Cycloaddition reactions of glycine imine anions to phenylazocarboxylic esters - A new access to 1,3,5-trisubstituted 1,2,4-triazoles

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Cycloaddition reactions of glycine imine

anions to phenylazocarboxylic esters – a new

access to 1,3,5-trisubstituted 1,2,4-triazoles

Leave this area blank for abstract info.

Roman Lasch and Markus R. Heinrich*

Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg,

Schuhstraße 19, 91052 Erlangen, Germany. Markus.Heinrich@fau.de

1

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Tetrahedron

journal homepage: www.elsevier.com

Cycloaddition reactions of glycine imine anions to phenylazocarboxylic esters – a

new access to 1,3,5-trisubstituted 1,2,4-triazoles

a

Roman Lasch and Markus R. Heinrich *

a

Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen,

Germany

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

Phenylazocarboxylic tert-butyl esters have recently been shown to be highly versatile building

blocks due to their ability to undergo nucleophilic aromatic substitutions under mild conditions,

1

8

particularly well with [ F]fluoride, and to act as precursors for aryl radicals. In this article, we

now report first examples for cycloaddition reactions to phenylazocarboxylates. In a one-pot

reaction with readily accessible glycine imines, a variety of highly substituted 1,2,4-triazoles

could be obtained with an unexpected preference for one regioisomer.

Available online

Keywords:

Azocarboxylic esters

2

1

,2,4-Triazoles

Glycine imines

Cycloaddition

Azo compounds

1

. Introduction

,2,4-Triazoles represent a common structural motif in a broad

Corresponding author. Tel.: +49 9131 85 24115; fax: +49 9131 85 22585; e-

mail address: markus.heinrich@fau.de (M.R. Heinrich)

1

variety of commercial products, including pharmaceuticals and

2

3

agrochemicals such as rilmazafone and flupoxam. Which

synthetic strategy is chosen for the preparation of a particular

triazole – from the numerous options and variants being available₄

today - mainly depends on the required substitution pattern.

5

Syntheses of 3,4,5-trisubstituted 1,2,4-triazoles, for example,

most often proceed via acylated amidrazones, which finally

6

undergo condensation reactions. Alternatively, the 3,4,5-

substitution pattern can be established by reactions of 1,3,4-oxa-

diazoles with amines, in which the oxygen atom in the

heterocyclic system is exchanged for a substituted nitrogen

Scheme 1. Cycloaddition reactions of glycine imines 3 to

azodicarboxylates 2 and phenylazocarboxylates 1.

20

7

atom. Regarding the second major subgroup of 1,3,5-

8

trisubstituted 1,2,4-triazoles,

condensation reactions are

9

Cycloadditions to azo compounds, on the other hand, so far

applicable as well, but cycloaddition strategies now play a more

15

10

appear to be limited to activated N-benzoylphenyldiazenes,

important role.

16

17

diazirines, azobenzenes and most importantly, to the group of

dialkyl azodicarboxylates 2. Azodiesters 2 have thereby success-

fully been allowed to react with such diverse reagents as α-

Our interest in cycloaddition reactions was due to recent

studies on phenylazocarboxylic esters 1 (Scheme 1), which were

shown to be versatile bifunctional reagents as they are able to

undergo mild nucleophilic aromatic substitutions and a large

1

8

19

20

isocyano-esters, azidoacrylates or glycine imines to give

1

2

1

,2,4-triazolines. A generalized example illustrating the base-

1

1,12

variety of reactions proceeding via aryl radicals.

Up to date,

mediated preparation of triazolines 4 from glycine imines 3 and

13

20

however, only single nucleophilic attacks on the N-N double

bond of phenylazo-carboxylates 1 or related phenylazosulfones₁

have been reported with organobismut compounds,

azodiesters 2 is depicted in Scheme 1. Whereas the fact that no

regioisomeric products can be formed from glycinates 3 and

azodiesters 2 is certainly advantageous, reaction conditions for

the further conversion of the highly functionalized triazolines 4

into triazoles have yet to be developed.

14

3a

13b-d,14

organolithium and Grignard reagents

as well as arylboronic

13e

13f,g

acids and enamines.

2

st

Against this background, it was an interesting question whether

9

a

CH

3

CN

1 step at rt, then O

2

atmosphere

48:17

ACCEPTED MANUSCRIPT

b

the reactivity of phenylazocarboxylates 1 would at all be

sufficient to allow cycloadditions. In this article, we now report

first examples for [3+2]-cycloadditions of glycine imines 3 to

phenyl-azocarboxylates 1 leading to triazoles 5, as well as

insights into the effects governing the regioselectivity of these

reactions.

The second and third step of the procedure were conducted at rt. Yields

determined by H-NMR using 1,3,5-trimethoxybenzene as internal standard.

1

c

2

Reaction carried out in the absence of MnO .

An improvement in yield could however be observed by the

addition of a larger amount of DBU and molecular sieves (4Å) to

reduce moisture (entry 5). Experiments in the less polar solvents

20

toluene and methyl tert-butyl ether (MTBE) gave far lower

yields and a reversed regioselectivity, which points to the fact

that the stabilization of charged intermediates might play a

critical role in the mechanism (entries 6 and 7). Attempts to

influence the regioselectivity by accelerating the oxidation step

by an oxygen-atmosphere produced 5a and 6a in a slightly better

ratio of 3:1, but with a remarkably decreased overall yield. In

further experiments, Lewis acids such as TiCl or BF were

2

. Results and discussion

The first experiments on the feasibility of cycloaddition

reactions were carried out with 4-fluorophenylazocarboxylate 1a

and N-4-chlorobenzylidene glycinate 3a (Table 1) or methyl 2-

isocyano-3-phenylpropanoate, as the latter starting materials

had successfully been applied as dipoles in reactions with azo-

22

4

3

added to tune the reactivity of the deprotonated glycine imine 3a

18,20

diesters.

towards an azomethine ylide bearing a positively charged

25

These early attempts readily confirmed DBU as preferred

nitrogen atom. All these reactions however gave far lower

yields as well as they did not lead to improvements in

regioselectivity. Azomethine ylides were not yet investigated as

alternative starting materials for 3a, since they could only lead to

triazolium salts as final products. With the best conditions

available (Table 1, entry 5), we explored the scope and the

limitations of the access to triazoles.

20

additive compared to potassium carbonate with regard to

conversion of the starting materials, but complex mixtures of

products were yet obtained from 1a and 3a, which could not be

well analyzed or separated due to the low stability of the

compounds they contained. As several analyses of those product

1

mixtures by H-NMR had suggested the presence of at least one

23

triazoline, we reasoned that an oxidant such as manganese

dioxide might be helpful to convert this intermediate to a more

stable triazole. Furthermore, trifluoroacetic acid was added to

facilitate the cleavage of the tert-butyloxycarbonyl (Boc) group

Table 2. Scope and limitations of the cycloaddition to

phenylazocarboxylic esters 1.

24

on the heterocyclic core and thus to allow final aromatization.

Results from the improved one-pot procedure leading to triazoles

a and 6a, as well as subsequently performed variations, are

5

summarized in Table 1. The first attempt, in which all sub-steps

were carried out in acetonitrile at room temperature, gave

triazoles 5a and 6a in a ratio of 2.5:1 and in a combined yield of

8

0% (entry 1). As the initial attack of deprotonated glycine imine

3

a onto 1a appeared to determine the regioselectivity of the

reaction, we varied the temperature at that particular stage.

Unexpectedly, these changes had almost no effect on the overall

yield and regioselectivity (entries 2-4).

a

entry

azocarboxylate

glycine imine

triazoles

1

2

3

b

1

: R =

3: R = R =

5:6 (%:%)

1

2

3

4

5

6

7

1a: 4-F

3a: Me

3b: Et

4-Cl

5a:6a (58:36)

5b:6b (41:30)

Table 1. Optimization of reaction conditions.

4-Cl

H

c

3c: tBu

3d: Me

3e: Et

5c:6c (48:16)

c

5d:6d (42:12)

5e:6e (12:20)

5f:6f (68:25)

5g:6g (41:18)

2,4-Cl

4-Br

3,4-

2

3f: Me

3g: Me

(OMe)

2

8

1b: 4-Br

1c: 4-I

3h: Me

3c: tBu

3i: Me

3j: Me

3k: Me

3f: Me

3i: Me

3a: Me

4-F

5h:6h (51:29)

5i:6i (62:27)

5j:6j (52:23)

5k:6k (41:25)

5l:6l (61:37)

5m:6m (58:22)

5n:6n (58:26)

5o:6o (22:33)

9

4-Cl

3-Br

Ph

a

entry

solvent

variations

yield

a:6a

%:%)

10

5

(

1

2

3

4

5

4-CN

4-Br

3-Br

4-Cl

st

1

2

3

4

5

CH

3

CN

1 step at rt

57:23

51:23

1c: 4-I

st

1 step at 40°C

1c: 4-I

st

1 step at 0°C

56:30

1d: 4-F,

2-

st

1 step at -20°C

54:28

Me

st

1 step at -20°C, MS,

DBU (1 58:36

e

1

6

7

1e: 2,4-Cl

2

3a: Me

4-Cl

5p:7 (40:32)

eq.)

d

1f:

5q:6q (55:19)

st

6

7

8

Toluene

MTBE

1 step at rt

9:16

1:4

4

-(4-FPhO)

st

1 step at rt

e

c

1

8

1g: 4-NO

2

3a: Me

3c: tBu

4-Cl

5r:8 (32:17)

5s:6s (47:24)

st

CH

3

CN

1 step at 0°C, then O

2

47:16

c

19

2

1h: 4-NO , 3-

atmosphere

OMe

3

a

Standard conditions: glycine imine 3 (1 mmol), azocarboxylate 1 (2 equiv),

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3 2

CN (5 mL), -15°C, 45 min, then MnO (2.5 equiv), rt, 4

b

DBU (1 equiv), CH

h, then CF COOH, rt, 60 min. Yields after purification by column

chromatography. First step at rt. First step at 0°C. Decarboxylated products

An attempt to extend the reaction principle to heterocyclic

glycine imines such as 10 provided the thiophene-substituted

triazoles 11 and 12 in a ratio comparable to those observed before

3

c

d

e

7

and 8 obtained instead of 6p and 6r (Scheme 3).

