All chemicals were reagent grade and used as purchased. The Merriﬁeld resin (loading

capacity 1.29 mmol/g, 100–200 mesh) was purchased from BeadTech (Seoul, Korea). Reactions were

monitored by TLC analysis using silica gel 60 F-254 thin layer plates (Merck, Darmstadt, Germany) or

ATR-FRIR analysis using a Cary 630 instrument (Agilent Technologies, Santa Clara, CA, USA). Flash

column chromatography was carried out on Merck silica gel 60 (230–400 mesh). The crude products

1

were puriﬁed by parallel chromatography using CombiFlash (Isco, Lincoln, NE, USA). H-NMR

(500 MHz) and ¹³C-NMR (125 MHz) spectra were recorded in δ units relative to deuterated solvent

(CDCl₃, DMSO-d₆, etc.) as internal reference on a 500 MHz NMR instrument (Bruker, Billerca, MA,

USA). LC-MS analysis was performed on ESI mass spectrometer with PDA detection. LC-MS area%

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Molecules 2015, 20, 19984–20013

purities of all products were determined by LC peak area analysis (XBD C18 column, 4.6 mm ˆ 100 mm

;

PDA detector at 200–400 nm; isocratic, 5 mM ammonium formate/CH₃CN (30:70)).

3.2. General Procedure for the Preparation of Secondary α-1,2,3-Triazoloamides 1 on Solid-Phase

A typical procedure for the desired secondary α-1,2,3-triazoloamides 1, as exempliﬁed for

N-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1aaa; R¹= R³= Ph, A = CH₂) follows.

3.2.1. Preparation of AMEBA Resin 4

Merriﬁeld resin (53.2 g, 50.0 mmol, 0.94 mmol/g) was treated with 4-formyl-3-methoxyphenol

(22.8 g, 150.0 mmol), potassium iodide (83.0 mg, 0.5 mmol), and potassium carbonate (20.7 g,

150.0 mmol) in DMF (300 mL). The mixture was shaken at room temperature for 10 h, and then

ﬁltered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuo to give

AMEBA resin 4 (59.0 g): On-bead ATR-FTIR (neat) υ

1678, 1598, 1259 (cm^´1).

max

3.2.2. Preparation of Secondary Amine Resin 3

A mixture of AMEBA resin 4 (10 g, theoretically 8.5 mmol), aniline (5a; (2.3 mL, 25.5 mmol),

sodium triacetoxyborohydride (5.4 g, 25.5 mmol), and acetic acid (0.49 mL, 8.5 mmol) in

˝

1,2-dichloroethane was heated at 50 C for 12 h. The reaction mixture was cooled to room

temperature, and then ﬁltered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried

in a vacuum oven to give secondary amine resin 3a (10.6 g): On-bead ATR-FTIR (neat) υ

1597, 1489 (cm^´1).

3424,

max

3.2.3. Preparation of α-Chloroamide Resin 7

The amine resin 3a (3.0 g, theoretically 2.4 mmol) was treated with 2-chloroacetyl chloride (6a;

˝

0.57 mL, 7.2 mmol) and triethylamine (1.0 mL, 7.2 mmol) in CH₂Cl₂at 0 C. The reaction mixture

was shaken at room temperature for 5 h, and then ﬁltered, washed several times with H₂O, DMF,

MeOH, and CH₂Cl₂, and dried in a vacuum oven to give α-chloroamide resin 7aa (3.16 g): On-bead

ATR-FTIR (neat) υ_max1666, 1593, 1489 (cm^´1).

3.2.4. Preparation of α-Azidoamide Resin 8

The α-chloroamide resin 7aa (2.8 g, theoretically 2.1 mmol) was treated with sodium azide

(0.47 g, 7.2 mmol) in DMF. The reaction mixture was shaken at room temperature for 12 h, and then

ﬁltered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂, and dried in a vacuum oven to

give α-azidoamide resin 8aa (2.8 g): On-bead ATR-FTIR (neat) υ_max2101, 1670, 1590, 1491 (cm^´1).

3.2.5. Preparation of α-1,2,3-Triazoloamide Resin 10

To a mixture of α-azidoamide resin 8aa (570 mg, theoretically 0.42 mmol) and phenylacetylene

(9a, 0.07 mL, 0.6 mmol) in DMF/piperidine (4:1) was added copper(I) iodide (229 mg, 1.27 mmol) and

sodium ascorbate (57 mg, 1.27 mmol) at room temperature. The reaction mixture was shaken at room

temperature for 12 h, and then ﬁltered, washed several times with H₂O, DMF, MeOH, and CH₂Cl₂,

and dried in a vacuum oven to give α-1,2,3-triazoloamide resin 10aaa (606 mg): On-bead ATR-FTIR

(neat) υ_max1669, 1590, 1489 (cm^´1).

3.2.6. Preparation of α-1,2,3-Triazoloamide 1

The α-1,2,3-triazoloamide resin 10aaa (157 mg, theoretically 0.10 mmol) was added 30% TFA

˝

in CH₂Cl₂(3 mL). The reaction mixture was stirred at 45 C for 1day and the mixture was ﬁltered

and washed with CH₂Cl₂and MeOH. The ﬁltrate was evaporated in vacuo and the residue was

dissolved in CH₂Cl₂and extracted with saturated NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂twice and the combined organic extracts were washed with brine, dried over MgSO₄, ﬁltered

19991

Molecules 2015, 20, 19984–20013

and concentrated in vacuo to give the target N-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide

˝

(1aaa) was obtained as a light yellow solid (23 mg, 93% from Merriﬁeld resin). Mp 247–249 C;

¹H-NMR (DMSO-d₆) δ 5.39 (s, 2H), 7.09 (m, 1H), 7.33–7.36 (m, 3H), 7.46 (m, 2H), 7.60 (m, 2H), 7.88

(m, 2H), 8.60 (s, 1H), 10.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 119.3, 123.1, 123.8, 125.1, 127.9, 128.9,

130.7, 138.4, 146.2, 164.2; IR (ATR) υ

3273, 3061, 1677, 1601, 1545, 1442, 1365, 1253, 1202, 1080,

max

753 (cm^´1); LC-MS (ESI) m/z 279 ([M + 1]⁺); HRMS (FAB) calcd for C₁₆H₁₅N₄O ([M + H]⁺) 279.1240,

found 279.1239.

3.3. Characterization Data of Secondary α-1,2,3-Triazoloamides 1

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-N-phenylacetamide (1aab). White solid; Yield: 91%.

¹H-NMR (DMSO-d₆) δ 3.79 (s, 3H), 5.36 (s, 2H), 7.03 (d, J = 8.9 Hz, 2H), 7.09 (m, 1H), 7.35 (m, 2H), 7.60

(m, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.48 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.2, 114.4,

119.3, 122.1, 123.3, 123.8, 126.5, 128.9, 138.4, 146.2, 159.0, 164.2; LC-MS (ESI) m/z 309 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-phenylacetamide (1aac). Light brown solid; Yield: 83%.

¹H-NMR (DMSO-d₆) δ 5.43 (s, 2H), 7.09 (m, 1H), 7.34 (m, 2H), 7.59 (m, 2H), 7.93 (d, J = 8.6 Hz,

2H), 8.09 (d, J = 8.5 Hz, 2H), 8.82 (s, 1H), 10.53 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.5, 110.1, 118.8, 119.2,

123.8, 124.8, 125.7, 128.9, 133.0, 135.2, 138.4, 144.7, 164.0; LC-MS (ESI) m/z 304 ([M + 1]⁺).

1

N-Phenyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1aad). White solid; Yield: 82%. H-NMR

(DMSO-d₆) δ 5.37 (s, 2H), 7.09 (m, 1H), 7.34 (m, 2H), 7.55 (dd, J = 1.2, 5.0 Hz, 1H), 7.59 (m, 2H), 7.66

(dd, J = 3.0, 5.0 Hz, 1H), 7.88 (dd, J = 1.2, 2.9 Hz, 1H), 8.46 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 52.3, 119.2, 120.8, 122.8, 123.8, 125.8, 127.1, 128.9, 132.0, 138.4, 142.8, 164.2; LC-MS (ESI) m/z 285

([M + 1]⁺).

N-Phenyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1aae). White solid; Yield: 85%. ¹H-NMR

(DMSO-d₆) δ 5.42 (s, 2H), 7.09 (m, 1H), 7.33–7.36 (m, 3H), 7.59 (m, 2H), 7.91 (t, J = 7.7 Hz, 1H), 8.06 (d,

J = 7.6 Hz, 1H), 8.62 (s, 2H), 10.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 119.2, 119.4, 123.0, 123.8, 125.0,

128.9, 137.2, 138.4, 147.1, 149.7, 150.0, 164.1; LC-MS (ESI) m/z 280 ([M + 1]⁺).

2-(4-Butyl-1H-1,2,3-triazol-1-yl)-N-phenylacetamide (1aaf).

White solid; Yield: 92%.

¹H-NMR

(DMSO-d₆) δ 0.90 (t, J = 7.3 Hz, 3H), 1.34 (m, 2H), 1.59 (m, 2H), 2.64 (m, 2H), 5.26 (s, 2H), 7.08 (m,

1H), 7.33 (m, 2H), 7.58 (m, 2H), 7.86 (s, 1H), 10.43 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.7, 21.7, 24.6, 31.1,

52.1, 119.2, 123.4, 123.7, 128.9, 138.4, 146.7, 164.4; LC-MS (ESI) m/z 259 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1baa). White solid; Yield: 92%.

¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.34 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.34 (m, 1H), 7.44–7.47

(m, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.87-7.88 (m, 2H), 8.59 (s, 1H), 10.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

52.3, 55.2, 114.1, 120.9, 123.1, 125.2, 127.9, 129.0, 130.7, 131.5, 146.2, 155.6, 163.7; LC-MS (ESI) m/z 309

([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1bab). Yellow solid; Yield:

94%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 3.79 (s, 3H), 5.31 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.02 (d,

J = 8.9 Hz, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.79 (d, J = 8.9 Hz, 2H), 8.47 (s, 1H), 10.36 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 52.3, 55.18, 55.21, 114.1, 114.4, 120.9, 122.1, 123.4, 126.5, 131.5, 155.6, 158.0, 159.0, 163.7;

LC-MS (ESI) m/z 339 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(4-methoxyphenyl)acetamide (1bac). Yellow solid; Yield:

89%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.38 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.50 (d, J = 9.1 Hz,

2H), 7.93 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.81 (s, 1H), 10.39 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 52.9, 55.7, 110.6, 114.5, 119.3, 121.3, 125.2, 126.2, 131.9, 133.5, 135.6, 145.1, 156.1, 163.9; LC-MS (ESI)

m/z 334 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1bad). Light brown solid;

Yield: 85%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.33 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.51 (d,

19992

Molecules 2015, 20, 19984–20013

J = 9.1 Hz, 2H) 7.55 (dd, J = 1.3, 5.0 Hz, 1H), 7.65 (dd, J = 3.0, 5.0 Hz, 1H), 7.88 (dd, J = 1.2, 2.9 Hz,

1H), 8.45 (s, 1H), 10.36 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.2, 114.0, 120.8, 122.7, 125.8, 127.1, 131.5,

132.0, 142.8, 155.6, 163.6; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1bag). White solid; Yield:

87%. ¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 3.88 (s, 3H), 5.23 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 6.93 (ddd,

J = 1.3, 2.5, 7.9 Hz, 1H), 7.34–7.40 (m, 4H), 7.46 (m, 1H), 7.78 (br s, 1H), 7.97 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 52.3, 55.1, 55.2, 110.3, 113.6, 114.0, 117.5, 120.8, 123.2, 130.0, 131.5, 132.1, 146.1, 155.6,

159.7, 163.6; LC-MS (ESI) m/z 339 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1baj). White solid; Yield: 89%.

¹H-NMR (CDCl₃) δ 2.42 (s, 3H), 3.78 (s, 3H), 5.22 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 7.19 (d, J = 7.6 Hz,

1H), 7.34 (t, J = 7.7 Hz, 1H), 7.36 (d, J = 9.1 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.83 (br s, 1H),

7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.0, 52.3, 55.2, 114.0, 120.8, 122.3, 122.9, 125.7, 128.5, 128.8, 130.6,

131.5, 138.0, 146.3, 155.6, 163.6;LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1bak). Light yellow solid; Yield: 84%.

¹H-NMR (CDCl₃) δ 2.50 (s, 3H), 3.79 (s, 3H), 5.25 (s, 2H), 6.86 (d, J = 9.1 Hz, 2H), 7.30–7.32 (m, 3H),

7.38 (d, J = 9.0 Hz, 2H), 7.80 (m, 1H), 7.86 (br s, 1H), 7.87 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 52.2,

55.2, 114.0, 120.8, 124.9, 126.0, 127.8, 128.1, 130.0, 130.9, 131.5, 134.8, 145.3, 155.6, 163.7; LC-MS (ESI)

m/z 323 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(4-methoxyphenyl)acetamide (1bal). Brown solid;

1

Yield: 79%. H-NMR (DMSO-d₆) δ 2.94 (s, 6H), 3.72 (s, 3H), 5.32 (s, 2H), 6.68 (dd, J = 1.9, 8.3 Hz, 1H),

6.79 (d, J = 9.0 Hz, 2H), 7.11 (dd, J = 1.0, 8.1 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H),

7.67 (d, J = 8.9 Hz, 2H), 8.36 (s, 1H), 10.48 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 40.1, 52.2, 55.2, 112.4, 114.1,

118.7, 121.2, 126.1, 131.5, 146.9, 150.1, 155.6, 163.8; LC-MS (ESI) m/z 352 ([M + 1]⁺).

N-(4-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1bam). Light yellow solid;

1

Yield: 92%. H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.34 (s, 2H), 6.91 (d, J = 9.1 Hz, 2H), 7.06–7.10 (m, 4H),

7.17 (m, 1H), 7.40–7.44 (m, 2H), 7.51 (d, J = 9.1 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 8.55 (s, 1H), 10.37 (s,

1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.2, 114.1, 118.9, 119.0, 120.9, 122.7, 123.7,126.1,127.0, 130.2, 131.5,

145.8, 155.6, 156.5, 163.7; LC-MS (ESI) m/z 401 ([M + 1]⁺).

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-N-(4-methoxyphenyl)acetamide (1ban).

Light yellow

solid; Yield: 87%. ¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 5.24 (s, 2H), 6.85 (d, J = 9.1 Hz, 2H), 6.93 (ddd,

J = 2.4, 8.6, 11.0 Hz, 1H), 7.03 (m, 1H), 7.36 (d, J = 9.1 Hz, 2H), 7.70 (br s, 1H), 8.10 (d, J = 3.6 Hz,

1H), 8.30 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.2, 104.6 (t, J_CF= 26.0 Hz), 112.3 (dd,

J_CF= 21.2, 3.5 Hz), 115.2 (dd, J_CF= 13.3, 3.6 Hz), 114.0, 125.2 (d, J_CF= 10.8 Hz), 120.8, 128.5 (dd,

J_CF= 9.8, 5.1 Hz), 131.5, 138.8 (d, J_CF= 2.6 Hz), 155.5, 158.5 (dd, J_CF= 250.3, 12.7 Hz), 161.7 (dd,

J

_CF= 247.4, 12.7 Hz), 163.6; LC-MS (ESI) m/z 345 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(4-methoxyphenyl)acetamide (1bao). White solid; Yield: 85%.

¹H-NMR (CDCl₃) δ 3.78 (s, 3H), 4.13 (s, 2H), 5.09 (s, 2H), 6.84 (d, J = 9.0 Hz, 2H), 7.22–7.34 (m, 7H),

7.37 (s, 1H), 7.81 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 31.3, 52.1, 55.2, 114.0, 120.8, 124.2, 126.2, 128.4,

128.6, 131.5, 139.6, 145.9, 155.6, 163.8; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1caa). Light yellow solid; Yield: 91%.

¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 5.24 (s, 2H), 6.70 (dd, J = 2.2, 8.1 Hz, 1H), 6.97 (dd, J = 1.5, 7.9 Hz,

1H), 7.19–7.23 (m, 2H), 7.37 (m, 1H), 7.44–7.47 (m, 2H), 7.85–7.87 (m, 2H), 7.95 (s, 1H), 7.98 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 52.4, 55.0, 105.0, 109.3, 111.5, 123.0, 125.1, 127.8, 128.9, 129.7, 130.7,139.5, 146.2,

159.6, 164.2; LC-MS (ESI) m/z 309 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1cab). White solid; Yield:

1

90%. H-NMR (CDCl₃) δ 3.79 (s, 3H), 3.86 (s, 3H), 5.22 (s, 2H), 6.70 (dd, J = 2.3, 7.9 Hz, 1H), 6.96–6.99

19993

Molecules 2015, 20, 19984–20013

(m, 3H), 7.18 (t, J = 2.2 Hz, 1H), 7.21 (t, J = 8.2 Hz, 1H), 7.78 (d, J = 8.9 Hz, 2H), 7.88 (s, 1H), 7.91 (s,

1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.0, 55.1, 105.0, 109.3, 111.5, 114.3, 122.1, 123.3, 126.5, 129.7, 139.6,

146.1, 159.0, 159.6, 164.3; LC-MS (ESI) m/z 339 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(3-methoxyphenyl)acetamide (1cac). White solid; Yield:

87%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.41 (s, 2H), 6.68 (dd, J = 1.9, 8.3 Hz, 1H), 7.11 (d,

J = 8.1 Hz, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.29 (t, J = 2.1 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H), 8.08 (d,

J = 8.6 Hz, 2H), 8.81 (s, 1H), 10.52 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.5, 55.0, 105.0, 109.3, 110.1, 111.5,

124.7, 125.7, 129.7, 133.0, 135.2, 139.5, 144.6, 159.6, 164.0; LC-MS (ESI) m/z 334 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1cad). Light brown solid;

Yield: 76%. ¹H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.36 (s, 2H), 6.68 (dd, J = 2.2, 7.9 Hz, 1H), 7.11 (dd,

J = 0.9, 8.1 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H), 7.55 (dd, J = 1.3, 5.0 Hz, 1H), 7.66

(dd, J = 3.0, 5.0 Hz, 1H), 7.88 (dd, J = 1.2, 3.0 Hz, 1H), 8.46 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 52.3, 55.0, 105.0, 109.3, 111.5, 120.8, 122.8, 125.8, 127.1, 129.7, 132.0, 139.5, 142.8, 159.6, 164.2; LC-MS

(ESI) m/z 315 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1cae). Brown solid; Yield: 81%.

¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 5.26 (s, 2H), 6.70 (dd, J = 2.1, 8.2 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H),

7.18–7.22 (m, 2H), 7.28 (m, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.87 (s, 1H), 8.19 (d, J = 7.4 Hz, 1H), 8.33 (s, 1H),

8.61 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.1, 105.1, 109.4, 115.6, 119.5, 123.1, 125.1, 129.9, 137.4,

139.6, 147.1, 149.8, 150.0, 159.7, 164.3; LC-MS (ESI) m/z 310 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1cah). Light yellow solid;

1

Yield: 83%. H-NMR (CDCl₃) δ 3.78 (s, 3H), 3.96 (s, 3H), 5.24 (s, 2H), 6.96 (dd, J = 1.3, 8.1 Hz, 1H), 7.01

(d, J = 8.3 Hz, 1H), 7.11 (dt, J = 0.9, 7.6 Hz, 1H), 7.17 (t, J = 2.2 Hz, 1H), 7.20 (t, J = 8.2 Hz, 1H), 7.36 (m,

1H), 7.92 (br s, 1H), 8.24 (s, 1H), 8.36 (dd, J = 1.7, 7.8 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.0, 55.5,

105.0, 109.2, 111.4, 111.5, 119.1, 120.6, 125.6, 126.5, 128.8, 129.7, 139.6, 141.6, 155.3, 159.5, 164.4; LC-MS

(ESI) m/z 339 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1caj). White solid; Yield: 93%.

¹H-NMR (CDCl₃) δ 2.42 (s, 3H), 3.79 (s, 3H), 5.23 (s, 2H), 6.70 (dd, J = 2.2, 8.1 Hz, 1H), 6.97 (dd,

J = 1.3, 8.0 Hz, 1H), 7.19–7.23 (m, 3H), 7.34 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.71 (s, 1H), 7.94

(br s, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.0, 55.1, 105.0, 109.3, 110.3, 111.5, 113.6, 117.5,

123.7, 129.7, 130.0, 132.0, 139.5, 146.1, 159.6, 159.7, 164.2; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1cak). Light yellow solid; Yield: 90%.

¹H-NMR (CDCl₃) δ 2.50 (s, 3H), 3.79 (s, 3H), 5.26 (s, 2H), 6.71 (dd, J = 2.1, 8.3 Hz, 1H), 6.98 (dd, J = 1.3,

8.0 Hz, 1H), 7.19–7.24 (m, 2H), 7.28-7.32 (m, 3H), 7.79 (m, 1H), 7.87 (s, 1H), 8.00 (br s, 1H); ¹³C-NMR

(DMSO-d₆) δ 21.1, 52.3, 55.0, 105.0, 109.3, 111.5, 124.9, 126.1, 127.8, 128.1, 129.7, 123.0, 130.9, 134.8,

139.6, 145.4, 159.6, 164.3; LC-MS (ESI) m/z 323 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(3-methoxyphenyl)acetamide (1cal). Brown solid;

1

Yield: 91%. H-NMR (DMSO-d₆) δ 2.94 (s, 6H), 3.72 (s, 3H), 5.32 (s, 2H), 6.68 (dd, J = 1.9, 8.3 Hz, 1H),

6.79 (d, J = 9.0 Hz, 2H), 7.11 (dd, J = 1.0, 8.1 Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.1 Hz, 1H),

7.67 (d, J = 8.9 Hz, 2H), 8.36 (s, 1H), 10.48 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 40.0, 52.3, 55.0, 105.0, 109.3,

111.5, 112.4, 118.6, 121.2, 126.1, 129.7, 139.6, 146.8, 150.1, 159.6, 164.3; LC-MS (ESI) m/z 352 ([M + 1]⁺).

N-(3-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1cam). Yellow solid; Yield:

1

91%. H-NMR (DMSO-d₆) δ 3.72 (s, 3H), 5.37 (s, 2H), 6.68 (dd, J = 1.8, 8.3 Hz, 1H), 7.06–7.10 (m, 4H),

7.12 (dd, J = 1.0, 8.1 Hz, 1H), 7.17 (m, 1H), 7.25 (t, J = 8.2 Hz, 1H), 7.30 (t, J = 2.2 Hz, 1H), 7.40–7.44 (m,

2H), 7.88 (d, J = 8.8 Hz, 2H), 8.55 (s, 1H), 10.50 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.0, 105.0, 109.3,

111.5, 118.8, 118.9, 122.7, 123.7, 126.0, 126.9, 129.7, 130.1, 139.5, 145.7, 156.4, 159.6, 164.2; LC-MS (ESI)

m/z 401 ([M + 1]⁺).

19994

Molecules 2015, 20, 19984–20013

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-N-(3-methoxyphenyl)acetamide (1can). Light yellow solid;

Yield: 92%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 5.25 (s, 2H), 6.70 (dd, J = 2.0, 8.4 Hz, 1H), 6.93 (ddd,

J = 2.5, 8.7, 11.1 Hz, 1H), 6.95 (dd, J = 1.7, 7.7 Hz, 1H), 7.03 (m, 1H), 7.19 (t, J = 2.2 Hz, 1H), 7.22 (t,

J = 8.2 Hz, 1H), 7.81 (br s, 1H), 8.10 (d, J = 3.5 Hz, 1H), 8.30 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR

(DMSO-d₆) δ 52.3, 55.0, 104.6 (t, J_CF= 26.1 Hz), 105.0, 109.27, 111.4, 112.3 (dd, J_CF= 21.4, 3.5 Hz),

115.2 (dd, J_CF= 13.4, 3.7 Hz), 125.2 (d, J_CF= 10.9 Hz), 128.5 (dd, J_CF= 9.8, 5.3 Hz), 129.7, 138.9 (d,

J_CF= 2.6 Hz), 139.6, 158.5 (dd, J_CF= 250.7, 12.8), 159.6, 161.7 (dd, J_CF= 247.5, 12.5 Hz), 164.2; LC-MS

(ESI) m/z 345 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(3-methoxyphenyl)acetamide (1cao).

White solid; Yield: 88%.

¹H-NMR (CDCl₃) δ 3.77 (s, 3H), 4.12 (s, 2H), 5.10 (s, 2H), 6.68 (dd, J = 2.1, 8.2 Hz, 1H), 6.94 (dd,

J = 1.1, 7.9 Hz, 1H), 7.17–7.32 (m, 7H), 7.39 (s, 1H), 8.15 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 31.2, 52.1,

55.0, 105.0, 109.2, 111.4, 124.1, 126.1, 128.4, 128.5, 129.7, 139.56, 139.59, 145.9, 159.5, 164.3; LC-MS (ESI)

m/z 323 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1daa). Light yellow solid; Yield: 94%.

¹H-NMR (CDCl₃) δ 3.80 (s, 3H), 5.27 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.96 (dt, J = 1.1, 7.8 Hz, 1H), 7.08

(dt, J = 1.4, 7.9 Hz, 1H), 7.37 (m, 1H), 7.44–7.47 (m, 2H), 7.86–7.88 (m, 2H), 7.99 (s, 1H), 8.24 (s, 1H),

8.27 (dd, J = 1.4, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 111.3, 120.3, 121.7, 123.0, 124.9, 125.1,

126.6, 127.8, 128.9, 130.7, 146.2, 149.6, 164.4; LC-MS (ESI) m/z 309 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dab). White solid; Yield:

90%. ¹H-NMR (CDCl₃) δ 3.79 (s, 3H), 3.85 (s, 3H), 5.25 (s, 2H), 6.84 (dd, J = 1.0, 8.2 Hz, 1H), 6.95

(dt, J = 1.1, 7.7 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.07 (dt, J = 1.5, 7.9 Hz, 1H), 7.79 (d, J = 8.9 Hz,

2H), 7.90 (s, 1H), 8.24 (s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.1, 55.7,

111.3, 114.3, 120.3, 121.7, 122.1, 123.3, 124.9, 126.5, 126.6, 146.1, 149.6, 159.0, 164.5; LC-MS (ESI) m/z 339

([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)acetamide (1dac). White solid; Yield:

86%. ¹H-NMR (DMSO-d₆) δ 3.88 (s, 3H), 5.52 (s, 2H), 6.91 (m, 1H), 7.08–7.13 (m, 2H), 7.92–7.94 (m,

3H), 8.08 (d, J = 8.4 Hz, 2H), 8.80 (s, 1H), 9.81 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.7, 110.1, 111.3,

120.3, 121.8, 124.8, 125.0, 125.7, 126.5, 132.6, 132.6, 133.0, 135.2, 144.6, 149.6, 164.3; LC-MS (ESI) m/z 334

([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1dad). Light brown solid;

Yield: 91%. ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 5.25 (s, 2H), 6.85 (dd, J = 1.0, 8.2 Hz, 1H), 6.96 (dt,

J = 1.1, 7.9 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.41 (dd, J = 3.0, 5.0 Hz, 1H), 7.49 (dd, J = 1.2, 5.1 Hz,

1H), 7.74 (dd, J = 1.2, 3.0 Hz, 1H), 7.89 (s, 1H), 8.22 (br s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR

(DMSO-d₆) δ 52.3, 55.7, 111.3, 120.3, 120.8, 121.7, 122.8, 124.9, 125.8, 126.6, 127.1, 132.0, 142.7, 149.6,

164.4; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1dae). Light brown solid; Yield:

84%. ¹H-NMR (CDCl₃) δ 3.80 (s, 3H), 5.28 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.95 (m, 1H), 7.07 (dt,

J = 1.4, 7.9 Hz, 1H), 7.27 (m, 1H), 7.80 (dt, J = 1.7, 7.8 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 8.25 (br s, 1H),

8.27 (dd, J = 1.4, 8.1 Hz, 1H), 8.34 (s, 1H), 8.61 (d, J = 4.2 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.4, 55.8,

111.4, 119.5, 120.4, 121.9, 123.1, 125.06., 125.10, 126.6, 137.3, 147.1, 149.7, 150.1, 164.5; LC-MS (ESI) m/z

310 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dag). White solid; Yield:

86%. ¹H-NMR (CDCl₃) δ 3.81 (s, 3H), 3.88 (s, 3H), 5.26 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.92 (ddd,

J = 1.0, 2.6, 8.1 Hz, 1H), 6.96 (dt, J = 1.0, 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.35 (t, J = 7.9 Hz,

1H), 7.40 (td, J = 1.2, 7.6 Hz, 1H), 7.48 (dd, J = 1.5, 2.4 Hz, 1H), 7.98 (s, 1H), 8.23 (br s, 1H), 8.27 (dd,

J = 1.3, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.1, 55.7, 110.3, 111.3, 113.6, 117.5, 120.3, 121.8, 123.3,

124.9, 126.6, 130.1, 132.1, 146.1, 149.6, 159.7, 164.4; LC-MS (ESI) m/z 339 ([M + 1]⁺).

19995

Molecules 2015, 20, 19984–20013

N-(2-Methoxyphenyl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dah). Light yellow solid;

Yield: 80%. ¹H-NMR (CDCl₃) δ 3.77 (s, 3H), 3.95 (s, 3H), 5.26 (s, 2H), 6.83 (dd, J = 1.1, 8.2 Hz, 1H),

6.95 (dt, J = 1.2, 7.8 Hz, 1H), 7.00 (dd, J = 0.6, 8.3 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.11 (dt,

J = 1.0, 7.6 Hz, 1H), 7.35 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.25 (s, 1H), 8.27 (br s, 1H), 8.28 (dd,

J = 1.5, 8.1 Hz, 1H), 8.39 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.2, 55.5, 55.7, 111.3,

111.5, 119.1, 120.3, 120.7, 121.7, 124.9, 125.6, 126.5, 126.6, 128.9, 141.6, 149.6, 155.3, 164.6; LC-MS (ESI)

m/z 339 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1dai). Light yellow solid; Yield: 78%.

¹H-NMR (CDCl₃) δ 2.39 (s, 3H), 3.80 (s, 3H), 5.25 (s, 2H), 6.85 (d, J = 8.2 Hz, 1H), 6.96 (t, J = 7.8 Hz,

1H), 7.07 (dt, J = 1.4, 7.9 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H), 8.23 (br

s, 1H), 8.27 (dd, J = 1.5, 8.0 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 52.3, 55.7, 111.3, 120.3, 121.7, 122.6,

124.9, 125.1, 126.6, 128.0, 129.5, 137.1, 146.2, 149.6, 164.5; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (1daj). Light yellow solid; Yield: 85%.

¹H-NMR (CDCl₃) δ 2.42 (s, 3H), 3.80 (s, 3H), 5.26 (s, 2H), 6.85 (dd, J = 0.9, 8.2 Hz, 1H), 6.95 (dt,

J = 1.0, 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.64 (d,

J = 7.7 Hz, 1H), 7.72 (s, 1H), 7.97 (s, 1H), 8.25 (br s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H); ¹³C-NMR

(DMSO-d₆) δ 21.1, 52.3, 55.7, 111.3, 120.3, 121.7, 122.3, 123.0, 124.9, 125.7, 126.6, 128.5, 128.8, 130.6,

138.1, 146.3, 149.6, 164.4; LC-MS (ESI) m/z 323 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(2-methoxyphenyl)acetamide (1dal). Brown solid;

1

Yield: 88%. H-NMR (CDCl₃) δ 3.00 (s, 6H), 3.78 (s, 3H), 5.23 (s, 2H), 6.78 (d, J = 8.9 Hz, 2H), 6.84 (dd,

J = 1.0, 8.1 Hz, 1H), 6.95 (dt, J = 1.1, 7.8 Hz, 1H), 7.07 (dt, J = 1.4, 7.8 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H),

7.83 (s, 1H), 8.24 (br s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 40.0, 52.3, 55.7, 111.3,

112.4, 118.6, 120.3, 121.1, 121.7, 124.9, 126.0, 146.8, 149.6, 150.0, 164.5; LC-MS (ESI) m/z 352 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1dam). Yellow solid; Yield:

1

92%. H-NMR (CDCl₃) δ 3.81 (s, 3H), 5.26 (s, 2H), 6.86 (dd, J = 1.0, 8.2 Hz, 1H), 6.96 (dt, J = 1.1, 7.8 Hz,

1H), 7.02–7.09 (m, 5H), 7.14 (m, 1H), 7.35–7.38 (m, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.94 (s, 1H), 8.24

(br s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 111.3, 118.8, 120.3, 121.7,

122.7, 123.6, 124.9, 126.1, 126.6, 126.9, 130.1, 145.7, 149.6, 156.40, 156.41, 166.4; LC-MS (ESI) m/z 401

([M + 1]⁺).

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)acetamide (1dan).

Light yellow

solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 3.82 (s, 3H), 5.28 (s, 2H), 6.86 (dd, J = 1.0, 8.2 Hz, 1H), 6.93

(ddd, J = 2.5, 8.6, 11.0 Hz, 1H), 6.96 (dt, J = 1.1, 7.8 Hz, 1H), 7.03 (m, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H),

8.12 (d, J = 3.6 Hz, 1H), 8.21 (br s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H), 8.31 (dt, J = 6.5, 8.6 Hz, 1H);

¹³C-NMR (DMSO-d₆) δ 52.3, 55.7, 104.6 (t, J = 26.0 Hz), 111.3, 112.3 (dd, J = 21.4, 3.5 Hz), 115.2 (dd,

J = 13.5, 3.7 Hz), 120.3, 121.8, 124.9, 125.2 (d, J = 11.1 Hz), 126.6, 128.5 (dd, J = 9.7, 5.3 Hz), 138.8 (d,

J = 2.9 Hz), 149.6, 158.5 (dd, J_CF= 250.5, 12.5 Hz), 161.7 (dd, J_CF= 247.4, 12.5 Hz), 164.4; LC-MS (ESI)

m/z 345 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)acetamide (1dao). White solid; Yield: 88%.

¹H-NMR (CDCl₃) δ 3.77 (s, 3H), 4.14 (s, 2H), 5.14 (s, 2H), 6.84 (dd, J = 0.9, 8.2 Hz, 1H), 6.94 (dt,

J = 1.1, 7.8 Hz, 1H), 7.07 (dt, J = 1.4, 7.9 Hz, 1H), 7.20–7.32 (m, 5H), 7.40 (s, 1H), 8.20 (br s, 1H), 8.25

(dd, J = 1.4, 8.0 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 31.2, 52.1, 55.7, 111.3, 120.3, 121.6, 124.1, 124.8, 126.1,

126.5, 128.4, 128.5, 139.6, 145.8, 149.5, 164.5; LC-MS (ESI) m/z 323 ([M + 1]⁺).

N-Butyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1eaa). White solid; Yield: 81%. ¹H-NMR

(DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.12 (m, 2H), 5.11 (s, 2H), 7.33 (t,

J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.86 (d, J = 7.5 Hz, 2H), 8.32 (br s, 1H), 8.51 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 13.6, 19.5, 31.0, 38.4, 51.8, 122.9, 125.1, 127.8, 128.9, 130.7, 146.1, 165.1; LC-MS (ESI) m/z

259 ([M + 1]⁺).

19996

Molecules 2015, 20, 19984–20013

N-Butyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1eab).

White solid; Yield: 88%.

¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.11 (m, 2H), 3.79 (s, 3H),

5.09 (s, 2H), 7.01 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 8.31 (br s, 1H), 8.39 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 13.6, 19.5, 31.0, 38.4, 51.7, 55.1, 114.3, 121.9, 123.4, 126.4, 146.0, 158.9, 165.2; LC-MS (ESI)

m/z 289 ([M + 1]⁺).

N-Butyl-2-[4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl]acetamide (1eac). White solid; Yield: 83%. ¹H-NMR

(DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.09 (m, 2H), 5.15 (s, 2H), 7.92 (d,

J = 8.5 Hz, 2H), 8.07 (d, J = 8.5 Hz, 2H), 8.36 (br s, 1H), 8.74 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 19.5,

31.0, 38.5, 51.9, 110.0, 118.8, 124.6, 125.6, 133.0, 135.2, 144.5, 164.9; LC-MS (ESI) m/z 284 ([M + 1]⁺).

N-Butyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1ead). White solid; Yield: 80%. ¹H-NMR

(DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.11 (m, 2H), 5.10 (s, 2H), 7.53 (dd,

J = 1.3, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 4.9 Hz, 1H), 7.86 (dd, J = 1.2, 2.9 Hz, 1H), 8.32 (br s, 1H), 8.38 (s,

1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 13.7, 19.5, 21.6, 24.6, 31.0, 31.1, 38.4, 51.5, 123.2, 146.5, 165.3; LC-MS

(ESI) m/z 265 ([M + 1]⁺).

N-Butyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1eae). Light yellow solid; Yield: 89%.

¹H-NMR (DMSO-d₆) δ 0.88 (t, J = 7.3 Hz, 3H), 1.31 (m, 2H), 1.43 (m, 2H), 3.11 (m, 2H), 5.15 (s, 2H),

7.34 (dd, J = 5.1, 6.6 Hz, 1H), 7.89 (dt, J = 1.7, 7.7 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H),8.31 (br s, 1H), 8.51

(s, 1H), 8.60 (d, J = 4.4 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6,19.5, 31.0, 38.4, 51.8, 119.3, 122.9, 124.8,

137.1, 146.9, 149.6, 150.0, 165.0; LC-MS (ESI) m/z 260 ([M + 1]⁺).

1

N-Butyl-2-(4-butyl-1H-1,2,3-triazol-1-yl)acetamide (1eaf). White solid; Yield: 89%. H-NMR (DMSO-d₆)

δ 0.87 (t, J = 7.3 Hz, 3H), 0.89 (t, J = 7.4 Hz, 3H), 1.31 (m, 4H), 1.40 (m, 2H), 1.57 (m, 2H), 2.61 (t,

J = 7.6 Hz, 2H), 3.09 (m, 2H), 4.99 (s, 2H), 7.76 (s, 1H), 8.23 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6,

19.5, 31.0, 38.5, 51.7, 120.7, 122.7, 125.8, 127.1, 132.1, 142.7, 165.1; LC-MS (ESI) m/z 239 ([M + 1]⁺).

N-Isopropyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (1faa). White solid; Yield: 79%. ¹H-NMR

(DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.86 (m, 1H), 5.08 (s, 2H), 7.33 (t, J = 7.4 Hz, 1H), 7.45 (t,

J = 7.7 Hz, 2H), 7.86 (d, J = 7.1 Hz, 1H), 8.29 (d, J = 7.4 Hz, 1H), 8.51 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

22.3, 40.9, 51.8, 122.9, 125.1, 127.8, 128.9, 130.8, 146.1, 164.2; LC-MS (ESI) m/z 245 ([M + 1]⁺).

N-Isopropyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]acetamide (1fab). Light yellow solid; Yield:

87%. ¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.79 (s, 3H), 3.85 (m, 1H), 5.05 (s, 2H), 7.01

(d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 8.28 (d, J = 7.6 Hz, 1H), 8.39 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 22.3, 40.9, 51.8, 55.1, 114.3, 122.0, 123.4, 126.5, 146.0, 159.0, 164.3; LC-MS (ESI) m/z 275 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-isopropyl-acetamide (1fac). Light brown solid; Yield: 75%.

¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.85 (m, 1H), 5.12 (s, 2H), 7.92 (d, J = 8.6 Hz, 2H), 8.07

(d, J = 8.6 Hz, 2H), 8.32 (d, J = 7.4 Hz, 1H), 8.73 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 22.2, 41.0, 51.9, 110.1,

118.8, 124.7, 125.7, 133.0, 135.2, 144.5, 164.0; LC-MS (ESI) m/z 270 ([M + 1]⁺).

N-Isopropyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (1fad).

White solid; Yield: 77%.

¹H-NMR (DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.85 (m, 1H), 5.07 (s, 2H), 7.53 (dd, J = 1.2, 5.0 Hz,

1H), 7.64 (dd, J = 2.9, 5.0 Hz, 1H), 7.86 (dd, J = 1.2, 2.9 Hz, 1H), 8.28 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 22.3, 40.9, 51.7, 120.7, 122.7, 125.8, 127.1, 132.1, 142.7, 164.2; LC-MS (ESI) m/z

251 ([M + 1]⁺).

1

N-Isopropyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (1fae). White solid; Yield: 84%. H-NMR

(DMSO-d₆) δ 1.10 (d, J = 6.6 Hz, 6H), 3.85 (m, 1H), 5.11 (s, 2H), 7.34 (ddd, J = 1.2, 4.8, 7.5 Hz, 1H),

7.89 (dt, J = 1.8, 7.7 Hz, 1H), 8.03 (td, J = 1.0, 7.9 Hz, 1H),8.28 (d, J = 7.5 Hz, 1H), 8.51 (s, 1H), 8.60 (m,

1H); ¹³C-NMR (DMSO-d₆) δ 22.3, 41.0, 51.8, 119.4, 122.9, 124.8, 137.2, 146.9, 149.6, 150.0, 164.2; LC-MS

(ESI) m/z 246 ([M + 1]⁺).

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Molecules 2015, 20, 19984–20013

2-(4-Butyl-1H-1,2,3-triazol-1-yl)-N-isopropylacetamide (1faf). White solid; Yield: 83%. ¹H-NMR

(DMSO-d₆) δ 0.89 (t, J = 7.3 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 1.32 (m, 2H), 1.57 (m, 2H), 2.61 (d,

J = 7.6 Hz, 2H), 3.82 (m, 1H), 4.96 (s, 2H), 7.76 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ

13.7, 21.7, 22.2, 24.6, 31.1, 40.8, 51.5, 123.2, 146.5, 164.4; LC-MS (ESI) m/z 251 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide (1dba). Yellow solid; Yield: 88%.

¹H-NMR (CDCl₃) δ 1.98 (d, J = 7.3 Hz, 3H), 3.81 (s, 3H), 5.50 (q, J = 7.2 Hz, 1H), 6.84 (dd, J = 1.2,

8.2 Hz, 1H), 6.95 (dt, J = 1.1, 7.8 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.36 (m, 1H), 7.43–7.46 (m,

2H), 7.85–7.87 (m, 2H), 8.01 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.32 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 18.0, 55.8, 58.5, 111.3, 120.2, 120.8, 122.1, 125.1, 127.8, 128.9, 146.1, 149.9, 167.6; LC-MS (ESI) m/z 323

([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbb). White solid;

1

Yield: 91%. H-NMR (CDCl₃) δ 3.79 (s, 3H), 3.85 (s, 3H), 5.25 (s, 2H), 6.84 (dd, J = 1.0, 8.2 Hz, 1H), 6.95

(dt, J = 1.1, 7.7 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 7.07 (dt, J = 1.5, 7.9 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H),

7.90 (s, 1H), 8.24 (s, 1H), 8.27 (dd, J = 1.5, 8.1 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.1, 55.8, 58.5,

111.3, 114.3, 119.9, 120.2, 122.1, 123.4, 125.2, 126.38, 126.44, 146.0, 149.9, 158.9, 167.6; LC-MS (ESI) m/z

353 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)propanamide (1dbc). Light yellow solid;

1

Yield: 87%. H-NMR (CDCl₃) δ 1.98 (d, J = 7.2 Hz, 3H),5.53 (q, J = 7.2 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H),

6.96 (t, J = 7.8 Hz, 1H), 7.08 (dt, J = 1.4, 7.9 Hz, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.98 (d, J = 8.5 Hz, 2H),

8.15 (s, 1H), 8.27 (dd, J = 1.4, 8.1 Hz, 1H), 8.30 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.7, 110.1,

111.4, 118.8, 120.2, 122.2, 122.7, 125.3, 125.6, 126.3, 133.0, 135.2, 144.6, 150.0, 167.5; LC-MS (ESI) m/z 348

([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propanamide (1dbd). Light brown oil;

Yield: 80%. ¹H-NMR (CDCl₃) δ 1.94 (d, J = 7.3 Hz, 3H), 3.78 (s, 3H), 5.52 (q, J = 7.2 Hz, 2H), 6.83

(dd, J = 1.1, 8.2 Hz, 1H), 6.90 (dt, J = 1.2, 8.4 Hz, 1H), 7.05 (m, 1H), 7.38 (dd, J = 3.0, 5.0 Hz, 1H), 7.47

(dd, J = 1.2, 5.0 Hz, 1H), 7.71 (dd, J = 1.2, 3.0 Hz, 1H), 7.95 (s, 1H), 8.26 (dd, J = 1.5, 8.1 Hz, 1H), 8.38

(br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.1, 55.8, 58.4, 111.4, 120.3, 120.6, 120.7, 122.1, 125.2, 125.8, 127.1,

132.1, 142.7, 149.9, 167.6; LC-MS (ESI) m/z 329 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide (1dbe). Colorless oil; Yield:

1

83%. H-NMR (CDCl₃) δ 1.97 (d, J = 7.2 Hz, 3H), 3.78 (s, 3H), 5.53 (q, J = 7.2 Hz, 1H), 6.82 (dd, J = 1.1,

8.2 Hz, 1H), 6.92 (dt, J = 1.1, 7.8 Hz, 1H), 7.04 (dt, J = 1.5, 7.9 Hz, 1H), 7.24 (ddd, J = 1.2, 4.9, 7.6 Hz,

1H), 7.78 (dt, J = 1.8, 7.8 Hz, 1H), 8.18 (dd, J = 0.9, 8.8 Hz, 1H), 8.26 (dd, J = 1.6, 8.1 Hz, 1H), 8.36 (br

s, 1H), 8.39 (s, 1H), 8.59 (ddd, J = 0.9, 1.7, 4.8 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.7, 111.4,

119.4, 120.3, 122.2, 122.7, 123.0, 125.2, 126.4, 137.2, 147.0, 149.6, 149.9, 150.0, 167.5; LC-MS (ESI) m/z 324

([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbg). Light yellow oil;

1

Yield: 94%. H-NMR (CDCl₃) δ 1.95 (d, J = 7.2 Hz, 3H), 3.77 (s, 3H), 3.85 (s, 3H), 5.53 (q, J = 7.2 Hz,

1H), 6.82 (dd, J = 1.2, 8.2 Hz, 1H), 6.89 (ddd, J = 1.0, 2.6, 8.2 Hz, 1H), 6.92 (dt, J = 1.2, .8 Hz, 1H), 7.04

(dt, J = 1.6, 7.9 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.39 (td, J = 1.3, 7.7 Hz, 1H), 7.46 (dd, J = 1.5, 2.5 Hz,

1H), 8.04 (s, 1H), 8.26 (dd, J = 1.6, 8.1 Hz, 1H), 8.39 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.1, 55.8,

58.5, 110.3, 111.4, 113.7, 117.4, 120.3, 121.2, 122.1, 125.2, 126.4, 130.0, 132.1, 146.0, 149.9, 159.7, 167.6;

LC-MS (ESI) m/z 353 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbh). Light yellow oil;

1

Yield: 89%. H-NMR (CDCl₃) δ 1.98 (d, J = 7.3 Hz, 3H), 3.75 (s, 3H), 3.92 (s, 3H), 5.51 (q, J = 7.3 Hz,

1H), 6.80 (dd, J = 1.2, 8.2 Hz, 1H), 6.92 (dt, J = 1.2, 7.8 Hz, 1H), 6.97 (dd, J = 0.6, 8.3 Hz, 1H), 7.03 (dt,

J = 1.5, 7.9 Hz, 1H), 7.08 (dt, J = 1.0, 7.5 Hz, 1H), 7.32 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.25 (s, 1H), 8.27

(dd, J = 1.6, 8.1 Hz, 1H), 8.37 (dd, J = 1.7, 7.7 Hz, 1H), 8.41 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.1. 55.5.