(

Scheme 3). Submission of the aliphatic glycine imine 13 to the

27

same reaction conditions however furnished triazoline 14 along

with triazole 15 as single regioisomers hereby indicating that the

replacement of the aromatic unit by an aliphatic side chain

significantly complicates aromatization and cleavage of the tert-

In the first series of experiments, 4-fluorophenylazocarboxylic

ester 1a reacted with a variety of glycine imines 3a-g (entries 1-

). Methyl ester 3a hereby gave a better yield than its

corresponding ethyl or tert-butyl esters (entries 1-3), and the only

low yield, which was combined with a reversed regioselectivity,

resulted from the 2,4-dichlorophenyl-substituted glycine imine 3e

7

28

butyloxycarbonyl (Boc) group.

(

entry 5). Triazole 5d (entry 4) was further helpful to unam-

biguously assign the regioisomers 5 and 6 through its comparison

with literature data.

Scheme 3. Decarboxylation and extension to heterocyclic and

aliphatic glycine imines.

10

In the next series, 4-bromo- and 4-iodophenylazocarboxylates

1

b,c could be shown to be well suited precursors for triazoles 5h-

n (entries 8-14), with the biphenyl-4-carboxaldehyde-derived

glycine imine 3j leading to the only yield lower than 50%.

Within the structural variations on the phenylazocarboxylate

(entries 15-19), it was interesting to see that neither the weakly

donating phenoxy substituent (entry 17) nor the strongly

electron-withdrawing nitro group (entry 18) had been able to

significantly change the ratio of regioisomers through directing

the attack of anion 3* to the phenylazocarboxylate 1 (pathways A

and B, Scheme 2). Only steric hindrance, with ortho-substituents

being placed on either the aryl group of 1 (entry 5) or 3 (entries

1

5, 16) showed an impact, as it complicates the formation of

triazole 5 (Scheme 2, left) while the formation of triazole 6

remains more or less unaffected (Scheme 2, right).

A nearly quantitative combined yield of 5 and 6 could only be

reached with the acceptor-substituted glycine imine 3k (entry

1

2). Whereas the glycine imine anions 3* can reliably, although

not regioselectively, be trapped even with unactivated

phenylazocarboxylates such as 1c, only an electrophilic imine, as

it is present in 3k, allows both pathways A and B to proceed

efficiently.

In the second part of the sequence the intermediate 1,2,4-

triazolidines 5* and 6* are oxidized along with cleavage of the

tert-butyloxycarbonyl group to give the final products 5 and 6.

Finally, we ran a number of experiments to get further insights

into the reaction course (Scheme 4). In experiment (1) a second

azocarboxylate 1h was added to the reaction mixture containing

glycine imine 3c, azocarboxylate 1b, and DBU, which had been

added first. As only triazoles derived from 1b were found as

products, the overall reaction is not able to reversibly form the

anion of glycine imine 3c after DBU has been added. To further

verify this hypothesis we have conducted the same experiment

Scheme 2. Pathways leading to regioisomeric triazoles 5 and 6.

(2) with a modified order of addition of 1h and 1b, and again,

only the triazoles 5s and 6s derived from the initially added

azocarboxylate 1h were obtained. The assumed irreversibility

was also supported by experiment (3), in which the even more

reactive electrophile diethyl azodicarboxylate (DEAD) was

added to the reaction mixture containing 3h, 1b and DBU, but

the desired products were still obtained.

In experiment (4), in which DBU was added to a mixture

containing the two azocarboxylates 1b and DEAD as well as

glycine imine 3h, no formation of triazoles 5h and 6h could be

observed any more. This indicates that the addition of the anion

of glycine imine 3h to DEAD proceeds significantly faster than

to phenyl-azocarboxylic ester 1b.

In two reactions (entries 16 and 18), ester hydrolysis and

decarboxylation were found to occur spontaneously for the minor

regioisomer 6, so that triazoles 7 and 8 were isolated instead of

6

p and 6r (Scheme 3). This effect could be attributed to

26

particular steric or electronic effects. The same conversion can

otherwise be cleanly achieved in concentrated hydrochloric acid,

as exemplified by the formation of 1,3-disubstituted triazole 9

from 1,3,5-trisubstituted triazole 6a.

4

The following abbreviations are used for the description of

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signals: s (singlet), d (doublet), t (triplet), q (quartet), m

multiplet), mc (centered multiplet) and bs (broad singlet). Mass

(

spectra were recorded using electron impact (EI) or electron

spray ionization (ESI). A sector field mass analyzer or TOF were

used for HRMS measurements.

Analytical TLC was carried out on Merck silica gel plates using

short wave (254 nm) UV light, KMnO [3.0 g KMnO , 20 g

4

potassium carbonate, 5.0 mL aqueous sodium hydroxide (5%

w/w) in 300 mL H O] and ninhydrin [200 mg ninhydrin in

2

1

00 mL ethanol] to visualize components. For flash column

chromatography silica gel (Kieselgel 60, grain size 40 - 63 ꢀm,

Merck) was used.

General procedure for the synthesis of imine esters (GP 1)

A suspension of the glycine ester hydrochloride (5.00 mmol),

aldehyde (4.00 mmol) and sodium sulfate (5.00 mmol) in dry

dichloromethane (10 mL) is stirred at 0 °C. Triethylamine

(

5.00 mmol) is added dropwise. The reaction is allowed to warm

to ambient temperature and stirred for 15 hours. Diethyl ether

10 mL) is added and the solution is filtered. The filtrate is

(

washed with water (3 × 30 mL), a saturated aqueous solution of

sodium chloride (3 × 20 mL) and dried over sodium sulfate. The

solvent is removed under reduced pressure and the product is

dried in vacuum. The product is used without further purification.

General procedure for the synthesis of isomeric 1,2,4-triazoles

(

GP 2)

A mixture of the imine (1.00 mmol, from GP 1), tert-butyl

phenylazocarboxylate (2.00 mmol) and molecular sieve (4 Å,

.00 g) in dry acetonitrile (10 mL) under nitrogen is cooled to -

15 C and treated with 1,8-diazabicyclo[5.4.0]undec-7-ene

Scheme 4. Competition experiments

1

3

. Conclusions

(

1.00 mmol) and stirred for 45 minutes. Manganese dioxide

2.50 mmol) is added, the cooling is removed and the reaction is

In summary, this study presents first examples for

3+2]cycloadditions to phenylazocarboxylates. Since all known

[

stirred for four hours at ambient air. Trifluoroacetic acid

20.0 mmol) is added and the reaction is stirred for one hour.

nucleophilic attacks on phenylazocarboxylic esters so far

(

13

occurred at the nitrogen atom located in β-position to the ester,

hereby following the orientation of the underlying diaza-Michael

After addition of a saturated aqueous solution of potassium

carbonate (40 mL), the mixture is filtered and then extracted with

dichloromethane (4 × 30 mL). The combined organic phases are

washed with a saturated aqueous solution of sodium chloride

29,30

system,

it was surprising to find that the major isomers ob-

tained in our experiments resulted from an attack of the nucleo-

philic glycine imine onto the α-nitrogen atom. Whereas

electronic modifications on the glycine imine or the

azocarboxylate had no or small impacts on the regioselectivity,

only increased steric demand was able to reverse it, but at the

cost of lower yields. Studies on the reaction course revealed that

the initial addition of the deprotonated glycine imine to the

azocarboxylate is irreversible for both regioisomers. Differences

between both pathways were, on the other hand, observed in the

subsequently occuring cyclization step, which turned out to be in

one case sensitive to the presence of additional azo compounds.

Further experiments are now directed towards shorter reactions

times which would allow the extension of the methodology to

(20 mL) and dried over sodium sulfate. The solvent is removed

under reduced pressure and the residue is subjected to column

chromatography.

4.1.1 (4-Chlorobenzylidene-amino)-acetic acid methyl ester

[

30a]

(3a)

is prepared from glycine methyl ester hydrochloride

(8.89 mmol, 1.12 g) and 4-chlorobenzaldehyde (7.11 mmol,

1.00 g) according to general procedure GP 1. The title compound

3a is identified as a white solid (6.24 mmol, 1.32 g, 87%):

1

R

= 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz,

f

CDCl

7.73 (d, J = 8.5 Hz, 2 H), 8.27 (mc, 1 H).

) δ 3.79 (s, 3 H), 4.42 (mc, 2 H), 7.41 (d, J = 8.5 Hz, 2 H),

3

18

radiosyntheses with readily available tert-butyl 4-[ F]fluoro-

12

phenylazocarboxylate.

4

.1.2

(4-Chlorobenzylidene-amino)-acetic acid ethyl ester

is prepared from glycine ethyl ester hydrochloride

[

30b]

(3b)

4

. Experimental section

.1 General information

(

1

3

8.89 mmol, 1.35 g) and 4-chlorobenzaldehyde (7.11 mmol,

.00 g) according to general procedure GP 1. The title compound

b is identified as a white solid (6.04 mmol, 1.38 g, 85%):

1

Solvents and reagents were used as received. H NMR spectra

were recorded on 360 and 600 MHz spectrometers using CDCl₃

R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz,

CDCl ) δ 1.30 (t, J = 7.1 Hz, 3 H), 4.42 (q, J = 7.1 Hz, 2 H), 4.39

f

3

as solvent₁referenced to TMS (0.00 ppm) or CDCl₃

(mc, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H),

8.26 (mc, 1 H).

3

(

7.26 ppm). C NMR spectra were recorded at 91 or 151 MHz in

CDCl (77.0 ppm) as standard. Chemical shifts are reported in

3

parts per million (ppm). Coupling constants are in Hertz (J Hz).

5

4

.1.3

ester (3c)

hydrochloride (2.98 mmol, 500 mg) and 4-chlorobenzaldehyde

2.38 mmol, 335 mg) according to general procedure GP 1.

Compound 3c is identified as a pale yellow solid (2.36 mmol,

(4-Chlorobenzylidene-amino)-acetic acid tert-butyl

CDCl ) δ 3.79 (s, 3 H), 4.41 (mc, 2 H), 7.16 (t, J = 8.7 Hz, 2 H),

3

ACCEPTED MANUSCRIPT

[

30c]

is prepared from glycine tert-butyl ester

7.79 (dd, J = 5.5 Hz, J = 8.7 Hz, 2 H), 8.27 (mc, 1 H).