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Molecules 2015, 20, 19984–20013

55.8. 58.5. 111.4. 111.5. 119.0. 120.3. 120.6. 122.1. 123.0. 125.2. 126.4. 126.6. 128.9. 141.7. 149.9. 155.4.

167.6; LC-MS (ESI) m/z 353 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)propanamide (1dbi). Light yellow solid; Yield:

94%. ¹H-NMR (CDCl₃) δ 1.97 (d, J = 7.3 Hz, 3H), 2.38 (s, 3H), 3.80 (s, 3H), 5.49 (q, J = 7.2 Hz, 1H),

6.84 (dd, J = 1.0, 8.2 Hz, 1H), 6.94 (dt, J = 1.1, 7.8 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.25 (d,

J = 7.9 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H), 7.97 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.33 (br s, 1H);

¹³C-NMR (DMSO-d₆) δ 18.0, 20.8, 55.8, 58.5, 111.3, 120.2, 120.4, 122.1, 125.0, 125.2, 126.4, 128.0, 129.4,

137.1, 146.2, 149.9, 167.6; LC-MS (ESI) m/z 337 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)propanamide (1dbj). Light yellow solid; Yield:

1

83%. H-NMR (CDCl₃) δ 1.97 (d, J = 7.3 Hz, 3H), 2.41 (s, 3H), 3.80 (s, 3H), 5.51 (q, J = 7.2 Hz, 1H), 6.84

(dd, J = 1.1, 8.2 Hz, 1H), 6.94 (dt, J = 1.2, 7.8 Hz, 1H), 7.06 (dt, J = 1.5, 7.9 Hz, 1H), 7.17 (d, J = 7.6 Hz,

1H), 7.32 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 8.00 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz,

1H), 8.34 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 20.8, 55.8, 58.5, 111.3, 120.2, 120.4, 122.1, 125.0, 125.1,

126.4, 128.0, 129.4, 137.1, 146.2, 149.9, 167.6; LC-MS (ESI) m/z 337 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)propanamide (1dbk). Light yellow solid; Yield:

74%. ¹H-NMR (acetone-d₆) δ 1.97 (d, J = 7.2 Hz, 3H), 2.52 (s, 3H), 3.84 (s, 3H), 5.85 (q, J = 7.3 Hz,

1H), 6.93 (m, 1H), 7.02 (d, J = 7.1 Hz, 1H), 7.25–7.32 (m, 3H), 7.82 (m, 1H), 8.26 (m, 1H), 8.41 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 18.5, 21.5, 56.3, 59.1, 111.8, 120.8, 122.6, 123.2, 125.7, 126.5, 127.0, 128.3, 128.8,

130.5, 131.3, 135.5, 146.0, 150.4, 166.3; LC-MS (ESI) m/z 337 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-N-(2-methoxyphenyl)propanamide (1dbl). Brown

solid; Yield: 82%. ¹H-NMR (CDCl₃) δ 1.96 (d, J = 7.3 Hz, 3H), 3.00 (s, 6H), 3.79 (s, 3H), 5.47 (q,

J = 7.2 Hz, 2H), 6.77 (d, J = 9.0 Hz, 2H), 6.83 (dd, J = 1.1, 8.2 Hz, 1H), 6.94 (dt, J = 1.2, 7.8 Hz, 1H), 7.05

(dt, J = 1.5, 7.9 Hz, 1H), 7.72 (d, J = 8.9 Hz, 2H), 7.85 (s, 1H), 8.28 (dd, J = 1.6, 8.1 Hz, 1H), 8.32 (br s,

1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 40.0, 55.8, 58.4, 111.3, 112.3, 118.7, 118.9, 120.3, 122.0, 125.1, 126.0,

126.4, 146.7, 149.9, 150.0, 167.7; LC-MS (ESI) m/z 366 ([M + 1]⁺).

N-(2-Methoxyphenyl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1dbm). Light yellow oil;

Yield: 87%. ¹H-NMR (CDCl₃) δ 1.97 (d, J = 7.3 Hz, 3H), 3.80 (s, 3H), 5.52 (q, J = 7.2 Hz, 1H), 6.84

(dd, J = 1.2, 8.2 Hz, 1H), 6.94 (m, 1H), 7.02–7.08 (m, 5H), 7.15 (m, 1H), 7.34–7.37 (m, 2H), 7.82 (d,

J = 8.8 Hz, 2H), 7.99 (s, 1H), 8.28 (dd, J = 1.5, 8.1 Hz, 1H), 8.37 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0,

55.8, 80.0, 111.3, 118.2, 118.81, 118.86, 119.4, 120.3, 120.5, 123.6, 126.9, 130.1, 130.2, 133.6, 145.7, 149.9,

156.39, 156.42, 167.6; LC-MS (ESI) m/z 415 ([M + 1]⁺).

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-N-(2-methoxyphenyl)propanamide (1dbn). Light yellow

solid; Yield: 92%. ¹H-NMR (CDCl₃) δ 1.99 (d, J = 7.3 Hz, 3H), 3.82 (s, 3H), 5.51 (q, J = 7.2 Hz, 2H),

6.85 (dd, J = 1.2, 8.2 Hz, 1H), 6.92 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.95 (dt, J = 1.1, 7.8 Hz, 1H), 7.01

(m, 1H), 7.07 (dt, J = 1.5, 7.9 Hz, 1H), 8.12 (d, J = 3.5 Hz, 1H), 8.28 (dd, J = 1.6, 8.1 Hz, 1H), 8.29 (dt,

J = 6.5, 8.6 Hz, 1H), 8.31 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 55.8, 58.7, 104.6 (t, J_CF= 25.9 Hz), 111.4,

112.30 (dd, J_CF= 21.6, 3.6 Hz), 115.20 (dd, J_CF= 13.4, 3.8 Hz), 120.3, 122.2, 122.8 (d, J_CF= 10.3 Hz),

125.3, 126.3, 128.7 (dd, J_CF= 9.8, 5.2 Hz), 139.1 (d, J_CF= 2.6 Hz), 150.0, 158.5 (dd, J_CF= 250.5, 12.8 Hz),

161.86 (dd, J_CF= 247.8, 12.6 Hz), 167.5; LC-MS (ESI) m/z 359 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-N-(2-methoxyphenyl)propanamide (1dbo). Light yellow oil; Yield: 86%.

¹H-NMR (CDCl₃) δ 1.88 (d, J = 7.3 Hz, 3H), 3.77 (s, 3H), 4.12 (s, 2H), 5.39 (q, J = 7.3 Hz, 1H), 6.83 (dd,

J = 1.1, 8.2 Hz, 1H), 6.93 (dt, J = 1.2, 7.8 Hz, 1H), 7.05 (dt, J = 1.5, 7.9 Hz, 1H), 7.23 (m, 1H), 7.26–7.31

(m, 4H), 7.42 (s, 1H), 8.25 (dd, J = 1.5, 8.1 Hz, 1H), 8.33 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 31.2,

55.7, 58.3, 111.3, 120.2, 121.8, 122.0, 125.1, 126.1, 126.4, 128.4, 128.5, 139.6, 145.8, 149.9, 167.6; LC-MS

(ESI) m/z 337 ([M + 1]⁺).

N-Butyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide (1eba). White solid; Yield: 83%. ¹H-NMR

(DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.41 (m, 2H), 1.71 (d, J = 7.2 Hz, 3H), 3.10 (m,

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Molecules 2015, 20, 19984–20013

2H), 5.38 (q, J = 7.2 Hz, 1H)„ 7.33(t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.7 Hz, 2H), 7.88 (d, J = 7.1 Hz, 2H),

8.38 (br s, 1H), 8.68 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.4, 58.4, 120.6, 125.1, 127.8,

128.9, 130.9, 146.0, 168.3; LC-MS (ESI) m/z 273 ([M + 1]⁺).

N-Butyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1ebb). White solid; Yield: 81%.

¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.70 (d, J = 7.2 Hz, 3H),

3.79 (s, 3H), 5.36 (q, J = 7.2 Hz, 1H), 7.01(d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.36 (br s, 1H), 8.56

(s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.4, 55.1, 58.3, 114.3, 119.6, 123.5, 126.4, 146.0,

158.9, 168.4; LC-MS (ESI) m/z 303 ([M + 1]⁺).

N-Butyl-2-[4-(4-cyanophenyl)-1H-1,2,3-triazol-1-yl]propanamide (1ebc).

White solid; Yield: 79%.

¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.72 (d, J = 7.2 Hz, 3H),

3.09 (m, 2H), 5.42 (q, J = 7.2 Hz, 1H), 7.92 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 8.6 Hz, 2H), 8.40 (br s, 1H),

8.92 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.5, 58.5, 110.0, 118.8, 122.5, 125.6, 133.0,

135.3, 144.5, 168.2; LC-MS (ESI) m/z 298 ([M + 1]⁺).

N-Butyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propanamide (1ebd). Light yellow solid; Yield: 78%.

¹H-NMR (DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.69 (d, J = 7.2 Hz, 3H), 3.08

(m, 2H), 5.37 (q, J = 7.1 Hz, 1H), 7.55 (dd, J = 1.2, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 5.0 Hz, 1H), 7.86 (dd,

J = 1.2, 2.9 Hz, 1H), 8.38 (br s, 1H), 8.55 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.4, 58.3,

120.3, 120.6, 125.8, 127.0, 132.2, 142.7, 168.3; LC-MS (ESI) m/z 279 ([M + 1]⁺).

1

N-Butyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide (1ebe). White solid; Yield: 84%. H-NMR

(DMSO-d₆) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (m, 2H), 1.40 (m, 2H), 1.73 (d, J = 7.2 Hz, 3H), 3.09 (m, 2H),

5.42 (q, J = 7.2 Hz, 1H), 7.35 (m, 1H), 7.89 (dt, J = 1.7, 7.7 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 8.37 (br

s, 1H), 8.61 (m, 1H), 8.62 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 18.0, 19.4, 30.9, 38.5, 58.5, 119.4, 122.4,

123.0, 137.2, 147.0, 149.6, 150.0, 168.2; LC-MS (ESI) m/z 274 ([M + 1]⁺).

N-Butyl-2-(4-butyl-1H-1,2,3-triazol-1-yl)propanamide (1ebf). White solid; Yield: 81%. ¹H-NMR

(DMSO-d₆) δ 0.85(t, J = 7.3 Hz, 3H), 0.89(t, J = 7.4 Hz, 3H), 1.26 (m, 2H), 1.32 (m, 2H), 1.37 (m, 2H),

1.59 (m, 2H), 1.61 (d, J = 7.2 Hz, 3H), 2.60 (d, J = 7.6 Hz, 2H), 3.06 (m, 2H), 5.27 (d, J = 7.2 Hz, 1H),

7.88 (s, 1H), 8.29 (br s, 1H); ¹³C-NMR (DMSO-d₆) δ 13.6, 13.7, 18.0, 19.4, 21.7, 24.7, 30.9, 31.1, 38.4, 58.0,

120.7, 146.6, 168.4; LC-MS (ESI) m/z 253 ([M + 1]⁺).

N-Isopropyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanamide (1fba). White solid; Yield: 88%. ¹H-NMR

(DMSO-d₆) δ 1.07 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.70 (d, J = 7.2 Hz, 3H), 3.81 (m, 1H), 5.35

(q, J = 7.1 Hz, 1H), 7.33 (m, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.88 (d, J = 7.1 Hz, 1H), 8.33 (d, J = 7.5 Hz, 1H),

8.68 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 58.3, 120.6, 125.1, 127.8, 128.9, 130.9, 146.0, 167.5;

LC-MS (ESI) m/z 259 ([M + 1]⁺).

N-Isopropyl-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]propanamide (1fbb). Light brown solid; Yield:

1

83%. H-NMR (DMSO-d₆) δ 1.06 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.69 (d, J = 7.2 Hz, 3H),

3.79 (s, 3H), 3.82 (m, 1H), 5.33 (q, J = 7.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 8.32

(d, J = 7.5 Hz, 1H), 8.56 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 55.1, 58.3, 114.3, 119.6, 123.5,

126.4, 145.9, 158.9, 167.5; LC-MS (ESI) m/z 289 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-isopropyl-propanamide (1fbc). White solid; Yield: 78%.

¹H-NMR (DMSO-d₆) δ 1.07 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.71 (d, J = 7.3 Hz, 3H),

3.80 (m, 1H), 5.38 (q, J = 7.2 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 8.36 (d, J = 7.3 Hz,

1H), 8.93 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 58.4, 110.0, 118.8, 122.5, 125.6, 133.0, 135.3,

144.5, 167.3; LC-MS (ESI) m/z 284 ([M + 1]⁺).

N-Isopropyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propanamide (1fbd). White solid; Yield: 75%.

¹H-NMR (DMSO-d₆) δ 1.06 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.68 (d, J = 7.2 Hz, 3H),

3.81 (m, 1H), 5.34 (q, J = 7.1 Hz, 1H), 7.55 (dd, J = 1.2, 5.0 Hz, 1H), 7.64 (dd, J = 2.9, 5.0 Hz, 1H), 7.86

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Molecules 2015, 20, 19984–20013

(dd, J = 1.2, 3.0 Hz, 1H), 8.33 (d, J = 7.4 Hz, 1H), 8.55 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.1, 22.1, 40.9,

58.2, 120.3, 120.6, 125.8, 127.0, 132.2, 142.6, 167.5; LC-MS (ESI) m/z 265 ([M + 1]⁺).

N-Isopropyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propanamide (1fbe). White solid; Yield: 81%.

¹H-NMR (DMSO-d₆) δ 1.06 (d, J = 6.6 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H), 1.72 (d, J = 7.2 Hz, 3H),

3.82 (m, 1H), 5.38 (q, J = 7.2 Hz, 1H), 7.35 (ddd, J = 1.2, 4.8, 7.5 Hz, 1H), 7.89 (dt, J = 1.8, 7.7 Hz, 1H),

8.31 (d, J = 7.5 Hz, 1H), 8.60 (m, 1H), 8.61 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 18.0, 22.1, 40.9, 58.4, 119.4,

122.3, 122.9, 137.2, 146.9, 149.6, 150.0, 167.3; LC-MS (ESI) m/z 260 ([M + 1]⁺).