HF

(

4.1.9

(3-Bromobenzylidene-amino)-acetic acid methyl ester

is prepared from glycine methyl ester hydrochloride

(8.11 mmol, 1.02 g) and 3-bromobenzaldehyde (6.49 mmol,

1.20 g) according to general procedure GP 1. The title compound

3i is identified as a white solid (6.48 mmol, 1.77 g, 100%):

[

30d]

(3i)

1

6

37 mg, 99%): R = 0.8 (hexane / ethyl acetate = 3:1) (UV); H

f

NMR (600 MHz, CDCl ) δ 1.49 (s, 9 H), 4.30 (mc, 2 H), 7.39 (d,

J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 8.22 (mc, 1 H);

NMR (91 MHz, CDCl ) δ 28.1 (3 × CH ), 62.5 (CH ), 81.5 (C ),

3

13

C

1

R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz,

3

2

q

f

1

28.8 (2 × CH), 129.6 (2 × CH), 134.2 (C ), 137.1 (C ), 163.7

CDCl ) δ 3.79 (s, 3 H), 4.42 (mc, 2 H), 7.30 (t, J = 7.8 Hz, 1 H),

q

3

(

CH), 169.2 (C_q).

7.57 (ddd, J = 1.1 Hz, J = 2.0 Hz, J = 8.0 Hz, 1 H), 7.67 (td,

J = 1.3 Hz, J = 7.8 Hz, 1 H), 7.98 (t, J = 1.8 Hz, 1 H), 8.24 (mc,

1 H).

[

30a]

4

.1.4

(Benzylidene-amino)-acetic acid methyl ester (3d)

is

prepared from glycine methyl ester hydrochloride (3.98 mmol,

00 mg) and benzaldehyde (3.31 mmol, 335 µL) according to

5

4.1.10 (4-Phenylbenzylidene-amino)-acetic acid methyl ester

general procedure GP 1. Compound 3d is identified as a colorless

(3j) is prepared from glycine methyl ester hydrochloride

oil (3.63 mmol, 644 mg, 91%): R = 0.8 (hexane / ethyl

(6.86 mmol,

861 mg)

and

biphenyl-4-carboxaldehyde

f

1

acetate = 3:1) (UV); H NMR (360 MHz, CDCl ) δ 1.49 (s, 9 H),

(5.49 mmol, 1.00 mg) according to general procedure GP 1. The

3

4

2

.30 (mc, 2 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz,

H), 8.22 (mc, 1 H).

title compound 3j is identified as a white solid (4.39 mmol,

1

1.35 g, 80%): R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H

f

NMR (360 MHz, CDCl ) δ 3.80 (s, 3 H), 4.45 (mc, 2 H), 7.35-

3

4

.1.5

(2,4-Dichlorobenzylidene-amino)-acetic acid ethyl ester

7.51 (m, 3 H), 7.61-7.64 (m, 2 H), 7.66 (d, J = 8.3 Hz, 2 H), 7.86

13

(3e) is prepared from glycine ethyl ester hydrochloride

(d, J = 8.3 Hz, 2 H), 8.34 (mc, 1 H); C NMR (91 MHz, CDCl₃)

δ 52.1 (CH ), 62.1 (CH ), 127.2 (2 × CH), 127.3 (2 × CH), 127.8

(5.00 mmol, 698 mg) and 2,4-dichlorobenzaldehyde (4.00 mmol,

3

2

7

00 mg) according to general procedure GP 1. The title

(CH), 128.8 (2 × CH), 128.9 (2 × CH), 134.5 (C ), 140.3 (C ),

q q

compound 3e is identified as a white oil (4.00 mmol, 1.05 g,

144.0 (C ), 165.0 (CH), 170.5 (C ); HRMS (ESI) calcd for

q q

+ +

1

quant.): R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR

C H NO [M +Na ]: 276.0995, found: 276.1000.

16 15 2

f

(600 MHz, CDCl₃) δ 1.32 (t, J = 7.2 Hz, 3 H), 4.26 (q,

J = 7.2 Hz, 2 H), 4.45 (mc, 2 H), 7.30 (ddd, J = 0.7 Hz,

J = 2.0 Hz, J = 8.5 Hz, 1 H), 7.41 (d, J = 2.0 Hz, 1 H), 8.07 (d,

4.1.11 (4-Cyanobenzylidene-amino)-acetic acid methyl ester

[30c]

(3k)

is prepared from glycine methyl ester hydrochloride

13

J = 8.5 Hz, 1 H), 8.67 (mc, 1 H); C NMR (151 MHz, CDCl₃)

δ 14.2 (CH ), 61.2 (CH ), 62.0 (CH ), 127.6 (CH), 131.3 (C ),

(9.54 mmol, 1.20 g) and 4-cyanobenzaldehyde (7.63 mmol,

1.00 g) according to general procedure GP 1. The crude product

is purified by recrystallization in diethyl ether to afford the pure

3

2

q

1

35.9 (C ), 137.6 (C ), 160.9 (CH), 169.7 (C ); HRMS (ESI)

q q q

+ +

calcd for C H Cl NO [M +Na ]: 282.0059, found: 282.0056.

compound 3k as a pale yellow solid (5.80 mmol, 1.17 g, 76%):

11

2

1

R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz,

f

4

.1.6

(4-Bromobenzylidene-amino)-acetic acid methyl ester

is prepared from glycine methyl ester hydrochloride

CDCl ) δ 3.80 (s, 3 H), 4.47 (mc, 2 H), 7.73 (d, J = 8.4 Hz, 2 H),

7.90 (d, J = 8.4 Hz, 2 H), 8.34 (mc, 1 H).

3

[

30a]

(3f)

(8.11 mmol, 1.02 g) and 4-bromobenzaldehyde (6.49 mmol,

1

3

.20 g) according to general procedure GP 1. The title compound

4.1.122-((Thiophen-2-ylmethylene)amino)-acetic acid methyl

[

30a]

f is identified as a white solid (6.00 mmol, 1.59 g, 93%):

ester (10)

(7.80 mmol,

is prepared from glycine methyl ester hydrochloride

979 mg) and 2-thiophenecarboxaldehyde

1

R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz,

f

CDCl ) δ 3.78 (s, 3 H), 4.41 (mc, 2 H), 7.56 (d, J = 8.4 Hz, 2 H),

(6.24 mmol, 583 µg) according to general procedure GP 1. The

3

7

.64 (d, J = 8.4 Hz, 2 H), 8.24 (mc, 1 H).

title compound 10 is identified as a pale yellow solid (3.56 mmol,

1

6

52 mg, 57%): R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H

f

4

.1.7 2-(3,4-Dimethoxybenzylidene-amino)-acetic acid methyl

NMR (360 MHz, CDCl ) δ 3.77 (s, 3 H), 4.37 (mc, 2 H), 7.08

3

ester (3g) is prepared from glycine methyl ester hydrochloride

(dd, J = 3.7 Hz, J = 5.0 Hz, 1 H), 7.37 (dd, J = 1.0 Hz,

J = 3.7 Hz, 1 H), 7.45 (td, J = 1.0 Hz, J = 5.0 Hz, 1 H), 8.34 (mc,

1 H).

(7.53 mmol,

945 mg)

and

3,4-dimethoxybenzaldehyde

(6.02 mmol, 1.00 g) according to general procedure GP 1.

Compound 3g is identified as a pale yellow solid (5.21 mmol,

1

.36 g, 86%): R = 0.8 (hexane / ethyl acetate = 3:1) (UV); H

f

[

11b]

4

.1.13 Tert-butyl 2-(4-fluorophenyl)azocarboxylate (1a) . A

NMR (360 MHz, CDCl ) δ 3.77 (s, 3 H), 3.91 (s, 3 H), 3.93 (s,

3

solution of 4-fluoroaniline (20.0 mmol, 1.92 mL) in glacial acetic

acid (10 mL) is treated with concentrated hydrochloric acid

50 mL) and cooled to 0 °C. A solution of sodium nitrite

20.0 mmol, 1.38 g) in water (4.0 mL) is added over a period of

3

H), 4.38 (mc, 2 H), 6.88 (d, J = 8.2 Hz, 1 H), 7.18 (dd,

J = 1.9 Hz, J = 8.2 Hz, 1 H), 7.46 (d, J = 1.9 Hz, 1 H), 8.19 (mc,

13

(

2

1

H); C NMR (91 MHz, CDCl ) δ 52.0 (CH ), 55.9 (CH ), 56.0

3 3 3

(

CH ), 61.8 (CH ), 108.9 (CH), 110.3 (CH), 123.8 (CH), 128.8

3 2

0 minutes and the reaction is stirred for one hour at 0° C. A

(

C ), 149.3 (C ), 151.8 (C ), 164.9 (CH), 170.7 (C ); HRMS

q q q q

+ +

prechilled solution of tin chloride dihydrate (44.0 mmol, 9.93 g)

in concentrated hydrochloric acid (10 mL) is added drop wise

over a period of 45 minutes. After stirring for one hour at 0 °C

(ESI) calcd for C H NO [M +Na ]: 260.0893, found:

12 15 4

2

60.0900.

the precipitate is collected by filtration and dissolved in a 3

M

4

.1.8

(4-Fluorobenzylidene-amino)-acetic acid methyl ester

30c]

[

solution of potassium hydroxide (200 mL). The composite is

extracted with diethyl ether (4 × 50 mL). The combined organic

phases are washed with a saturated aqueous solution of sodium

chloride and dried over sodium sulfate. The crude product is used

without further purification. The crude product is dissolved in dry

acetonitrile (20 mL) and treated with di-tert-butyl dicarbonate

(3h)

is prepared from glycine methyl ester hydrochloride

(10.1 mmol, 1.27 g) and 4-fluorobenzaldehyde (8.06 mmol,

1

3

.00 g) according to general procedure GP 1. The title compound

h is identified as a white solid (7.44 mmol, 1.60 g, 96%):

1

R = 0.5 (hexane / ethyl acetate = 9:1) (UV); H NMR (600 MHz,

f

6

(

18.0 mmol, 3.93 g) under argon atmosphere. After complete

over a period of 45 minutes. After stirring for one hour at 0 °C

ACCEPTED MANUSCRIPT

consumption of the reactants, as monitored by TLC, the solvent

is removed under reduced pressure. The residue is subjected to

column chromatography (silica gel, hexane / ethyl acetate = 4:1)

to give tert-butyl 2-(4-fluorophenyl)hydrazine carboxylate as an

orange solid (9.75 mmol, 2.21 g, 49%): R = 0.6 (hexane / ethyl

acetate = 3:1) (KMnO ); H NMR (360 MHz, CDCl ) δ 1.45 (s,

the precipitate is collected by filtration and dissolved in a

saturated aqueous solution of potassium carbonate (200 mL). The

composite is extracted with diethyl ether (4 × 50 mL). The

combined organic phases are washed with a saturated aqueous

solution of sodium chloride and dried over sodium sulfate. The

crude product is used without further purification. The crude

product is dissolved in dry acetonitrile (40 mL) and treated with

di-tert-butyl dicarbonate (18.6 mmol, 4.06 g) under argon

atmosphere. After complete consumption of the reactants, as

monitored by TLC, the solvent is removed under reduced

pressure. The crude product is purified by recrystallization in

f

1

4

3

9

6

H), 6.36 (bs, 1 H), 6.77 (dd, J_H_F= 4.5 Hz, J = 9.0 Hz, 2 H),

.94 (dd, J_H_F= 8.5 Hz, J = 9.0 Hz, 2 H). To a stirred solution of

tert-butyl 2-(4-fluorophenyl)hydrazine carboxylate (10.0 mmol,

.26 g) in dry dichloromethane (15 mL), manganese dioxide

50.0 mmol, 4.35 g) is subsequently added under nitrogen

2

(

atmosphere. After complete consumption of the reactants, as

monitored by TLC, the mixture is filtered over Celite. Removal

of the solvent under reduced pressure and column

chromatography (silica gel, hexane / ethyl acetate = 19:1) give

hexane / ethyl

acetate

to

afford

tert-butyl

2-(4-

iodophenyl)hydrazine carboxylate as a white solid (9.90 mmol,

3.29 g, 35%): R = 0.3 (hexane / ethyl acetate = 6:1) (UV); H

NMR (360 MHz, CDCl ) δ 1.45 (9 H), 6.36 (bs, 1 H), 6.60 (d,

1

f

3

the title compound 1a as an orange oil (7.86 mmol, 1.76 g, 79%):

J = 8.8 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H). To a stirred solution

of tert-butyl 2-(4-iodophenyl)hydrazine carboxylate (9.90 mmol,

3.29 g) in dry dichloromethane (40 mL), manganese dioxide

(50.0 mmol, 4.35 g) is subsequently added under nitrogen

atmosphere. After complete consumption of the reactants, as

monitored by TLC, the mixture is filtered over Celite. Removal

of the solvent under reduced pressure and column

chromatography (silica gel, hexane / ethyl acetate = 10:1) give

1

R = 0.6 (hexane / ethyl acetate = 19:1) (UV);

f

H

NMR

(

360 MHz, CDCl ) δ 1.66 (s, 9 H), 7.19 (dd, J = 8.2 Hz,

3

H

F

J = 9.0 Hz, 2 H), 7.94 (dd, J_H_F= 5.0 Hz, J = 9.0 Hz, 2 H).

4

.1.14 Tert-butyl 2-(4-bromophenyl)azocarboxylate (1b). A

solution of 4-bromoaniline (28.0 mmol, 4.82 g) in glacial acetic

acid (15 mL) is treated with concentrated hydrochloric acid

(

60 mL) and cooled to 0 °C. A solution of sodium nitrite

28.0 mmol, 1.93 g) in water (6.5 mL) is added over a period of

the title compound 1c as an orange solid (8.21 mmol, 2.73 g,

1

83%): R = 0.9 (hexane / ethyl acetate = 6:1) (UV); H NMR

f

2

0 minutes and the reaction is stirred for one hour at 0° C. A

(600 MHz, CDCl ) δ 1.66 (s, 9 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.88

3

prechilled solution of tin chloride dihydrate (62.0 mmol, 14.0 g)

in concentrated hydrochloric acid (15 mL) is added drop wise

over a period of 45 minutes. After stirring for one hour at 0 °C

the precipitate is collected by filtration and dissolved in a

saturated aqueous solution of potassium carbonate (200 mL). The

composite is extracted with diethyl ether (4 × 50 mL). The

combined organic phases are washed with a saturated aqueous

solution of sodium chloride and dried over sodium sulfate. The

crude product is used without further purification. The crude

product is dissolved in dry acetonitrile (30 mL) and treated with

di-tert-butyl dicarbonate (27.1 mmol, 5.92 g) under argon

atmosphere. After complete consumption of the reactants, as

monitored by TLC, the solvent is removed under reduced

pressure. The residue is subjected to column chromatography

(d, J = 8.8 Hz, 2 H).

4.1.16 Tert-butyl 2-(4-fluoro-2-methylphenyl)azocarboxylate

(1d).

A solution of 4-fluoro-2-methylaniline (32.0 mmol,

3.55 mL) in glacial acetic acid (16 mL) is treated with

concentrated hydrochloric acid (70 mL) and cooled to 0 °C. A

solution of sodium nitrite (32.0 mmol, 2.21 g) in water (7 mL) is

added over a period of 20 minutes and the reaction is stirred for

one hour at 0° C. A prechilled solution of tin chloride dihydrate

(70.4 mmol, 15.9 g) in concentrated hydrochloric acid (15 mL) is

added drop wise over a period of 45 minutes. After stirring for

one hour at 0 °C the precipitate is collected by filtration and

dissolved in a saturated aqueous solution of potassium carbonate

(200 mL). The composite is extracted with diethyl ether

(4 × 50 mL). The combined organic phases are washed with a

saturated aqueous solution of sodium chloride and dried over

sodium sulfate. The crude product is used without further

purification. The crude product is dissolved in dry acetonitrile

(40 mL) and treated with di-tert-butyl dicarbonate (25.6 mmol,

5.58 g) under argon atmosphere. After complete consumption of

the reactants, as monitored by TLC, the solvent is removed under

reduced pressure. The residue is subjected to column

chromatography (silica gel, hexane / ethyl acetate = 10:1) to give

tert-butyl 2-(4-fluoro-2-methylphenyl)hydrazine carboxylate as a

pale yellow solid (18.0 mmol,₁4.33 g, 65%): R_f= 0.5

(

silica gel, hexane / ethyl acetate = 6:1) to give tert-butyl 2-(4-

bromophenyl)hydrazine carboxylate as white solid

16.4 mmol, 4.70 g, 59%): R = 0.6 (hexane / ethyl acetate = 3:1)

a

(

f

1

UV); H NMR (600 MHz, CDCl ) δ 1.46 (s, 9 H), 6.35 (bs, 1 H),

3

6

.71 (d, J = 8.8 Hz, 2 H), 7.32 (d, J = 8.8 Hz, 2 H). To a stirred

solution of tert-butyl 2-(4-bromophenyl)hydrazine carboxylate

16.5 mmol, 4.70 g) in dry dichloromethane (30 mL), manganese

(

dioxide (82.5 mmol, 7.17 g) is subsequently added under

nitrogen atmosphere. After complete consumption of the

reactants, as monitored by TLC, the mixture is filtered over

Celite. Removal of the solvent under reduced pressure and

column chromatography (silica gel, hexane / ethyl acetate = 20:1)

(hexane / ethyl acetate = 3:1) (UV); H NMR (360 MHz, CDCl )

3

give the title compound 1b as an orange solid (14.7 mmol,

δ 1.45 (9 H), 2.19 (3 H), 6.32 (bs, 1 H), 6.74-6.83 (m, 3 H). To a

1

4

.18 g, 89%): R = 0.7 (hexane / ethyl acetate = 15:1) (UV); H

stirred

solution

of

tert-butyl

2-(4-fluoro-2-

f

NMR (600 MHz, CDCl ) δ 1.65 (s, 9 H), 7.65 (d, J = 8.9 Hz,

methylphenyl)hydrazine carboxylate (18.0 mmol, 4.33 g) in dry

dichloromethane (40 mL), manganese dioxide (90.0 mmol,

3

2

H), 7.77 (d, J = 8.9 Hz, 2 H).

7

.82 g) is subsequently added under nitrogen atmosphere. After

[

13c]

4

.1.15 Tert-butyl 2-(4-iodophenyl)azocarboxylate (1c) . A

complete consumption of the reactants, as monitored by TLC, the

mixture is filtered over Celite. Removal of the solvent under

reduced pressure give the title compound 1d as an orange solid

solution of 4-iodoaniline (28.0 mmol, 6.13 g) in glacial acetic

acid (15 mL) is treated with concentrated hydrochloric acid

(

65 mL) and cooled to 0 °C. A solution of sodium nitrite

28.0 mmol, 1.93 g) in water (6.5 mL) is added over a period of

(16.6 mmol, 3.96 g, 92%): R = 0.8 (hexane / ethyl acetate = 9:1)

f

1

(UV); H NMR (360 MHz, CDCl ) δ 1.66 (s, 9 H), 2.69 (3 H),

3

2

0 minutes and the reaction is stirred for one hour at 0° C. A

6.90-6.93 (m, 1 H), 7.04 (dd, J_H_F= 2.6 Hz, J = 9.0 Hz, 1 H), 7.62

13

prechilled solution of tin chloride dihydrate (62.0 mmol, 14.0 g)

in concentrated hydrochloric acid (15 mL) is added drop wise

(dd, J_H_F= 5.7 Hz, J = 9.0 Hz, 1 H); C NMR (91 MHz, CDCl₃)

δ 17.5 (CH ), 27.9 (3 × CH ), 84.7 (C ), 113.8 (d, J = 23.2 Hz,

3

q

CF

7

CH), 117.7 (d, J_C_F= 1.8 Hz, C ), 117.8 (d, J_C_F= 10.5 Hz, CH),

2.36 g) in ethanol (20 mL) is treated with hydrazine

q

ACCEPTED MANUSCRIPT

1

43.5 (d, J_C_F= 9.2 Hz, CH), 146.4 (d, J_C_F= 2.9 Hz, C ), 161.3

monohydrate (69.0 mmol, 5.58 g) and heated to reflux for six

hours at 65° C. The yellow precipitate is filtered and washed with

cold ethanol. Drying in vacuum gives the pure 3-methoxy-4-

q

(

C ), 165.8 (d, J = 254.8 Hz, C_q).

q CF

4

.1.17 Tert-butyl 2-(2,4-dichlorophenyl)azocarboxylate (1e). A

nitrophenylhydrazine as fluffy yellow powder (9.80 mmol,

1

solution of 2,4-dichloroaniline (31.0 mmol, 5.00 g) in glacial

acetic acid (15 mL) is treated with concentrated hydrochloric acid

1.80 g, 71%): R = 0.5 (hexane / ethyl acetate = 4:1) (UV); H

f

NMR (600 MHz, CDCl ) δ 3.89 (3 H), 6.36 (dd, J = 2.3 Hz,

3

(

70 mL) and cooled to 0 °C. A solution of sodium nitrite

31.0 mmol, 2.14 g) in water (7 mL) is added over a period of 20

J = 9.2 Hz, 1 H), 6.55 (d, J = 2.3 Hz, 1 H), 6.61 (bs, 1 H), 7.88

(d, J = 9.2 Hz, 1 H).