2-(4-Butyl-1H-1,2,3-triazol-1-yl)- N-isopropyl-propanamide (1fbf). White solid; Yield: 82%. ¹H-NMR

(DMSO-d₆) δ 0.89 (t, J = 7.43 Hz, 3H), 1.04 (d, J = 6.6 Hz, 3H), 1.07 (d, J = 6.6 Hz, 3H), 1.32 (m, 2H), 1.57

(m, 2H), 1.61 (d, J = 7.2 Hz, 3H), 2.60 (t, J = 7.6 Hz, 2H), 3.79 (m, 1H), 5.24 (q, J = 7.2 Hz, 1H), 7.88 (s,

1H), 8.24 (d, J = 7.4 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 13.7, 18.1, 21.7, 22.1, 24.7, 31.1, 40.8, 58.0, 120.7,

146.5, 167.6; LC-MS (ESI) m/z 239 ([M + 1]⁺).

3.4. General Procedure for the Preparation of Tertiary 1,2,3-Triazoloamides 2 in Solution-Phase

A typical procedure for the desired tertiary 1,2,3-triazoloamide 2, as exempliﬁed for

1-morpholino-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone (2aaa; R¹R²N = morpholine, A = CH₂,

R³= Ph).

3.4.1. Preparation of Chloro-Amide 15

To a solution of morpholine (14a; 4.50 mL, 51.45 mmol) and triethylamine (7.90 mL, 56.68 mmol)

˝

in CH₂Cl₂(80 mL) was slowly added 2-chloroacetyl chloride (6a; 3.70 mL, 46.45 mmol) at 0 C. The

reaction mixture was stirred at room temperature for 6 h, and then diluted with CH₂Cl₂, washed

with saturated NaHCO₃and brine, dried over MgSO₄and ﬁltered. The residue was concentrated

1

under reduced pressure to afford α-chloroamide 15aa (7.55 g, 99%) as a light yellow liquid: H-NMR

(CDCl₃) δ 3.54 (t, J = 4.5 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H), 3.70–3.74 (m, 4H), 4.07 (s, 2H); ¹³C-NMR

(CDCl₃) δ 40.7, 42.5, 46.8, 66.6, 66.7, 165.3; LC-MS (ESI) m/z 164 ([M + 1]⁺).

3.4.2. Preparation of Azidoamide 16

To a solution of α-chloroamide 15aa (1.41 g, 8.62 mmol) in acetonitrile (20 mL) and H₂O (1 mL)

was added sodium azide (700 mg, 10.77 mmol). The reaction mixture was stirred at room temperature

for 1 day, and then diluted with EtOAc, washed with brine, dried over MgSO₄and ﬁltered. The

solvent was removed, and the residue was passed through a short plug of silica to give α-azidoamide

1

16aa (1.40 g, 99%) as a colorless oil: H-NMR (CDCl₃) δ 3.38 (t, J = 4.8 Hz, 2H), 3.64 (t, J = 4.4 Hz, 2H),

3.67–3.71 (m, 4H), 3.92 (s, 2H); ¹³C-NMR (CDCl₃) δ 42.3, 45.6, 50.6, 66.5, 66.8, 165.9; LC-MS (ESI) m/z

171 ([M + 1]⁺).

3.4.3. Preparation of Tertiary 1,2,3-Triazoloamide 2

To a mixture of α-azidoamide 16aa (34 mg, 0.20 mmol) and phenylacetylene (9a; 24 µL,

0.20 mmol) in t-BuOH/H₂O (2 mL, 1:1) were added 0.5 M CuSO₄(0.020 mL, 0.010 mmol) and

1.0 M sodium ascorbate (0.020 mL, 0.020 mmol). The reaction mixture was stirred at room

temperature for 1 day, and then the resulting reaction mixture was ﬁltered. The separated

solid was washed with H₂O and hexanes, and triturated with hexane/EtOAc (10:1) to give the

1-morpholino-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone (2aaa; 52 mg, 96%) as a white solid: Mp

˝

1

229–231 C; H-NMR (CDCl₃) δ 3.62 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.71 (m, 4H), 5.28

(s, 2H), 7.34 (m, 1H), 7.41–7.45 (m, 2H), 7.84–7.86 (m, 2H), 7.99 (s, 1H); ¹³C-NMR (CDCl₃) δ 42.7, 46.0,

51.0, 66.5, 66.7, 121.3, 125.9, 128.4, 129.0, 130.5, 148.3, 163.7; IR (ATR) υ

3134, 2984, 2858, 1661,

max

1643, 1471, 1426, 1236, 1112, 1036, 768 (cm^´1); LC-MS (ESI) m/z 273 ([M + 1]⁺); HRMS (FAB) calcd for

C₁₄H₁₇N₄O₂([M + H]⁺) 273.1346, found 273.1342.

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Molecules 2015, 20, 19984–20013

3.5. Characterization Data of Tertiary 1,2,3-Triazoloamides 2

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aab). White solid; Yield: 96%.

¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.70 (m, 4H), 3.85 (s, 3H), 5.26

(s, 2H), 6.97 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7,

50.9, 65.87, 65.94, 114.3, 122.1, 123.4, 126.4, 146.0, 158.9, 164.5; LC-MS (ESI) m/z 303 ([M + 1]⁺).

4-[1-(2-Morpholino-2-oxoethyl)-1H-1,2,3-triazol-4-yl]benzonitrile (2aac). Yellow solid; Yield: 93%.

¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.8 Hz, 2H), 3.67 (t, J = 4.8 Hz, 2H), 3.72–3.76 (m, 4H), 5.31 (s, 2H),

7.72 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 8.10 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9. 44.7. 50.9.

65.86. 65.92. 110.2. 118.8. 124.8. 125.7. 133.0. 135.3. 144.6. 164.3; LC-MS (ESI) m/z 298 ([M + 1]⁺).

1-Morpholino-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2aad). Light brown solid; Yield: 92%.

¹H-NMR (CDCl₃) δ 3.60–3.62 (m, 2H), 3.65–3.66 (m, 2H), 3.69–3.71 (m, 4H), 5.26 (s, 2H), 7.39 (dd,

J = 3.0, 5.0 Hz, 1H), 7.46 (dd, J = 1.2, 5.0 Hz, 1H), 7.70 (dd, J = 1.3, 3.0 Hz, 1H), 7.88 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 41.9, 44.7, 50.6, 65.86, 65.93, 120.6, 122.8, 125.8, 127.1, 132.1, 142.7, 164.4; LC-MS (ESI) m/z

279 ([M + 1]⁺).

1-Morpholino-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanone (2aae). Light brown solid; Yield: 84%.

¹H-NMR (CDCl₃) δ 3.55 (t, J = 4.8 Hz, 2H), 3.61 (t, J = 4.7 Hz, 2H), 3.65–3.68 (m, 4H), 4.11 (s, 2H), 5.15

(s, 2H), 7.22 (m, 1H), 7.25–7.31 (m, 4H), 7.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.8, 65.8, 65.9,

119.3, 122.9, 125.0, 137.2, 147.0, 149.6, 150.0, 164.4; LC-MS (ESI) m/z 274 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aag). White solid; Yield: 94%.

¹H-NMR (CDCl₃) δ 3.62 (m, 2H), 3.66 (m, 2H), 3.69–3.71 (m, 4H), 3.87 (s, 3H), 5.27 (s, 2H), 6.89 (ddd,

J = 1.1, 2.6, 8.1 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.38 (td, J = 1.3, 7.6 Hz, 1H), 7.45 (dd, J = 1.5, 2.5 Hz,

1H), 7.97 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.8, 50.7, 55.1, 65.87, 65.94, 110.3, 113.5, 117.4, 123.3,

130.0, 132.1, 146.0, 159.7, 164.4; LC-MS (ESI) m/z 303 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aah). White solid; Yield: 93%.

¹H-NMR (CDCl₃) δ 3.62 (m, 2H), 3.66-3.69 (m, 6H), 3.94 (s, 3H), 5.27 (s, 2H), 6.98 (dd, J = 0.8, 8.3 Hz,

1H), 7.08 (dt, J = 1.0, 7.6 Hz, 1H), 7.32 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.23 (s, 1H), 8.34 (dd, J = 1.7,

7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 41.9, 44.7, 50.6, 55.4, 65.8, 65.9, 111.5, 119.1, 120.6, 125.6, 126.4,

128.8, 141.5, 155.3, 164.6; LC-MS (ESI) m/z 303 ([M + 1]⁺).

1-Morpholino-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2aai). White solid; Yield: 91. ¹H-NMR (CDCl₃)

δ 2.38 (s, 3H), 3.62 (m, 2H), 3.66 (m, 2H), 3.70 (m, 4H), 5.26 (s, 2H), 7.24 (d, J = 7.9 Hz, 2H), 7.73 (d,

J = 8.2 Hz, 2H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 41.9, 44.7, 50.7, 65.86, 65.93, 122.6, 125.0,

128.0, 129.4, 137.1, 146.1, 164.5; LC-MS (ESI) m/z 287 ([M + 1]⁺).

1-Morpholino-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2aaj).

Light yellow solid; Yield: 94%.

¹H-NMR (CDCl₃) δ 2.40 (s, 3H), 3.62 (m, 2H), 3.66 (m, 2H), 3.69 (m, 4H), 5.27 (s, 2H), 7.16 (d,

J = 7.6 Hz, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.97 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 21.1, 41.9, 44.8, 50.7, 65.88, 65.94, 122.3, 123.0, 125.7, 128.4, 128.8, 130.7, 138.0, 146.2, 164.4;

LC-MS (ESI) m/z 287 ([M + 1]⁺).

1-Morpholino-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2aak). White solid; Yield: 93%. ¹H-NMR

(CDCl₃) δ 2.49 (s, 3H), 3.62 (m, 2H), 3.66 (m, 2H), 3.69–3.71 (m, 4H), 5.30 (s, 2H), 7.27–7.29 (m, 3H),

7.79 (m, 1H), 7.87 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 41.9, 44.7, 50.6, 65.86, 65.94, 125.0, 126.0, 127.7,

128.1, 130.1, 130.9, 134.8, 145.2, 164.5; LC-MS (ESI) m/z 287 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-morpholinoethanone (2aal). Light green solid;

1

Yield: 86%. H-NMR (CDCl₃) δ 2.99 (s, 6H), 3.60–3.62 (m, 2H), 3.66–3.70 (m, 6H), 5.24 (s, 2H), 6.77 (d,

J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.84 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 40.5, 41.9, 44.8, 50.6, 65.87,

65.94, 112.4, 118.7, 121.2, 126.0, 146.7, 150.0, 164.6; LC-MS (ESI) m/z 316 ([M + 1]⁺).

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Molecules 2015, 20, 19984–20013

1-Morpholino-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2aam). Yellow solid; Yield: 99%.

¹H-NMR (CDCl₃) δ 3.62 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.70–3.72 (m, 4H), 5.27 (s, 2H),

7.04–7.08 (m, 4H), 7.15 (m, 1H), 7.34-7.38 (m, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.93 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 41.9, 44.8, 50.7, 65.87, 65.94, 118.8, 118.9, 122.7, 123.7, 126.1, 126.9, 130.1, 145.6, 156.36,

156.44, 164.4; LC-MS (ESI) m/z 365 ([M + 1]⁺).

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinoethanone (2aan). White solid; Yield: 92%.

¹H-NMR (CDCl₃) δ 3.60–3.62 (m, 2H), 3.65–3.67 (m, 2H), 3.70–3.73 (m, 4H), 5.29 (s, 2H), 6.90 (ddd,

J = 2.4, 8.7, 11.0 Hz, 1H), 7.00 (m, 1H), 8.09 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR

(DMSO-d₆) δ 41.9, 44.7, 50.8, 65.8, 65.9, 104.6 (t, J_CF= 26.0 Hz), 112.3 (dd, J_CF= 21.2, 3.6 Hz), 115.3 (dd,

J_CF= 13.3, 3.7 Hz), 125.2 (d, J_CF= 11.1 Hz), 128.4 (dd, J_CF= 9.7, 5.3 Hz), 138.8 (d, J_CF= 2.6 Hz), 158.5

(dd, J_CF= 250.1, 12.6 Hz), 161.7 (dd, J_CF= 247.5, 12.6 Hz), 164.4; LC-MS (ESI) m/z 309 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-morpholinoethanone (2aao). White solid; Yield: 94%. ¹H-NMR

(CDCl₃) δ 3.60 (t, J = 4.7 Hz, 2H), 3.66 (t, J = 4.6 Hz, 2H), 3.70–3.72 (m, 4H), 5.28 (s, 2H), 7.24 (m,

1H), 7.78 (m, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.32 (s, 1H), 8.59 (d, J = 4.2 Hz, 1H); ¹³C-NMR (DMSO-d₆)

δ 31.2, 41.9, 44.7, 50.4, 65.8, 65.9, 124.2, 126.1, 128.4, 128.5, 139.7, 145.7, 164.6; LC-MS (ESI) m/z 287

([M + 1]⁺).

2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(piperidin-1-yl)ethanone (2baa). Light yellow solid; Yield: 99%.

¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.68 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 5.28

(s, 2H), 7.33 (m, 1H), 7.41–7.44 (m, 2H), 7.84–7.86 (m, 2H), 8.00 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8,

25.1, 25.8, 42.5, 45.2, 50.9, 123.1, 125.1, 127.8, 128.9, 130.9, 146.0, 163.7; LC-MS (ESI) m/z 271 ([M + 1]⁺).

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bab). White solid; Yield: 85%.

¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.67 (m, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.59 (t, J = 5.5 Hz, 2H), 3.84

(s, 3H), 5.28 (s, 2H), 6.96 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 55.1, 114.3, 122.1, 123.5, 126.4, 146.0, 158.9, 163.8; LC-MS (ESI) m/z 301

([M + 1]⁺).

4-{1-[2-Oxo-2-(piperidin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}benzonitrile (2bac). Yellow solid; Yield: 98%.

¹H-NMR (CDCl₃) δ 1.59–1.67 (m, 4H), 1.70 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H),

5.30 (s, 2H), 7.72 (d, J = 8.3 Hz, 2H), 7.96 (d, J = 8.3 Hz, 2H), 8.10 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

23.8, 25.1, 25.8, 42.5, 45.2, 51.0, 110.0, 118.8, 124.8, 125.6, 133.0, 135.3, 144.5, 163.6; LC-MS (ESI) m/z 296

([M + 1]⁺).

1-(Piperidin-1-yl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2bad). Light brown solid; Yield:

99%. ¹H-NMR (CDCl₃) δ 1.57–1.62 (m, 4H), 1.65–1.69 (m, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.59 (t,

J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.38 (dd, J = 3.0, 5.0 Hz, 1H), 7.46 (dd, J = 0.9, 5.0 Hz, 1H), 7.69 (dd,

J = 1.0, 2.9 Hz, 1H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 120.6, 122.9,

125.8, 127.1, 132.2, 142.6, 163.4; LC-MS (ESI) m/z 277 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanone (2bae). White solid; Yield: 90%.

¹H-NMR (CDCl₃) δ 1.52–1.58 (m, 4H), 1.61–1.66 (m, 2H), 3.45 (t, J = 5.5 Hz, 2H), 3.54 (t, J = 5.6 Hz, 2H),

5.26 (s, 2H), 7.19 (ddd, J = 1.2, 4.9, 7.5 Hz, 1H), 7.74 (dt, J = 1.8, 7.8 Hz, 1H), 8.11 (td, J = 1.0, 7.9 Hz,

1H), 8.29 (s, 1H), 8.56 (ddd, J = 0.9, 1.7, 4.9 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2,

50.9, 119.3, 122.8, 125.0, 137.2, 146.9, 149.6, 150.1, 163.7; LC-MS (ESI) m/z 272 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bag). White solid; Yield: 93%.