A

suspension of 3-methoxy-4-

minutes and the reaction is stirred for one hour at 0° C. A

prechilled solution of tin chloride dihydrate (68.2 mmol, 15.4 g)

in concentrated hydrochloric acid (15 mL) is added drop wise

over a period of 45 minutes. After stirring for one hour at 0 °C

the precipitate is collected by filtration and dissolved in a

saturated aqueous solution of potassium carbonate (200 mL). The

composite is extracted with diethyl ether (4 × 50 mL). The

combined organic phases are washed with a saturated aqueous

solution of sodium chloride and dried over sodium sulfate. The

crude product is used without further purification. The crude

product is dissolved in dry acetonitrile (35 mL) and treated with

di-tert-butyl dicarbonate (23.9 mmol, 5.22 g) under argon

atmosphere. After complete consumption of the reactants, as

monitored by TLC, the solvent is removed under reduced

pressure. The residue is subjected to column chromatography

nitrophenylhydrazine (6.55 mmol, 1.20 g) in dry acetonitrile

(12 mL) and treated with di-tert-butyl dicarbonate (9.83 mmol,

2.15 g) under argon atmosphere and stirred overnight. After

complete consumption of the reactants, as monitored by TLC, the

solvent is removed under reduced pressure. The obtained residue

is subjected to column chromatography (silica gel, hexane / ethyl

acetate = 1:1)

nitrophenyl)hydrazine carboxylate as an orange solid

(6.55 mmol, 1.86 g, quant.): R = 0.5 (hexane / ethyl

to

afford

tert-butyl

2-(3-methoxy-4-

f

1

acetate = 1:1) (UV); H NMR (360 MHz, CDCl ) δ 1.50 (9 H),

3

3.89 (3 H), 6.21 (bs, 1 H), 6.34-6.38 (m, 2 H), 6.46 (bs, 1 H),

7.93 (d, J = 9.2 Hz, 1 H). To a stirred solution of tert-butyl 2-(3-

methoxy-4-nitrophenyl)hydrazine

carboxylate

(6.55 mmol,

1.86 g) in dry dichloromethane (20 mL), manganese dioxide

(35.3 mmol, 3.07 g) is subsequently added under nitrogen

atmosphere. After complete consumption of the reactants, as

monitored by TLC, the mixture is filtered over Celite. Removal

of the solvent under reduced pressure and column

chromatography (silica gel, hexane / ethyl acetate = 5:1) give the

(silica gel, hexane / ethyl acetate = 9:1) to give tert-butyl 2-(2,4-

dichlorophenyl)hydrazine carboxylate as a pale yellow solid

(

21.9 mmol, 6.07 g, 71%): R = 0.3 (hexane / ethyl acetate = 9:1)

f

1

(UV); H NMR (600 MHz, CDCl ) δ 1.45 (9 H), 6.16 (bs, 1 H),

3

6

.37 (bs, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 7.14 (dd, J = 2.3 Hz,

title compound 1h as an orange solid (5.54 mmol, 1.56 g, 84%):

1

J = 8.8 Hz, 1 H), 7.27 (d, J = 2.3 Hz, 1 H). To a stirred solution

of tert-butyl 2-(2,4-dichlorophenyl)hydrazine carboxylate

R = 0.5 (hexane / ethyl acetate = 5:1) (UV); H NMR (600 MHz,

f

CDCl ) δ 1.68 (s, 9 H), 4.03 (3 H), 7.57 (d, J = 1.9 Hz, 1 H), 7.59

3

1

3

(21.9 mmol, 6.07 g) in dry dichloromethane (35 mL), manganese

(d, J = 1.9 Hz, J = 8.5 Hz, 1 H), 7.96 (d, J = 8.5 Hz, 1 H);

C

dioxide (99.5 mmol, 8.65 g) is subsequently added under

nitrogen atmosphere. After complete consumption of the

reactants, as monitored by TLC, the mixture is filtered over

Celite. Removal of the solvent under reduced pressure and

column chromatography (silica gel, hexane / ethyl acetate = 15:1)

NMR (151 MHz, CDCl ) δ 27.8 (3 × CH ), 56.8 (CH ), 86.1 (C ),

3

q

106.9 (CH), 116.5 (CH), 126.3 (CH), 142.0 (C ), 153.4 (C ),

q

154.0 (C ), 160.5 (C ); HRMS (ESI) calcd for C H N O

[M +K ]: 304.0899, found: 304.0694.

q

12 15

3

5

+

give the title compound 1e as an orange solid (17.6 mmol, 4.85 g,

1

4.1.20 Methyl

1

3-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-

,2,4-triazole-5-carboxylate (6a) and methyl 5-(4-chlorophenyl)-

-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5a) are

8

0%): R = 0.3 (hexane / ethyl acetate = 9:1) (UV); H NMR

f

(

360 MHz, CDCl ) δ 1.66 (s, 9 H), 7.30 (dd, J = 2.2 Hz,

3

J = 8.7 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.59 (d, J = 2.2 Hz,

1

3

prepared from (4-chlorobenzylidene-amino) acetic acid methyl

ester (3a) (236 µmol, 50.0 mg) and tert-butyl 2-(4-

fluorophenyl)azocarboxylate (1a) (472 µmol, 106 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 100:1) to give the title compounds 6a (85.0 µmol,

28.2 mg, 36%) and 5a (137 µmol, 45.4 mg, 58%) as pale yellow

solids. Methyl 3-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-

1

H); C NMR (151 MHz, CDCl ) δ 28.2 (3 × CH ), 81.8 (C ),

3 3 q

14.1 (CH), 129.2 (C ), 125.1 (C ), 127.4 (CH), 128.9 (CH),

43.1 (C ), 155.6 (C ); HRMS (ESI) calcd for C H Cl N O

M +Na ]: 297.0168, found: 297.0167.

q

11 12

2

+

[

4

.1.18 Tert-butyl

fluorophenoxy)phenyl)azocarboxylate (1f) . A solution of 4-

fluorophenol (2.38 mmol, 268 mg) in dry N,N-

dimethylformamide (15 mL) is treated with cesium carbonate

9.52 mmol, 3.10 g) under argon at room temperature. After

stirring for 45 minutes tert-butyl-2-(4-nitrophenyl)azocarboxylate

1g) (1.99 mmol, 500 mg) is added and the reaction is stirred for

2-(4-(4-

[

11b]

triazole-5-carboxylate (6a): R = 0.8 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 3.95 (s,

f

1

3

(

3

H), 7.22 (dd, J_H_F= 8.1 Hz, J = 9.0 Hz, 2 H), 7.43 (d,

J = 8.8 Hz, 2 H), 7.50 (dd, J = 5.0 Hz, J = 9.0 Hz, 2 H ), 8.13

HF

(

13

(d, J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 53.3 (CH ),

3 3

five hours. Water (15 mL) is added at 0 °C and the mixture is

extracted with ethyl acetate (3 × 50 mL). The combined organic

phases are washed with a saturated aqueous solution of sodium

chloride and dried over sodium sulfate. The solvent is removed

under reduced pressure. The obtained residue is subjected to

column chromatography (silica gel, hexane / ethyl acetate = 19:1)

1

2

16.1 (d, J_C_F= 23.3 Hz, 2 × CH), 127.8 (d, J_C_F= 9.0 Hz,

× CH), 128.1 (2 × CH), 128.1 (C ), 129.0 (2 × CH), 133.9 (d,

q

J_C_F= 3.4 Hz, C ), 136.1 (C ), 145.3 (C ), 157.7 (C ), 161.3 (C ),

q

35

+

1

2

63.1 (d, J_C_F= 250.7 Hz, C ); MS (EI) m/z 331 (15) [ Cl-M ],

76 (10), 274 (33), 109 (52), 57 (100), 41 (13); HRMS (EI) calcd

q

+

for C H ClFN O [M ]: 331.0524, found: 331.0525. Methyl 5-

16

11

3

2

to afford 1f as an orange solid (1.42 mmol, 414 mg, 71%):

1

(4-chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-

carboxylate (5a): R = 0.4 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 4.06 (s,

R = 0.8 (hexane / ethyl acetate = 19:1) (UV);

f

H

NMR

f

(

600 MHz, CDCl ) δ 1.56 (s, 9 H), 7.01 (d, J = 9.1 Hz, 2 H),

1

3

7

.05-7.12 (m, 4 H), 7.91 (d, J = 9.1 Hz, 2 H).