¹H-NMR (CDCl₃) δ 1.57–1.62 (m, 4H), 1.67 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.60 (t, J = 5.6 Hz, 2H), 3.87

(s, 3H), 5.27 (s, 2H), 6.89 (ddd, J = 1.0, 2.6, 8.1 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.38 (td, J = 1.3, 7.6 Hz,

1H), 7.46 (dd, J = 1.5, 2.5 Hz, 1H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.9,

55.1, 110.2, 113.5, 117.4, 123.4, 130.0, 132.2, 145.9, 159.7, 163.7; LC-MS (ESI) m/z 301 ([M + 1]⁺).

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Molecules 2015, 20, 19984–20013

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bah). White solid; Yield: 95%.

¹H-NMR (CDCl₃) δ 1.52–1.58 (m, 4H), 1.65 (m, 2H), 3.50 (t, J = 5.9 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H),

3.92 (s, 3H), 5.26 (s, 2H), 6.97 (dd, J = 0.6, 8.3 Hz, 1H), 7.07 (dt, J = 1.0, 7.6 Hz, 1H), 7.30 (ddd,

J = 1.7, 7.4, 8.3 Hz, 1H), 8.23 (s, 1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1,

25.8, 42.5, 45.2, 50.7, 22.4, 111.5, 119.2, 120.6, 125.6, 126.4, 128.7, 141.4, 155.3, 163.9; LC-MS (ESI) m/z 301

([M + 1]⁺).

1-(Piperidin-1-yl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2bai). Light yellow solid; Yield: 91%.

¹H-NMR (CDCl₃) δ 1.57–1.60 (m, 4H), 1.67 (m, 2H), 2.38 (s, 3H), 3.52 (t, J = 5.5 Hz, 2H), 3.59 (t,

J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.23 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.95 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 20.8, 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 122.7, 125.0, 128.1, 129.4, 137.0, 146.1, 163.8; LC-MS

(ESI) m/z 285 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2baj). Light yellow solid; Yield: 99%.

¹H-NMR (CDCl₃) δ 1.56–1.62 (m, 4H), 1.67 (m, 2H), 2.40 (s, 3H), 3.51 (t, J = 5.5 Hz, 2H), 3.59 (t,

J = 5.6 Hz, 2H), 5.26 (s, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.70

(s, 1H), 7.97 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 122.3, 123.0, 125.6,

128.4, 128.8, 130.8, 138.0, 146.1, 163.7; LC-MS (ESI) m/z 285 ([M + 1]⁺).

1-(Piperidin-1-yl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2bak). Light yellow solid; Yield: 91%.

¹H-NMR (CDCl₃) δ 1.57–1.61 (m, 4H), 1.68 (m, 2H), 2.49 (s, 3H), 3.53 (t, J = 5.5 Hz, 2H), 3.60 (t,

J = 5.6 Hz, 2H), 5.29 (s, 2H), 7.27–7.28 (m, 3H), 7.79 (m, 1H), 7.88 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1,

23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 125.0, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.2, 163.8; LC-MS (ESI)

m/z 285 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(piperidin-1-yl)ethanone (2bal).

Light green

solid; Yield: 89%. ¹H-NMR (CDCl₃) δ 1.53-1.57 (m, 4H), 1.64–1.68 (m, 2H), 2.99 (s, 6H), 3.51 (t,

J = 5.5 Hz, 2H), 3.58 (t, J = 5.5 Hz, 2H), 5.24 (s, 2H), 6.77 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz,

2H), 7.84 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 40.0, 42.5, 45.2, 50.7, 112.4, 118.8, 121.2, 126.0,

146.6, 149.9, 163.9; LC-MS (ESI) m/z 314 ([M + 1]⁺).

2-[4-(4-Phenoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2bam). Light yellow solid;

Yield: 99%.¹H-NMR (CDCl₃) δ 1.59–1.62 (m, 4H), 1.66–1.71 (m, 2H), 3.52 (t, J = 5.5 Hz, 2H), 3.59

(t, J = 5.5 Hz, 2H), 5.27 (s, 2H), 7.04–7.07 (m, 4H), 7.13 (m, 1H), 7.34–7.37 (m, 2H), 7.81 (d, J = 8.8 Hz,

2H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.8, 42.5, 45.2, 50.8, 118.8, 118.9, 122.7, 123.6,

126.2, 126.8, 130.1, 145.6, 156.3, 156.4, 163.7; LC-MS (ESI) m/z 363 ([M + 1]⁺).

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-1-(piperidin-1-yl)ethanone (2ban). Yellow solid; Yield:

99%. ¹H-NMR (CDCl₃) δ 1.58–1.64 (m, 4H), 1.66–1.71 (m, 2H), 3.51 (t, J = 5.5 Hz, 2H), 3.60 (t,

J = 5.6 Hz, 2H), 5.29 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (m, 1H), 8.09 (d, J = 3.7 Hz,

1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.7, 42.5, 45.2, 50.9, 104.6 (t,

J_CF= 26.0 Hz), 112.3 (d, J_CF= 24.6 Hz), 115.3 (dd, J_CF= 13.1, 4.0 Hz), 125.2 (d, J_CF= 11.9 Hz), 128.4

(dd, J_CF= 9.4, 5.7 Hz), 138.7 (d, J_CF= 2.4 Hz), 158.5 (dd, J_CF= 250.0, 12.6 Hz), 161.6 (dd, J_CF= 247.5,

12.6 Hz), 163.7; LC-MS (ESI) m/z 307 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-(piperidin-1-yl)ethanone (2bao). White solid; Yield: 95%. ¹H-NMR

(CDCl₃) δ 1.52–1.57 (m, 4H), 1.63–1.67 (m, 2H), 3.45 (t, J = 5.5 Hz, 2H), 3.56 (t, J = 5.6 Hz, 2H), 4.10 (s,

2H), 5.15 (s, 2H), 7.20 (m, 1H), 7.24–7.30 (m, 4H), 7.37 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.8, 25.1, 25.7,

31.2, 42.4, 45.2, 50.5, 124.2, 126.1, 128.4, 128.5, 139.7, 145.6, 163.9; LC-MS (ESI) m/z 285 ([M + 1]⁺).

2-(4-Phenyl-1H-1,2,3-triazol-1-yl)-1-(pyrrolidin-1-yl)ethanone (2caa). Light yellow solid; Yield: 94%.

¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.7, 7.0 Hz, 2H), 2.05 (tt, J = 6.8, 7.0 Hz, 2H), 3.54 (t, J = 7.0 Hz,

2H), 3.58 (t, J = 6.9 Hz, 2H), 5.19 (s, 2H), 7.33 (m, 1H), 7.41–7.44 (m, 2H), 7.84–7.86 (m, 2H), 8.06 (s,

1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 123.0, 125.1, 127.8, 128.9, 130.8, 146.0, 163.7;

LC-MS (ESI) m/z 257 ([M + 1]⁺).

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Molecules 2015, 20, 19984–20013

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cab). White solid; Yield: 89%.

¹H-NMR (CDCl₃) δ 1.91 (tt, J = 6.8, 7.1 Hz, 2H), 2.03 (tt, J = 6.8, 7.0 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H),

3.58 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 5.17 (s, 2H), 6.96 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.9 Hz, 2H), 7.96

(s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 55.1, 114.3, 122.0, 1234, 126.4, 146.0, 158.9,

163.7; LC-MS (ESI) m/z 287 ([M + 1]⁺).

4-{1-[2-Oxo-2-(pyrrolidin-1-yl)ethyl]-1H-1,2,3-triazol-4-yl}benzonitrile (2cac). Yellow solid; Yield: 94%.

¹H-NMR (CDCl₃) δ 1.93 (tt, J = 6.9, 7.1 Hz, 2H), 2.07 (tt, J = 6.8, 6.9 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H),

3.60 (t, J = 6.9 Hz, 2H), 5.21 (s, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 8.17 (s, 1H);

¹³C- NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.9, 51.5, 110.0, 118.8, 124.7, 125.7, 133.0, 135.3, 144.5, 163.5;

LC-MS (ESI) m/z 282 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2cad). Light green solid; Yield:

1

88%. H-NMR (CDCl₃) δ 1.91 (tt, J = 6.7, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.53 (t, J = 7.0 Hz,

2H), 3.58 (t, J = 6.9 Hz, 2H), 5.18 (s, 2H), 7.38 (dd, J = 3.0, 5.0 Hz, 1H), 7.47 (dd, J = 1.2, 5.0 Hz, 1H), 7.69

(dd, J = 1.3, 3.0 Hz, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.3, 120.6, 122.7,

125.8, 127.1, 132.2, 142.6, 163.7; LC-MS (ESI) m/z 263 ([M + 1]⁺).

2-[4-(Pyridin-2-yl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cae). Light yellow solid; Yield:

1

87%. H-NMR (CDCl₃) δ 1.89 (tt, J = 6.9, 7.0 Hz, 2H), 2.02 (tt, J = 6.8, 6.9 Hz, 2H), 3.52 (t, J = 6.9 Hz,

2H), 3.54 (t, J = 6.8 Hz, 2H), 5.20 (s, 2H), 7.21 (ddd, J = 1.2, 4.9, 7.5 Hz, 1H), 7.76 (dt, J = 1.8, 7.7 Hz,

1H), 8.14 (td, J = 1.0, 7.9 Hz, 1H), 8.35 (s, 1H), 8.58 (ddd, J = 0.9, 1.7, 4.9 Hz, 1H); ¹³C-NMR (DMSO-d₆)

δ 23.7, 25.6, 45.2, 45.9, 51.5, 119.4, 122.9, 124.8, 137.2, 146.9, 149.6, 150.1, 163.6; LC-MS (ESI) m/z 258

([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cag). White solid; Yield: 93%.

¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.8, 6.8 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.54 (t, J = 7.0 Hz, 2H),

3.58 (t, J = 6.9 Hz, 2H), 3.87 (s, 3H), 5.19 (s, 2H), 6.88 (ddd, J = 1.0, 2.6, 8.2 Hz, 1H), 7.32 (t, J = 7.9 Hz,

1H), 7.39 (td, J = 1.3, 7.6 Hz, 1H), 7.46 (dd, J = 1.6, 2.5 Hz, 1H), 8.05 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

23.7, 25.6, 45.2, 45.8, 51.4, 55.1, 110.3, 113.5, 117.5, 123.2, 130.1, 132.2, 146.0, 159.7, 163.7; LC-MS (ESI)

m/z 287 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cah). White solid; Yield: 89%.

¹H-NMR (CDCl₃) δ 1.90 (tt, J = 6.8, 6.9 Hz, 2H), 2.02 (tt, J = 6.8, 6.8 Hz, 2H), 3.53 (t, J = 7.0 Hz, 2H), 3.56

(t, J = 6.9 Hz, 2H), 3.93 (s, 3H), 5.19 (s, 2H), 6.72 (dd, J = 0.7, 8.3 Hz, 1H), 7.07 (dt, J = 1.0, 7.5 Hz, 1H),

7.31 (ddd, J = 1.7, 7.4, 8.3 Hz, 1H), 8.29 (s, 1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C- NMR (DMSO-d₆) δ

23.7, 25.6, 45.1, 45.8, 51.2, 55.5, 111.5, 119.2, 120.7, 125.5, 126.4, 128.8, 141.5, 155.3, 163.9; LC-MS (ESI)

m/z 287 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2cai). White solid; Yield: 96%. ¹H-NMR

(CDCl₃) δ 1.91 (tt, J = 6.9, 6.9 Hz, 2H), 2.04 (tt, J = 6.8, 6.8 Hz, 2H), 2.38 (s, 3H), 3.53 (t, J = 7.0 Hz,

2H), 3.57 (t, J = 6.9 Hz, 2H), 5.18 (s, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 8.01 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 20.8, 23.7, 25.6, 45.2, 45.8 51.4, 122.5, 125.0, 128.1, 129.5, 137.1, 146.1, 163.7;

LC-MS (ESI) m/z 271 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2caj). White solid; Yield: 96%. ¹H-NMR

(CDCl₃) δ 1.91 (tt, J = 6.8, 6.8 Hz, 2H), 2.03 (tt, J = 6.8, 6.8 Hz, 2H), 2.40 (s, 3H), 3.53 (t, J = 7.0 Hz,

2H), 3.57 (t, J = 6.8 Hz, 2H), 5.18 (s, 2H), 7.14 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.61 (d,

J = 7.7 Hz, 1H), 7.70 (s, 1H), 8.03 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 23.7, 25.6, 45.1, 45.8, 51.4, 122.3,

122.9, 125.6, 128.4, 128.8, 130.7, 138.0, 146.1, 163.7; LC-MS (ESI) m/z 271 ([M + 1]⁺).

1-(Pyrrolidin-1-yl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2cak). White solid; Yield: 91%. ¹H-NMR

(CDCl₃) δ 1.92 (tt, J = 6.8, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.8 Hz, 2H), 2.49 (s, 3H), 3.54 (t, J = 7.0 Hz, 2H),

3.59 (t, J = 6.9 Hz, 2H), 5.21 (s, 2H), 7.26–7.28 (m, 3H), 7.79 (m, 1H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆)

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Molecules 2015, 20, 19984–20013

δ 21.1, 23.7, 25.6, 45.1, 45.8, 51.3, 124.8, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.2, 163.7; LC-MS (ESI)

m/z 271 ([M + 1]⁺).

2-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-(pyrrolidin-1-yl)ethanone (2cal). Light yellow

solid; Yield: 94%. ¹H-NMR (CDCl₃) δ 1.90 (tt, J = 6.7, 6.9 Hz, 2H), 2.02 (tt, J = 6.8, 6.9 Hz, 2H),

2.99 (s, 6H), 3.52 (t, J = 7.0 Hz, 2H), 3.56 (t, J = 6.9 Hz, 2H), 5.16 (s, 2H), 6.77 (d, J = 9.0 Hz, 2H), 7.71 (d,

J = 8.9 Hz, 2H), 7.90 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 40.0, 45.1, 45.8, 51.3, 112.4, 118.8, 121.1,

126.0, 146.6, 150.0, 163.8; LC-MS (ESI) m/z 300 ([M + 1]⁺).

2-[4-(4-Phenoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2cam). Light yellow solid;

Yield: 99%. ¹H-NMR (CDCl₃) δ 1.92 (tt, J = 6.8, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.53 (t,

J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 5.19 (s, 2H), 7.04–7.07 (m, 4H), 7.12 (m, 1H), 7.34–7.37 (m, 2H),

7.81 (d, J = 8.8 Hz, 2H), 8.00 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8, 51.4, 118.8, 118.9,

122.6, 123.6, 126.2, 126.8, 130.1, 145.6, 156.3, 156.4, 163.7; LC-MS (ESI) m/z 349 ([M + 1]⁺).

2-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-1-(pyrrolidin-1-yl)ethanone (2can). Light yellow solid;

Yield: 99%. ¹H-NMR (CDCl₃) δ. 1.92 (tt, J = 6.7, 6.9 Hz, 2H), 2.05 (tt, J = 6.8, 6.9 Hz, 2H), 3.53 (t,

J = 7.0 Hz, 2H), 3.58 (t, J = 6.9 Hz, 2H), 5.20 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (m, 1H),

8.14 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 23.7, 25.6, 45.1, 45.8,

51.4, 104.6 (t, J_CF= 26.0 Hz), 112.3 (dd, J_CF= 20.2, 4.8 Hz), 115.3 (dd, J_CF= 13.4, 3.8 Hz), 125.0 (d,

J_CF= 11.1 Hz), 128.5 (dd, J_CF= 9.8, 5.3 Hz),138.7, 158.5 (dd, J_CF= 250.0, 12.6 Hz), 161.7 (dd,

J_CF= 247.4, 12.7 Hz), 163.6; LC-MS (ESI) m/z 293 ([M + 1]⁺).