3

H), 7.18 (dd, J_H_F= 8.0 Hz, J = 9.0 Hz, 2 H), 7.36 (d,

J = 8.6 Hz), 7.40 (dd, J = 4.6 Hz, J = 9.0 Hz, 2 H), 7.49 (d,

HF

4

.1.19 Tert-butyl 2-(3-methoxy-4-nitrophenyl)azocarboxylate

13

J = 8.6 Hz); C NMR (91 MHz, CDCl ) δ 60.3 (CH ), 116.7 (d,

3

(1h). A solution 4-fluoro-2-methoxy-1-nitrobenzene (13.8 mmol,

J_C_F= 23.3 Hz, 2 × CH), 127.5 (d, J_C_F= 8.9 Hz, 2 × CH), 128.3

8

(

C ), 129.0 (2 × CH), 130.2 (2 × CH), 133.4 (d, J = 3.5 Hz, C ),

109 (100), 95 (11), 82 (12), 56 (10), 44 (10), 41 (19); HRMS

+

q

A

C

F

CEPTED MANUSCRIPT

q

1

37.1 (C ), 154.7 (C ), 160.0 (C ), 162.9 (d, J = 251.6 Hz, C ),

(EI) calcd for C H ClFN O [M ]: 373.0993, found: 373.0994.

3 2

5-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-

triazole-3-carboxylate (5c): R = 0.3 (dichloromethane / ethyl

q

CF

q 19 17

37

+

35

+

71.0 (C ); MS (EI) m/z 333 (15) [ Cl-M ], 331 (43) [ Cl-M ],

Tert-butyl

q

94 (34), 109 (100), 75 (10); HRMS (EI) calcd for

f

+

1

C H ClFN O [M ]: 331.0524, found: 331.0523.

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 1.67 (s,

16

11

3

2

3

9

H), 7.16 (dd, J_H_F= 8.0 Hz, J = 9.1 Hz, 2 H), 7.34 (d,

4

.1.21 Ethyl 3-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-

J = 8.8 Hz, 2 H), 7.38 (dd, J = 4.7 Hz, J = 9.1 Hz, 2 H), 7.47

HF

13

triazole-5-carboxylate (6b) and ethyl 5-(4-chlorophenyl)-1-(4-

fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5b) are prepared

from (4-chlorobenzylidene-amino) acetic acid ethyl ester (3b)

(d, J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 28.1

3

(3 × CH ), 83.4 (C ), 116.7 (d, J = 23.3 Hz, 2 × CH), 125.3

3

q

CF

(C ), 127.6 (d, J = 8.9 Hz, 2 × CH), 129.0 (2 × CH), 130.3

q

CF

(709 µmol,

160 mg)

and

tert-butyl

2-(4-

(2 × CH), 133.7 (d, J_C_F= 3.5 Hz, C ), 136.9 (C ), 154.4 (C ),

q q q

fluorophenyl)azocarboxylate

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 150:1) to give the title

compounds 6b (212µmol, 73.5 mg, 30%) and 5b (289 µmol,

(1a)

(1.42 mmol,

318 mg)

155.7 (C ), 159.0 (C ), 162.9 (d, J = 251.3 Hz, C ); MS (EI)

q q CF q

37 + 35 +

m/z 375 (10) [ Cl-M ], 373 (31) [ Cl-M ], 319 (25), 318 (25),

317 (70), 302 (10), 300 (31), 232 (16), 180 (25), 139 (16), 138

(25), 136 (24), 135 (21), 109 (100), 95 (31), 83 (11), 75 (17), 57

(58), 56 (22), 55 (10), 41 (55), 39 (17), 29 (15); HRMS (EI) calcd

+

1

00 mg, 41%) as white solids. Ethyl 3-(4-chlorophenyl)-1-(4-

for C H ClFN O [M ]: 373.0993, found: 373.0992.

19

17

3

2

fluorophenyl)-1H-1,2,4-triazole-5-carboxylate (6b):₁R = 0.8

f

(

dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

4.1.23 Methyl 1-(4-fluorophenyl)-3-phenyl-1H-1,2,4-triazole-

5-carboxylate (6d) and methyl 1-(4-fluorophenyl)-5-phenyl-1H-

1,2,4-triazole-3-carboxylate (5d) are prepared from (benzylidene-

amino) acetic acid methyl ester (3d) (339 µmol, 60.0 mg) and

tert-butyl 2-(4-fluorophenyl)azocarboxylate (1a) (678 µmol,

152 mg) according to general procedure GP 2. The crude product

is subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 50:1) to give the title

compounds 6d (41.7 µmol, 12.4 mg, 12%) and 5d (141 µmol,

41.9 mg, 42%) as pale yellow solids. Methyl 1-(4-fluorophenyl)-

(360 MHz, CDCl₃) δ 1.35 (t, J = 7.1 Hz, 3 H), 4.41 (q,

J = 7.1 Hz, 2 H), 7.21 (dd, J_H_F= 8.1 Hz, J = 9.1 Hz, 2 H), 7.44

(

8

d, J = 8.8 Hz, 2 H), 7.50 (dd, J = 4.7 Hz, J = 9.1 Hz, 2 H),

HF

13

.12 (d, J = 8.8 Hz, 2 H); C NMR (151 MHz, CDCl ) δ 14.0

3

(

CH ), 62.9 (CH ), 116.0 (d, J = 23.3 Hz, 2 × CH), 127.8 (d,

3 2 CF

J_C_F= 8.9 Hz, 2 × CH), 128.1 (2 × CH), 128.1 (C ), 128.9

q

(

2 × CH), 134.0 (d, J_C_F= 3.3 Hz, C ), 136.1 (C ), 145.8 (C ),

q q q

1

57.3 (C ), 161.3 (C ), 163.1 (d, J = 250.5 Hz, C ); MS (ESI)

q q CF q

37 + 35 +

m/z 348 [ Cl-MH ], 346 [ Cl-MH ]; HRMS (ESI) calcd for

C H ClFN O [M +Na ]: 368.0573, found: 368.0561. Ethyl 5-

+

3-phenyl-1H-1,2,4-triazole-5-carboxylate

(6d):

R = 0.7

f

17

13

3

2

1

(4-chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-

(dichloromethane / ethyl acetate = 50:1) (UV);

H

NMR

carboxylate (5b): R = 0.4 (dichloromethane / ethyl

(360 MHz, CDCl ) δ 3.96 (s, 3 H), 7.21 (dd, J = 8.1 Hz,

f

3

HF

1

acetate = 100:1) (UV); H NMR (360 MHz, CDCl ) δ 1.46 (t,

J = 9.1 Hz, 2 H), 7.44-7.49 (m, 2 H), 7.51 (dd, J = 4.7 Hz,

HF

13

3

J = 7.1 Hz, 3 H), 4.45 (q, J = 7.1 Hz, 2 H), 7.17 (dd,

J_H_F= 8.0 Hz, J = 9.1 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H), 7.38

J = 9.1 Hz, 2 H), 8.17-8.22 (m, 2 H); C NMR (151 MHz,

CDCl ) δ 52.3 (CH ), 116.0 (d, J = 23.3 Hz, 2 × CH), 126.8

3

CF

13

(dd, J_H_F= 4.6 Hz, J = 9.1 Hz, 2 H), 7.48 (d, J = 8.8 Hz, 2 H);

C

(2 × CH), 127.8 (d, J_C_F= 8.9 Hz, 2 × CH), 128.7 (2 × CH), 129.5

(C ), 130.1 (CH), 134.0 (d, J = 3.4 Hz, C ), 145.2 (C ), 157.9

NMR (91 MHz, CDCl ) δ 14.3 (CH ), 62.2 (CH ), 116.8 (d,

3

2

q

CF

q

J_C_F= 23.3 Hz, 2 × CH), 125.0 (C ), 127.6 (d, J_C_F= 8.9 Hz,

(C ), 162.2 (C ), 163.0 (d, J = 248.4 Hz, C ); MS (EI) m/z 297

q q CF q

+ +

q

2

× CH), 129.1 (2 × CH), 130.3 (2 × CH), 133.5 (d, J_C_F= 3.4 Hz,

(81) [M ], 109 (100); HRMS (EI) calcd for C H FN O [M ]:

16 12 3 2

C ), 137.1 (C ), 154.7 (C ), 154.7 (C ), 159.7 (C ), 162.9 (d,

297.0914, found: 297.0914. Methyl 1-(4-fluorophenyl)-5-phenyl-

q

37

+

35

J_C_F= 251.4 Hz, C ); MS (ESI) m/z 348 [ Cl-MH ], 346 [ Cl-

1H-1,2,4-triazole-3-carboxylate

(5d):

R_f= 0.3

q

+

1

MH ]; HRMS (ESI) calcd for C H ClFN O [M +Na ]:

(dichloromethane / ethyl acetate = 50:1) (UV);

H

NMR

17

13

3

2

3

68.0573, found: 368.0564.

(360 MHz, CDCl ) δ 4.05 (s, 3 H), 7.13 (dd, J = 8.0 Hz,

3 HF

13

J = 9.2 Hz, 2 H), 7.32-7.47 (m, 5 H), 7.50-7.55 (m, 2 H);

C

4

1

.1.22 Tert-butyl 3-(4-chlorophenyl)-1-(4-fluorophenyl)-1H-

,2,4-triazole-5-carboxylate (6c) and tert-butyl 5-(4-

NMR (91 MHz, CDCl ) δ 52.9 (CH ), 116.6 (d, J = 23.3 Hz,

3

CF

2 × CH), 126.5 (C ), 127.5 (d, J = 8.9 Hz, 2 × CH), 128.7

q

CF

chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-

(2 × CH), 129.1 (2 × CH), 130.7 (CH), 133.7 (d, J_C_F= 3.4 Hz,

C ), 154.3 (C ), 155.7 (C ), 160.2 (C ), 162.8 (d, J = 251.0 Hz,

carboxylate (5c) are prepared from (4-chlorobenzylidene-amino)

acetic acid tert-butyl ester (3c) (79.0 µmol, 20.0 mg) and tert-

butyl 2-(4-fluorophenyl)azocarboxylate (1a) (158 µmol, 35.4 mg)

according to general procedure GP 2. After addition of

trifluoroacetic acid, the reaction is stirred for three hours. The

crude product is subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 100:1) to give the title

compounds 6c (12.6 µmol, 4.70 mg, 16%) and 5c (37.7 µmol,

q

CF

+

C ); MS (EI) m/z 297 (81) [M ], 109 (100); HRMS (EI) calcd for

q

+

C H FN O [M ]: 297.0914, found: 297.0914.

16

12

3

2

4.1.24 Ethyl

1,2,4-triazole-5-carboxylate

dichlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-

3-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-1H-

(6e) and ethyl 5-(2,4-

carboxylate (5e) are prepared from 2-((2,4-dichlorobenzylidene)-

amino) acetic acid ethyl ester (3e) (577 µmol, 150 mg) and tert-

butyl 2-(4-fluorophenyl)azocarboxylate (1a) (1.15 mmol,

258 mg) according to general procedure GP 2. The crude product

is subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 100:1) to give the title

compounds 6e (115 µmol, 43.7 mg, 20%) and 5e (69.4 µmol,

26.4 mg, 12%) as white solids. Ethyl 3-(2,4-dichlorophenyl)-1-

1

4.1 mg, 48%) as pale yellow solids. Tert-butyl 3-(4-

chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-5-

carboxylate (6c): R = 0.7 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 1.45 (s,

f

1

3

9

H), 7.21 (dd, J_H_F= 8.1 Hz, J = 9.0 Hz, 2 H), 7.42 (d,

J = 8.7 Hz, 2 H), 7.46 (dd, J = 4.7 Hz, J = 9.0 Hz, 2 H), 8.13

HF

13

(d, J = 8.7 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 27.8

3

(

3 × CH ), 84.9 (C ), 116.0 (d, J = 23.2 Hz, 2 × CH), 127.7 (d,

(4-fluorophenyl)-1H-1,2,4-triazole-5-carboxylate (6e): R = 0.8

3

q

CF

f

1

J_C_F= 8.9 Hz, 2 × CH), 128.1 (2 × CH), 128.4 (C ), 128.9

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

q

(

1

2 × CH), 134.5 (d, J_C_F= 3.4 Hz, C ), 135.9 (C ), 147.2 (C ),

56.2 (C ), 161.1 (C ), 163.0 (d, J = 250.4 Hz, C ); MS (EI)

q q CF q

35 +

(600 MHz, CDCl₃) δ 1.35 (t, J = 7.1 Hz, 3 H), 4.40

(q, J = 7.1 Hz, 2 H), 7.21 (dd, J_H_F= 8.1 Hz, J = 9.0 Hz, 2 H),

7.35 (dd, J = 2.1 Hz, J = 8.4 Hz, 1 H), 7.50-7.54 (m, 3 H), 7.93

q

m/z 373 (12) [ Cl-M ], 317 (18), 275 (16), 273 (41), 136 (41),

9

1

3

(

6

d, J = 8.4 Hz, 1 H); C NMR (91 MHz, CDCl ) δ 14.0 (CH ),

(78.4 µmol, 28.0 mg, 18%) and 5g (173 µmol, 61.9 mg, 41%)

A

3

CCEPTED MANUSCRIPT

3

2.9 (CH ), 116.0 (d, J = 23.3 Hz, 2 × CH), 127.1 (CH), 127.4

as pale yellow solids. Methyl 3-(3,4-dimethoxyphenyl)-1-(4-

2

CF

(

1

C ), 127.8 (d, J = 9.0 Hz, 2 × CH), 130.6 (CH), 132.4 (CH),

fluorophenyl)-1H-1,2,4-triazole-5-carboxylate (6g):₁R = 0.4

q

CF

f

33.8 (C ), 133.9 (d, J = 3.3 Hz, C ), 136.1 (C ), 145.2 (C ),

(dichloromethane / ethyl acetate = 20:1) (UV);

H

NMR

q

CF

q

57.3 (C ), 159.8 (C ),163.1 (d, J = 250.6 Hz, C ); MS (ESI)

(600 MHz, CDCl ) δ 3.94 (s, 3 H), 3.95 (s, 3 H), 3.97 (s, 3 H),

q

CF

37 35

q

3

37

+

35

+

m/z 384 [ Cl -MH ], 382 [ Cl Cl-MH ], 380 [ Cl -MH ];

HRMS (ESI) calcd for C H Cl FN O [M +Na ]: 402.0183,

found:

6.94 (d, J = 8.4 Hz, 1 H), 7.21 (dd, J_H_F= 8.1 Hz, J = 9.0 Hz,

2 H), 7.51 (dd, J_H_F= 4.7 Hz, J = 9.0 Hz, 2 H), 7.68 (d,

2

+

17

12

2

3

2

1

3

402.0171.

Ethyl

5-(2,4-dichlorophenyl)-1-(4-

J = 1.9 Hz, 1 H), 7.80 (dd, J = 1.9 Hz, J = 8.4 Hz, 1 H); C NMR

(91 MHz, CDCl ) δ 53.2 (CH ), 56.0 (CH ), 56.1 (CH ), 109.6

fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5e):₁R = 0.6

f

3

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

(CH), 111.1 (CH), 116.0 (d, J_C_F= 23.3 Hz, 2 × CH), 119.9 (CH),

122.4 (C_q), 127.9 (d, J_C_F= 9.0 Hz, 2 × CH), 134.0 (d,

J_C_F= 3.4 Hz, C ), 145.1 (C ), 149.1 (C ), 150.7 (C ), 157.8 (C ),

(600 MHz, CDCl₃) δ 1.48 (t, J = 7.1 Hz, 3 H), 4.55 (q,

J = 7.1 Hz, 2 H), 7.08 (dd, J_H_F= 8.0 Hz, J = 9.1 Hz, 2 H), 7.32

dd, J_H_F= 4.6 Hz, J = 9.1 Hz, 2 H), 7.39 (dd, J = 2.0 Hz,

J = 8.3 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.50 (d, J = 8.3 Hz,

q

(

162.2 (C ), 163.0 (d, J = 250.0 Hz, C ); MS (EI) m/z 358 (18)

q CF q

+ +

[MH ], 357 (100) [M ], 314 (12), 109 (22); HRMS (EI) calcd for

13

+

1

2

H); C NMR (91 MHz, CDCl ) δ 14.2 (CH ), 62.2 (CH ),

C H FN O [M ]: 357.1125, found: 357.1125. Methyl 5-(3,4-

3

2

18 16

3

4

16.3 (d, J_C_F= 23.3 Hz, 2 × CH), 125.6 (C ), 125.8 (J = 8.9 Hz,

dimethoxyphenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-

carboxylate (dichloromethane / ethyl

q

CF

× CH), 127.6 (CH), 130.0 (CH), 132.7 (CH), 133.0 (d,

(5g): ₁R = 0.2

f

J_C_F= 3.3 Hz, C ), 134.5 (C ), 137.7 (C ), 152.3 (C ), 154.7 (C ),

acetate = 20:1) (UV); H NMR (600 MHz, CDCl ) δ 3.80 (s,

q

3

1

[

59.5 (C ), 162.5 (d, J = 251.0 Hz, C ); MS (ESI) m/z 384

3 H), 3.90 (s, 3 H), 4.07 (s, 3 H), 6.80 (d, J = 8.5 Hz, 1 H), 7.00

(dd, J = 2.0 Hz, J = 8.4 Hz, 1 H), 7.15-7.21 (m, 3 H), 7.43 (dd,

J_H_F= 4.7 Hz, J = 9.0 Hz, 2 H); C NMR (151 MHz, CDCl₃)

q

CF

q

37

+

35

+

Cl -M ], 380 [ Cl-M ]; HRMS (ESI) calcd for

2

+ +

1

13

C H Cl FN O [M +Na ]: 402.0183, found: 402.0178.

7

12

2

3

2

δ 52.9 (CH ), 55.9 (CH ), 110.8 (CH), 112.0 (CH), 116.6 (d,

3

4

1

.1.25 Methyl

,2,4-triazole-5-carboxylate (6f) and methyl 5-(4-bromophenyl)-

-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5f) are

3-(4-bromophenyl)-1-(4-fluorophenyl)-1H-

J_C_F= 23.1 Hz, 2 × CH), 118.8 (C ), 122.3 (CH), 127.8 (d,

q

J_C_F= 8.9 Hz, 2 × CH), 134.0 (d, J_C_F= 3.3 Hz, C ), 149.0 (C ),

q

151.1 (C ), 154.2 (C ), 155.7 (C ), 160.4 (C ). (One CH and one

q

3

prepared from (4-bromobenzylidene-amino) acetic acid methyl

ester (3f) (377 µmol, 100 mg) and tert-butyl 2-(4-

fluorophenyl)azocarboxylate (1a) (754 µmol, 169 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 100:1) to give the title compounds 6f (94.0 µmol,

C signal are missing due to overlap); MS (EI) m/z 358 (15)

q

+ +

[MH ], 357 (75) [M ], 194 (10), 109 (100); HRMS (EI) calcd for

+

C H FN O [M ]: 357.1125, found: 357.1125.

18

16

3

4

4.1.27 Methyl

1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-

1,2,4-triazole-5-carboxylate (6h) and methyl 1-(4-bromophenyl)-

5-(4-fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5h) are

prepared from (4-fluorobenzylidene-amino) acetic acid methyl

ester (3h) (768 µmol, 150 mg) and tert-butyl 2-(4-

3

5.4 mg, 25%) and 5f (255 µmol, 95.8 mg, 68%) as white solids.