2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-(pyrrolidin-1-yl)ethanone (2cao). White solid; Yield: 94%. ¹H-NMR

(CDCl₃) δ 1.86 (tt, J = 6.8, 7.0 Hz, 2H), 1.99 (tt, J = 6.8, 7.0 Hz, 2H), 3.46 (t, J = 7.0 Hz, 2H), 3.49 (t,

J = 6.9 Hz, 2H), 4.08 (s, 2H), 5.05 (s, 2H), 7.19 (m, 1H), 7.24–7.29 (m, 4H), 7.42 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 23.7, 25.6, 31.2, 45.1, 45.7, 51.1, 124.0, 126.1, 128.4, 128.5, 139.7, 145.6, 163.8; LC-MS (ESI)

m/z 271 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-phenyl-1H-1,2,3-triazol-1-yl)ethanone (2daa). Light yellow solid; Yield: 95%.

¹H-NMR (CDCl₃) δ 1.58–1.63 (m, 4H), 1.72-1.77 (m, 2H), 1.78–1.83 (m, 2H), 3.57 (t, J = 6.0 Hz, 2H),

3.58 (t, J = 6.0 Hz, 2H), 5.27 (s, 2H), 7.33 (m, 1H), 7.41–7.44 (m, 2H), 7.84–7.86 (m, 2H), 8.04 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.7, 123.2, 125.1, 277, 128.9, 130.9, 146.0, 165.0;

LC-MS (ESI) m/z 285 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(4-methoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dab). White solid; Yield: 86%.

¹H-NMR (CDCl₃) δ 1.59-1.63 (m, 4H), 1.72-1.76 (m, 2H), 1.77–1.82 (m, 2H), 3.53–3.59 (m, 4H), 3.84 (s,

3H), 5.25 (s, 2H), 6.95 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 7.95 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.7, 55.1, 114.3, 122.2, 123.5, 126.4, 145.9, 158.9, 165.0; LC-MS (ESI) m/z

315 ([M + 1]⁺).

4-{1-[2-(Azepan-1-yl)-2-oxoethyl]-1H-1,2,3-triazol-4-yl}benzonitrile (2dac). Yellow solid; Yield: 97%.

¹H-NMR (CDCl₃) δ 1.57–1.66 (m, 4H), 1.75 (tt, J = 5.9, 6.0 Hz, 2H), 1.84 (tt, J = 5.9, 6.0 Hz, 2H),

3.56–3.60 (m, 4H), 5.29 (s, 2H), 7.71 (d, J = 6.7 Hz, 2H), 7.96 (d, J = 6.7 Hz, 2H), 8.15 (s, 1H); ¹³C-NMR

(DMSO-d₆) δ 26.2, 26.4, 27.0, 28.1, 45.5, 46.4, 50.9, 110.0, 118.8, 124.9, 125.6, 133.0, 133.3, 144.5, 164.8;

LC-MS (ESI) m/z 310 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]ethanone (2dad). Light brown solid; Yield:

98%. ¹H-NMR (CDCl₃) δ 1.58–1.61 (m, 4H), 1.75 (tt, J = 5.8, 5.8 Hz, 2H), 1.80 (tt, J = 5.8, 5.9 Hz,

2H), 3.57 (t, J = 6.0 Hz, 2H), 3.58 (t, J = 5.9 Hz, 2H), 5.26 (s, 2H), 7.37 (dd, J = 3.0, 5.0 Hz, 1H), 7.47 (dd,

J = 1.3, 5.0 Hz, 1H), 7.69 (dd, J = 1.2, 3.0 Hz, 1H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1,

28.2, 45.5, 46.4, 50.7, 120.6, 122.9, 125.8, 127.0, 132.2, 142.6, 165.0; LC-MS (ESI) m/z 291 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]ethanone (2dae). Light brown solid; Yield: 86%.

¹H-NMR (CDCl₃) δ 1.59–1.64 (m, 4H), 1.74 (tt, J = 5.9, 6.0 Hz, 2H), 1.80 (tt, J = 5.8, 6.0 Hz, 2H), 3.55 (t,

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Molecules 2015, 20, 19984–20013

J = 6.1 Hz, 2H), 3.57 (t, J = 6.0 Hz, 2H), 5.28 (s, 2H), 7.22 (ddd, J = 1.1, 4.9, 7.5 Hz, 1H), 7.76 (dt, J = 1.8,

7.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.59 (d, J = 4.3 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2,

26.7, 27.0, 28.2, 45.5, 46.4, 50.8, 119.3, 122.9, 125.1, 137.2, 146.9, 149.6, 150.1, 164.9; LC-MS (ESI) m/z 286

([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(3-methoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dag). Light yellow solid; Yield:

1

92%. H-NMR (CDCl₃) δ 1.58–1.61 (m, 4H), 1.75 (m, 2H), 1.80 (m, 2H), 3.56–3.59 (m, 4H), 3.87 (s, 3H),

5.27 (s, 2H), 6.88 (ddd, J = 1.0, 2.6, 8.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.39 (td, J = 1.2, 7.6 Hz, 1H), 7.46

(dd, J = 1.5, 2.5 Hz, 1H), 8.03 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.4, 50.8, 55.1,

110.2, 113.5, 117.4, 123.4, 130.0, 132.2, 145.9, 159.7, 165.0; LC-MS (ESI) m/z 315 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(2-methoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dah). White solid; Yield: 88%.

¹H-NMR (CDCl₃) δ 1.55–1.61 (m, 4H), 1.72–1.78 (m, 4H), 3.56–3.59 (m, 4H), 3.93 (s, 3H), 5.27 (s, 2H),

6.97 (dd, J = 0.7, 8.3 Hz, 1H), 7.07 (dt, J = 1.0, 7.6 Hz, 1H), 7.31 (ddd, J = 1.8, 7.4, 8.3 Hz, 1H), 8.27 (s,

1H), 8.34 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.1, 45.4, 46.4, 50.5, 55.5,

111.5, 119.2, 120.6, 125.7, 126.4, 128.7, 141.4, 155.3, 165.2; LC-MS (ESI) m/z 315 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2dai). White solid; Yield: 97%. ¹H-NMR

(CDCl₃) δ 1.55–1.62 (m, 4H), 1.74 (m, 2H), 1.79 (m, 2H), 2.38 (s, 3H), 3.55–3.59 (m, 4H), 5.26 (s, 2H),

7.23 (d, J = 7.9 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 26.2, 26.7,

27.1, 28.2, 45.5, 46.5, 50.7, 122.7, 125.0, 128.1, 129.4, 137.0, 146.1, 165.0; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2daj). White solid; Yield: 91%. ¹H-NMR

(CDCl₃) δ 1.56–1.62 (m, 4H), 1.74 (m, 2H), 1.79 (m, 2H), 2.40 (s, 3H), 3.55–3.59 (m, 4H), 5.26 (s, 2H),

7.15 (dd, J = 0.6, 7.6 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 8.02 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 21.1, 26.2, 26.7, 27.0, 28.2, 45.5, 46.5, 50.7, 122.2, 123.1, 125.6, 128.4, 128.8, 130.8,

138.0, 146.1, 165.0; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1-(Azepan-1-yl)-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)ethanone (2dak). Light yellow solid; Yield: 86%.

¹H-NMR (CDCl₃) δ 1.58–1.63 (m, 4H), 1.75 (m, 2H), 1.80 (m, 2H), 2.49 (s, 3H), 3.57–3.60 (m, 4H),

5.29 (s, 2H), 7.26–7.28 (m, 3H), 7.78 (m, 1H), 7.92 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 26.2, 26.7, 27.1,

28.2, 45.5, 46.4, 50.7, 125.1, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.1, 165.0; LC-MS (ESI) m/z 299

([M + 1]⁺).

1-(Azepan-1-yl)-2-{4-[4-(dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}ethanone (2dal). Light brown solid;

1

Yield: 89%. H-NMR (CDCl₃) δ 1.57–1.58 (m, 4H), 1.73–1.77 (m, 4H), 2.99 (s, 6H), 3.56 (t, J = 6.0 Hz,

2H), 3.57 (t, J = 6.0 Hz, 2H), 5.23 (s, 2H), 6.77 (d, J = 8.9 Hz, 2H), 7.71 (d, J = 8.9 Hz, 2H), 7.89 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 40.0, 45.5, 46.5, 50.6, 112.4, 118.8, 121.3, 126.0, 146.6, 150.0,

165.1; LC-MS (ESI) m/z 328 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dam). Light yellow solid; Yield:

99%. ¹H-NMR (CDCl₃) δ 1.59–1.66 (m, 4H), 1.73–1.77 (m, 2H), 1.7–1.83 (m, 2H), 3.57 (t, J = 6.0 Hz,

2H), 3.58 (t, J = 6.0 Hz, 2H), 5.27 (s, 2H), 7.04–7.06 (m, 4H), 7.12 (m, 1H), 7.34–7.37 (m, 2H), 7.81 (d,

J = 8.9 Hz, 2H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1, 28.2, 45.5, 46.5, 50.7, 118.8, 118.9,

122.8, 123.6, 126.2, 126.8, 130.1, 145.6, 456.3, 156.4, 165.0; LC-MS (ESI) m/z 377 ([M + 1]⁺).

1-(Azepan-1-yl)-2-[4-(2,4-diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]ethanone (2dan). Yellow solid; Yield: 98%.

¹H-NMR (CDCl₃) δ 1.57–1.65 (m, 4H), 1.75 (tt, J = 5.8, 5.9 Hz, 2H), 1.82 (tt, J = 5.8, 5.9 Hz, 2H), 3.56 (t,

J = 6.1 Hz, 2H), 3.58 (t, J = 6.1 Hz, 2H), 5.28 (s, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (dddd,

J = 1.0, 2.5, 8.0, 10.4 Hz, 1H), 8.13 (d, J = 3.7 Hz, 1H), 8.27 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆)

δ 26.2, 26.7, 27.1, 28.1, 45.5, 46.4, 50.8, 104.6 (t, J_CF= 26.0 Hz), 112.3 (dd, J_CF= 20.2, 4.8 Hz), 115.3 (dd,

J_CF= 13.2, 3.7 Hz), 125.3 (d, J_CF= 10.9 Hz), 128.5 (dd, J_CF= 9.7, 5.4 Hz), 138.7 (d, J_CF= 2.4 Hz), 158.5

(dd, J_CF= 249.9, 12.5 Hz), 161.7 (dd, J_CF= 247.4, 12.7 Hz), 165.0; LC-MS (ESI) m/z 321 ([M + 1]⁺).

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Molecules 2015, 20, 19984–20013

1-(Azepan-1-yl)-2-(4-benzyl-1H-1,2,3-triazol-1-yl)ethanone (2dao). White solid; Yield: 94%. ¹H-NMR

(CDCl₃) δ 1.55–1.57 (m, 4H), 1.68–1.75 (m, 4H), 3.50 (t, J = 6.1 Hz, 2H), 3.52 (t, J = 6.1 Hz, 2H), 4.10 (s,

2H), 5.15 (s, 2H), 7.21 (m, 1H), 7.26–7.30 (m, 4H), 7.41 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 26.2, 26.7, 27.1,

28.1, 31.3, 45.5, 46.5, 50.5, 124.3, 126.1, 128.4, 128.6, 139.7, 145.7, 165.1; LC-MS (ESI) m/z 299 ([M+1]⁺).

N-Methyl-N-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetamide (2eaa).

White solid; Yield: 99%.

¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 4.97 (s, 2H), 7.31–7.34 (m, 3H), 7.40–7.43 (m, 2H), 7.45 (m, 1H),

7.51–7.54 (m, 2H), 7.82–7.84 (m, 2H), 7.99 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 37.3, 51.1, 123.0, 125.1, 127.5,

127.8, 128.4, 129.0, 130.1, 130.8, 141.9, 146.0, 164.9; LC-MS (ESI) m/z 293 ([M + 1]⁺).

2-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-N-methyl-N-phenylacetamide (2eab). Yellow solid; Yield:

99%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 3.84 (s, 3H), 4.95 (s, 2H), 6.95 (d, J = 8.9 Hz, 2H), 7.30–7.32

(m, 2H), 7.45 (m, 1H), 7.50-7.53 (m, 2H), 7.75 (d, J = 8.9 Hz, 2H), 7.89 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

37.3, 51.0, 55.2, 114.3, 122.0, 123.4, 126.5, 127.5, 128.4, 130.1, 141.9, 146.0, 159.0, 164.9; LC-MS (ESI) m/z

323 ([M + 1]⁺).

2-[4-(4-Cyanophenyl)-1H-1,2,3-triazol-1-yl]-N-methyl-N-phenylacetamide (2eac). White solid; Yield: 99%.

¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 4.98 (s, 2H), 7.30–7.34 (m, 2H) ,7.47 (m, 1H), 7.56–7.51 (m, 2H), 7.70

(d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 8.10 (s, 1H); ¹³C-NMR (CDCl₃) δ 37.9, 51.4, 111.4, 118.9,

122.9, 126.2, 127.3, 129.2, 130.6, 132.7, 135.1, 141.7, 146.0, 164.7; LC-MS (ESI) m/z 318 ([M + 1]⁺).

N-Methyl-N-phenyl-2-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]acetamide (2ead). White solid; Yield: 89%.

¹H-NMR (CDCl₃) δ 3.34 (s, 3H), 4.97 (s, 2H), 7.21 (ddd, J = 1.1, 4.9, 7.5 Hz, 1H), 7.32 (d, J = 7.3 Hz,

2H), 7.45 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.75 (dt, J = 1.8, 7.7 Hz, 1H), 8.13 (d, J = 7.9 Hz,

1H), 8.29 (s, 1H), 8.58 (ddd, J = 4.9, 1.6, 0.9 Hz, 1H; ¹³C-NMR (CDCl₃) δ 37.9, 51.3, 121.1, 121.4, 126.0,

126.3, 127.4, 129.1, 130.6, 132.0, 141.9, 144.1, 164.9; LC-MS (ESI) m/z 294 ([M + 1]⁺).

N-Methyl-N-phenyl-2-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (2eae). White solid; Yield: 99%.

¹H-NMR (CDCl₃) δ 3.34 (s, 3H), 4.94 (s, 2H), 7.30 (d, J = 7.4 Hz, 2H), 7.36 (ddd, J = 5.0, 3.0, 0.6 Hz, 1H),

7.42–7.48 (m, 2H), 7.48–7.54 (m, 2H), 7.67 (m, 1H), 7.88 (s, 1H); ¹³C-NMR (CDCl₃) δ 37.9, 51.4, 120.3,

122.8, 124.0, 127.4, 129.1, 130.6, 136.8, 142.0, 148.6, 149.5, 150.4, 164.7; LC-MS (ESI) m/z 299 ([M + 1]⁺).

2-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-N-phenylacetamide (2eag). White solid; Yield:

93%. ¹H-NMR (CDCl₃) δ 3.35 (s, 3H), 3.86 (s, 3H), 4.96 (s, 2H), 6.88 (ddd, J = 1.1, 2.6, 8.1 Hz, 1H),

7.30–7.33 (m, 3H), 7.37 (td, J = 1.3, 7.6 Hz, 1H), 7.44 (dd, J = 1.5, 2.6 Hz, 1H), 7.45 (m, 1H), 7.50–7.53 (m,

2H), 7.98 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 37.3, 51.1, 55.1, 110.3, 113.6, 117.5, 123.2, 127.5, 128.4, 130.1,

132.1 (2C), 141.9, 146.0, 159.7, 164.9; LC-MS (ESI) m/z 315 ([M + 1]⁺).

2-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-N-methyl-N-phenylacetamide (2eah). Light yellow solid;

1

Yield: 95%. H-NMR (CDCl₃) δ 3.35 (s, 3H), 3.93 (s, 3H), 4.97 (s, 2H), 6.97 (d, J = 8.3 Hz, 1H), 7.06 (dt,

J = 0.9, 7.5 Hz, 1H), 7.28–7.33 (m, 3H), 7.45 (m, 1H), 7.50–7.53 (m, 2H), 8.22 (s, 1H), 8.33 (dd, J = 1.7,

7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 37.5, 51.2, 55.7, 111.8, 119.2, 120.9, 125.9, 126.7, 127.7, 128.7, 129.2,

130.3, 141.7, 142.1, 155.5, 165.3; LC-MS (ESI) m/z 315 ([M + 1]⁺).

N-Methyl-N-phenyl-2-(4-p-tolyl-1H-1,2,3-triazol-1-yl)acetamide (2eai). White solid; Yield: 99%. ¹H-NMR

(CDCl₃) δ 2.37 (s, 3H), 3.35 (s, 3H), 4.95 (s, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.30–7.32 (m, 2H), 7.45 (m, 1H),

7.50–7.53 (m, 2H), 7.72 (d, J = 8.2 Hz, 2H), 7.94 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 20.8, 37.2, 51.0, 122.5,

125.0, 127.4, 128.0, 128.4, 129.4, 130.0, 137.1, 141.9, 146.0, 164.9; LC-MS (ESI) m/z 299 ([M + 1]⁺).

N-Methyl-N-phenyl-2-(4-m-tolyl-1H-1,2,3-triazol-1-yl)acetamide (2eaj).

White solid; Yield: 87%.

¹H-NMR (CDCl₃) δ 2.39 (s, 3H), 3.33 (s, 3H), 4.95 (s, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.27–7.31 (m, 3H),

7.44 (m, 1H), 7.49–7.52 (m, 2H), 7.59 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.96 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 21.0, 37.3, 51.0, 122.3, 122.9, 125.6, 127.4, 128.4, 128.8, 130.0, 130.7, 138.0, 141.9, 146.1, 164.9; LC-MS

(ESI) m/z 299 ([M + 1]⁺).

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Molecules 2015, 20, 19984–20013

1

N-Methyl-N-phenyl-2-(4-o-tolyl-1H-1,2,3-triazol-1-yl)acetamide (2eak). Colorless oil; Yield: 98. H-NMR

(CDCl₃) δ 2.45 (s, 3H), 3.32 (s, 3H), 4.97 (s, 2H), 7.22–7.24 (m, 3H), 7.29–7.31 (m, 2H), 7.42 (m, 1H),

7.47–7.50 (m, 2H), 7.76 (m, 1H), 7.86 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 37.3, 51.0, 124.9, 126.0, 127.5,

127.7, 128.0, 128.4, 130.0, 130.9, 134.7, 141.9, 145.1, 164.9; LC-MS (ESI) m/z 299 ([M + 1]⁺).

1

1-Morpholino-3-(4-phenyl-1H-1,2,3-triazol-1-yl)propan-1-one (2aca). Colorless oil; Yield: 94%. H-NMR

(CDCl₃) δ 2.96 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 4.74 (t, J = 6.2 Hz, 2H),

7.30 (m, 1H), 7.38–7.41 (m, 2H), 7.78–7.81 (m, 2H), 7.93 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.4, 41.5, 45.2,

45.8, 65.97, 65.98, 121.8, 125.1, 127.8, 128.9, 130.8, 146.0, 168.0; LC-MS (ESI) m/z 287 ([M + 1]⁺).

3-[4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2acb). Colorless oil; Yield: 90%.

¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 3.81 (s, 3H), 4.72

(t, J = 6.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.83 (s, 1H); ¹³C-NMR (DMSO-d₆)

δ 32.5, 41.5, 45.2, 45.7, 55.1, 65.97, 65.99, 114.3, 120.8, 123.4, 126.4, 146.0, 158.9, 168.1; LC-MS (ESI) m/z

317 ([M + 1]⁺).

4-[1-(3-Morpholino-3-oxopropyl)-1H-1,2,3-triazol-4-yl]benzonitrile (2acc). White solid; Yield: 90%.

¹H-NMR (500 MHz, CDCl₃) δ 3.01 (t, J = 5.9 Hz, 2H), 3.42 (t, J = 4.9 Hz, 2H), 3.59-3.65 (m, 6H),

4.80 (t, J = 5.9 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 8.08 (s, 1H); ¹³C NMR (125

MHz, DMSO-d₆) δ 32.3, 41.5, 45.1, 46.0, 65.95, 65.97, 110.0, 118.8, 123.6, 125.6, 133.0, 135.3, 144.4, 168.0;

LC-MS (ESI) m/z 312 ([M + 1]⁺).

1-Morpholino-3-[4-(thiophen-3-yl)-1H-1,2,3-triazol-1-yl]propan-1-one (2acd). Yellow oil; Yield: 98%.

¹H-NMR (CDCl₃) δ 2.95 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.55–3.61 (m, 6H), 4.72 (t,

J = 6.1 Hz, 2H), 7.34 (dd, J = 3.0, 5.0 Hz, 1H), 7.42 (dd, J = 1.3, 5.0 Hz, 1H), 7.63 (dd, J = 1.2, 3.0 Hz, 1H),

7.83 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.5, 41.5, 45.2, 45.7, 65.96, 65.98, 120.6, 121.6, 125.7, 127.1, 132.1,

142.6, 168.0; LC-MS (ESI) m/z 293 ([M + 1]⁺).

1-Morpholino-3-[4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl]propan-1-one (2ace). Light yellow oil; Yield: 89%.

¹H-NMR (CDCl₃) δ 2.99 (t, J = 6.5 Hz, 2H), 3.39 (t, J = 4.8 Hz, 2H), 3.57–3.63 (m, 6H), 4.77 (t, J = 6.5 Hz,

2H), 7.20 (ddd, J = 1.0, 4.9, 7.5 Hz, 1H), 7.74 (dt, J = 1.7, 7.7 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.25 (s,

1H), 8.56 (d, J = 4.9 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 32.4, 41.5, 45.1, 45.8, 65.97, 65.99, 119.3, 122.9,

123.6, 137.2, 147.0, 149.6, 150.0, 168.1; LC-MS (ESI) m/z 288 ([M + 1]⁺).

3-[4-(3-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2acg). Colorless oil; Yield: 98%.

¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 3.83 (s, 3H), 4.73

(t, J = 6.2 Hz, 2H), 6.85 (ddd, J = 1.2, 2.6, 8.0 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.33 (td, J = 1.3, 7.6 Hz,

1H), 7.40 (dd, J = 1.5, 2.5 Hz, 1H), 7.92 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 32.4, 41.5, 45.2, 45.8, 55.1, 65.98,

66.00, 110.3, 13.5, 117.5, 122.1, 130.1, 132.2, 146.0, 459.7, 168.0; LC-MS (ESI) m/z 317 ([M + 1]⁺).

3-[4-(2-Methoxyphenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2ach). Light yellow oil; Yield:

99%. ¹H-NMR (CDCl₃) δ 3.00 (t, J = 6.5 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.56–3.61 (m, 6H), 3.91 (s,

3H), 4.74 (t, J = 6.5 Hz, 2H), 6.95 (dd, J = 0.7, 8.3 Hz, 1H), 7.05 (dt, J = 1.0, 7.5 Hz, 1H), 7.29 (ddd,

J = 1.7, 7.3, 8.3 Hz, 1H), 8.11 (s, 1H), 8.28 (dd, J = 1.7, 7.7 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 32.6, 41.5,

45.2, 45.6, 55.4, 66.0 (2C), 111.5, 119.2, 120.6, 124.3, 126.5, 128.8, 141.6, 155.3, 168.1; LC-MS (ESI) m/z

317 ([M + 1]⁺).

1-Morpholino-3-(4-p-tolyl-1H-1,2,3-triazol-1-yl)propan-1-one (2aci). Colorless oil; Yield: 93%. ¹H-NMR

(CDCl₃) δ 2.35 (s, 3H), 2.96 (t, J = 6.2 Hz, 2H), 3.37 (t, J = 4.9 Hz, 2H), 3.55–3.61 (m, 6H), 4.72 (t,

J = 6.2 Hz, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.87 (s, 1H); ¹³C-NMR (DMSO-d₆) δ

20.8, 32.4, 41.5, 45.2, 45.8, 65.96, 65.98, 121.4, 125.0, 128.1, 129.4, 137.0, 146.1, 168.0; LC-MS (ESI) m/z

301 ([M + 1]⁺).

1

1-Morpholino-3-(4-m-tolyl-1H-1,2,3-triazol-1-yl)propan-1-one (2acj). Colorless oil; Yield: 98%. H-NMR

(CDCl₃) δ 2.37 (s, 3H), 2.96 (t, J = 6.2 Hz, 2H), 3.38 (t, J = 4.9 Hz, 2H), 3.56–3.62 (m, 6H), 4.74 (t,

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Molecules 2015, 20, 19984–20013

J = 6.2 Hz, 2H), 7.12 (d, J = 7.8 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H),

7.91 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 32.4, 41.5, 45.2, 45.8, 65.98, 66.00, 121.7, 122.3, 125.6, 128.4,

128.8, 130.7, 138.0, 146.2, 168.1; LC-MS (ESI) m/z 301 ([M + 1]⁺).

1-Morpholino-3-(4-o-tolyl-1H-1,2,3-triazol-1-yl)propan-1-one (2ack). Light yellow oil; Yield: 90%.

¹H-NMR (CDCl₃) δ 2.45 (s, 3H), 3.00 (t, J = 6.3 Hz, 2H), 3.40 (t, J = 4.9 Hz, 2H), 3.57–3.62 (m, 6H),

4.77 (t, J = 6.3 Hz, 2H), 7.21–7.27 (m, 3H), 7.73 (m, 1H), 7.82 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 21.1, 32.5,

41.5, 45.2, 45.8, 66.0, 66.02, 123.6, 126.0, 127.7, 128.1, 130.1, 130.9, 134.8, 145.4, 168.1; LC-MS (ESI) m/z

301 ([M + 1]⁺).

3-{4-[4-(Dimethylamino)phenyl]-1H-1,2,3-triazol-1-yl}-1-morpholinopropan-1-one (2acl).

Light yellow

solid; Yield: 99%. ¹H-NMR (CDCl₃) δ 2.96 (t, J = 6.3 Hz, 2H), 2.97 (s, 6H), 3.38 (t, J = 4.9 Hz, 2H),

3.57–3.62 (m, 6H), 4.72 (t, J = 6.3 Hz, 2H), 6.75 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.77 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 32.5, 40.0, 41.5, 45.2, 45.7, 65.97, 65.99, 112.4, 119.9, 126.0, 130.2, 146.7, 149.9,

168.1; LC-MS (ESI) m/z 330 ([M + 1]⁺).

1-Morpholino-3-[4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl]propan-1-one (2acm). Light yellow oil; Yield:

99%. ¹H-NMR (CDCl₃) δ 2.98 (t, J = 6.1 Hz, 2H), 3.39 (t, J = 4.8 Hz, 2H), 3.58–3.63 (m, 6H), 4.75 (t,

J = 6.1 Hz, 2H), 7.02–7.05 (m, 4H), 7.12 (m, 1H), 7.32–7.35 (m, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.89 (s, 1H);

¹³C-NMR (DMSO-d₆) δ 32.44, 41.5, 45.2, 45.8, 65.96, 65.98, 118.8, 118.9, 123.6, 124.2, 126.2, 126.8, 130.1,

145.6, 156.3, 156.4, 168.0; LC-MS (ESI) m/z 379 ([M + 1]⁺).

3-[4-(2,4-Diﬂuorophenyl)-1H-1,2,3-triazol-1-yl]-1-morpholinopropan-1-one (2acn). Light yellow solid;

Yield: 92. ¹H-NMR (CDCl₃) δ 3.02 (t, J = 6.3 Hz, 2H), 3.41 (t, J = 4.9 Hz, 2H), 3.60–3.65 (m, 6H),

4.79 (t, J = 6.3 Hz, 2H), 6.90 (ddd, J = 2.4, 8.7, 11.0 Hz, 1H), 6.99 (m, 1H), 8.03 (d, J = 3.8 Hz,

1H), 8.24 (dt, J = 6.5, 8.6 Hz, 1H); ¹³C-NMR (DMSO-d₆) δ 32.5, 41.5, 45.2, 45.9, 66.0 (2C), 104.5 (t,

J_CF= 26.0 Hz), 112.3 (dd, J_CF= 21.1, 3.7 Hz), 115.3 (dd, J_CF= 11.8, 5.4 Hz), 123.9 (d, J_CF= 10.4

Hz), 128.5 (dd, J_CF= 9.6, 5.5 Hz), 138.8 (d, J_CF= 2.5 Hz), 158.4 (dd, J_CF= 250.1, 12.6 Hz), 161.7 (dd,

J

_CF= 247.5, 12.6 Hz), 168.1; LC-MS (ESI) m/z 323 ([M + 1]⁺).

3-(4-Benzyl-1H-1,2,3-triazol-1-yl)-1-morpholinopropan-1-one (2aco). Colorless oil; Yield: 98%. ¹H-NMR

(CDCl₃) δ 2.92 (t, J = 6.4 Hz, 2H), 3.35 (t, J = 4.9 Hz, 2H), 3.53–3.59 (m, 6H), 4.04 (s, 2H), 4.63 (t,

J = 6.4 Hz, 2H), 7.19 (m, 1H), 7.21–7.29 (m, 4H), 7.32 (s, 1H); ¹³C-NMR (DMSO-d₆) δ 31.3, 32.5, 41.5,

45.2, 45.5, 66.0 (2C), 122.8, 126.1, 128.4, 128.5, 139.6, 145.8, 168.1; LC-MS (ESI) m/z 301 ([M + 1]⁺).

4. Conclusions

In summary, the yields for secondary α-1,2,3-triazoloamides (80 examples) produced by

solid-phase synthetic route ranged from 75 to 94% for six linear steps starting with Merriﬁeld resin

(the average yield for each step was over 95%). The parallel solution-phase synthesis generated the

target tertiary 1,2,3-triazoloamides (80 examples) with 97%–73% yields for three linear steps from

the reaction of amines and chloro-acid chlorides. In addition, the target 1,2,3-triazoloamides were

1

obtained in high purities (>95%) as judged from LC-MS and H-NMR analyses. This investigation,

has led to the development of the solid- and solution-phase route for the synthesis of various

1,2,3-triazoloamides that contain three diversity sites that were introduced in reactions involving

amines (R¹and R²), chloro-acid chlorides (A), and terminal acetylenes (R³). The strategy allows

for a ready access to a large library and is potentially applicable to the preparation of other

1,2,3-triazole derivatives.

Acknowledgments: This research was supported by the National Research Foundation of Korea (NRF) grants

(NRF-2014R1A1A1037635 and NRF-2014R1A2A1A11052798) from the Basic Science Research Program, the

Ministry of Science, ICT and Future Planning, Republic of Korea, and by a grant of the Korea Health Technology

R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of

Health & Welfare, Republic of Korea (HI11C1300(A111345)).

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Molecules 2015, 20, 19984–20013

Author Contributions: T.L. and D.J.B. conceived and designed the experiments; D.L., D.K., S.L., T.K., J.K., S.K.,

S.L., and J.-S.B. performed experiments; K.-H.L., K.-S.S., C.-W.C., and Y.K.S. analyzed data; T.L., D.L., and D.J.B.

wrote the paper. All authors read and approved the ﬁnal manuscript.

Conﬂicts of Interest: The authors declare no conﬂict of interest.

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Efficient syntheses of 1,2,3-triazoloamide derivatives using solid- and solution-phase synthetic approaches

DOI: 10.3390/molecules201119673

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