Methyl 3-(4-bromophenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-

-carboxylate (6f): R = 0.7 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 3.95 (3 H),

5

f

1

bromophenyl)azocarboxylate

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

(1b)

(1.54 mmol,

439 mg)

3

7

.21 (dd, J_H_F= 8.2 Hz, J = 8.8 Hz, 2 H), 7.49 (dd, J_H_F= 4.7 Hz,

J = 8.8 Hz, 2 H), 7.59 (d, J = 8.6 Hz, 2 H), 8.06 (d, J = 8.6 Hz,

13

2

H); C NMR (151 MHz, CDCl ) δ 53.5 (CH ), 116.1 (d,

dichloromethane / ethyl acetate = 100:1) to give the title

compounds 6h (223 µmol, 83.9 mg, 29%) and 5h (389 µmol,

146 mg, 51%) as white solids. Methyl 1-(4-bromophenyl)-3-(4-

3

J_C_F= 23.4 Hz, 2 × CH), 124.5 (C ), 127.9 (d, J_C_F= 8.9 Hz,

q

2

× CH), 128.4 (2 × CH), 128.5 (C ), 131.9 (2 × CH), 133.8 (d,

q

J_C_F= 3.3 Hz, C ), 145.3 (C ), 157.7 (C ), 161.3 (C ), 163.1 (d,

fluorophenyl)-1H-1,2,4-triazole-5-carboxylate (6h):₁R = 0.9

q

f

81

+

79

J_C_F= 250.8 Hz, C ); MS (ESI) m/z 379 [ Cl-MH ], 376 [ Cl-

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

q

+

MH ]; HRMS (ESI) calcd for C H BrFN O [M +Na ]:

(600 MHz, CDCl ) δ 3.96 (s, 3 H), 7.14 (t, J = 8.8 Hz,

16

11

3

2

3

H

F

3

97.9911, found: 397.9903. Methyl 5-(4-bromophenyl)-1-(4-

J = 8.8 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 2 H), 7.66 (d, J = 8.8 Hz,

13

fluorophenyl)-1H-1,2,4-triazole-3-carboxylate (5f): ₁R_f= 0.3

2 H), 8.17 (dd, J_H_F= 5.4 Hz, J = 8.8 Hz, 2 H); C NMR

(151 MHz, CDCl ) δ 53.4 (CH ), 115.8 (d, J = 21.9 Hz,

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

3

CF

(600 MHz, CDCl₃) δ 4.04 (3 H), 7.16 (dd, J_H_F= 8.0 Hz,

2 × CH), 123.9 (C ), 125.7 (d, J = 3.2 Hz, C ), 127.3 (2 × CH),

q

CF

q

J = 9.0 Hz, 2 H), 7.38 (dd, J_H_F= 4.7 Hz, J = 9.0 Hz, 2 H), 7.40

128.8 (d, J_C_F= 8.6 Hz, 2 × CH), 132.2 (2 × CH), 136.8 (C_q),

145.2 (C ), 157.8 (C ), 161.6 (C ), 164.0 (d, J = 248.9 Hz, C_q);

13

(d, J = 8.6 Hz, 2 H), 7.50 (d, J = 8.6 Hz, 2 H); C NMR

q

CF

79

+

(

91 MHz, CDCl ) δ 53.0 (CH ), 116.8 (d, J = 23.4 Hz, 2 × CH),

MS (ESI) m/z 376 [ Br-MH ]; HRMS (ESI) calcd for

+ +

3

CF

1

25.4 (C ), 126.0 (C ), 127.6 (d, J = 8.9 Hz, 2 × CH), 130.5

C H BrFN O [M +Na ]: 397.9911, found: 397.9909. Methyl

16 11 3 2

q

CF

(

1

2 × CH), 132.1 (2 × CH), 133.5 (d, J_C_F= 3.3 Hz, C ), 154.4 (C ),

54.8 (C ), 160.1 (C ), 163.0 (d, J = 251.7 Hz, C ); MS (ESI)

q q CF q

81 + 79 +

1-(4-bromophenyl)-5-(4-fluorophenyl)-1H-1,2,4-triazole-3-

carboxylate (5h): R = 0.9 (dichloromethane / ethyl

q

f

1

m/z 379 [ Cl-MH ], 376 [ Cl-MH ]; HRMS (ESI) calcd for

C H BrFN O [M +Na ]: 397.9911, found: 397.9904.

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 4.06 (s,

3

+

3 H), 7.12 (t, J_H_F= 8.6 Hz, J = 8.6 Hz, 2 H), 7.29 (d, J = 8.8 Hz,

16

11

3

2

H), 7.54 (dd,₁J_H_F= 5.2 Hz, J = 8.9 Hz, 2 H), 7.61 (d,

3

4

1

.1.26 Methyl 3-(3,4-dimethoxyphenyl)-1-(4-fluorophenyl)-1H-

J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 53.0 (CH ), 116.1

3 3

,2,4-triazole-5-carboxylate

(6g)

and

methyl

5-(3,4-

(d, J_C_F= 22.1 Hz, 2 × CH), 122.7 (d, J_C_F= 3.5 Hz, C ), 123.8

q

dimethoxyphenyl)-1-(4-fluorophenyl)-1H-1,2,4-triazole-3-

carboxylate (5g) are prepared from

(C ), 126.9 (2 × CH), 131.3 (d, J = 8.8 Hz, 2 × CH), 132.9

q

CF

2-((3,4-

(2 × CH), 136.4 (C ), 154.5 (C ), 154.8 (C ), 160.1 (C ), 164.1 (d,

q q q q

79 +

dimethoxybenzylidene)amino)-acetic acid methyl ester (3g)

422 µmol, 100 mg) and tert-butyl 2-(4-

J_C_F= 253.0 Hz, C ); MS (ESI) m/z 376 [ Br-MH ]; HRMS (ESI)

q

+ +

(

calcd for C H BrFN O [M +Na ]: 397.9911, found: 397.9904.

16 11 3 2

fluorophenyl)azocarboxylate (1a) (844 µmol, 190 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 20:1 → 10:1) to give the title compounds 6g

4.1.28 Tert-butyl 1-(4-bromophenyl)-3-(4-chlorophenyl)-1H-

1,2,4-triazole-5-carboxylate (6i) and tert-butyl 1-(4-

chlorophenyl)-5-(4-bromophenyl)-1H-1,2,4-triazole-3-

1

0

carboxylate (5i) are prepared from (4-chlorobenzylidene-amino)

acetic acid tert-butyl ester (3c) (591 µmol, 150 mg) and tert-butyl

4-yl)-1-(4-bromophenyl)-1H-1,2,4-triazole-3-carboxylate (5k)

ACCEPTED MANUSCRIPT

are prepared from methyl 2-(([1,1'-biphenyl]-4-ylmethylene)-

2

-(4-bromophenyl)azocarboxylate (1b) (1.18 mmol, 336 mg)

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

amino)acetate (3j) (592 µmol, 150 mg) and tert-butyl 2-(4-

bromophenyl)azocarboxylate

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

(1b)

(1.18 mmol,

336 mg)

dichloromethane / ethyl acetate = 150:1) to give the title

compounds 6i (160 µmol, 69.6 mg, 27%) and 5i (365 µmol,

dichloromethane / ethyl acetate = 100:1) to give the title

compounds 6k (148 µmol, 64.3 mg, 25%) and 5k (141 µmol,

105 mg, 41%) as white solids. Methyl 3-([1,1'-biphenyl]-4-yl)-1-

1

59 mg, 62%) as white solids. Tert-butyl 1-(4-bromophenyl)-3-

(

4-chlorophenyl)-1H-1,2,4-triazole-5-carboxylate (6i): R = 0.7

f

1

dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

(4-bromophenyl)-1H-1,2,4-triazole-5-carboxylate (6k): R = 0.9

f

1

600 MHz, CDCl ) δ 1.47 (9 H), 7.38 (d, J = 8.8 Hz, 2 H), 7.42

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

3

d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 2 H), 8.12 (d,

(360 MHz, CDCl ) δ 3.98 (s, 3 H), 7.35-7.40 (m, 1 H), 7.42-7.49

3

13

J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 27.7 (3 × CH ),

(m, 4 H), 7.64-7.72 (m, 6 H), 8.27 (d, J = 8.6 Hz, 2 H); C NMR

3

8

5.0 (C ), 123.5 (C ), 127.2 (2 × CH), 128.0 (2 × CH), 128.2

(91 MHz, CDCl ) δ 53.2 (CH ), 123.7 (C ), 127.0 (2 × CH),

q

3

q

(

1

C ), 128.8 (2 × CH), 132.1 (2 × CH), 135.9 (C ), 137.2 (C ),

50.0 (C ), 156.2 (C ), 161.2 (C ); MS (ESI) m/z 438 [ Cl Br-

q q q

+ 37 79 + 35 81 + 35 79

127.1 (2 × CH), 127.2 (2 × CH), 127.2 (2 × CH), 127.6 (CH),

128.2 (C ), 128.7 (2 × CH), 132.1 (2 × CH), 136.7 (C ), 140.3

q

37

81

q

MH ], 436 [ Cl Br-MH ], 436 [ Cl Br-MH ], 434 [ Cl Br-

MH ]; HRMS (ESI) calcd for (C H BrClN O ) [M +Na ]:

8

(C ), 142.7 (C ), 145.0 (C ), 157.7 (C ), 162.0 (C ); MS (ESI)

q q q q q

81 +

+

m/z 436 [ Br-MH ]; HRMS (ESI) calcd for C H BrN O

22 16 3 2

+ +

19

17

3

2 2

91.0258, found: 891.0254. Tert-butyl 1-(4-chlorophenyl)-5-(4-

[M +Na ]: 456.0318, found: 456.0317. Methyl 5-([1,1'-

bromophenyl)-1H-1,2,4-triazole-3-carboxylate (5i):₁R = 0.5

biphenyl]-4-yl)-1-(4-bromophenyl)-1H-1,2,4-triazole-3-

f

(

dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

carboxylate

(5k):

R = 0.5

(dichloromethane / ethyl

f

1

600 MHz, CDCl ) δ 1.67 (9 H), 7.27 (d, J = 8.8 Hz, 2 H), 7.36

acetate = 100:1) (UV); H NMR (360 MHz, CDCl ) δ 4.06 (s,

3

d, J = 8.8 Hz, 2 H), 7.47 (d, J = 8.8 Hz, 2 H), 7.59 (d,

3 H), 7.33 (d, J = 8.8 Hz, 2 H), 7.36-7.40 (m, 1 H), 7.43-7.47 (m,

13

J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 28.0 (3 × CH ),

2 H), 7.59-7.61 (m, 8 H); C NMR (91 MHz, CDCl ) δ 52.9

3

8

3.4 (C ), 123.6 (C ), 125.1 (C ), 127.0 (2 × CH), 129.0

(CH ), 123.7 (C ), 125.1 (C ), 127.0 (2 × CH), 127.0 (2 × CH),

q

3

q

(

[

2 × CH), 130.3 (2 × CH), 132.8 (2 × CH), 136.4 (C ), 137.0

127.3 (2 × CH), 128.1 (CH), 128.9 (2 × CH), 129.5 (2 × CH),

132.8 (2 × CH), 136.6 (C ), 139.5 (C ), 143.5 (C ), 154.5 (C ),

q

C ), 154.3 (C ), 155.8 (C ), 158.9 (C ); MS (ESI) m/z 438

q

3

7

5

81

+

37

79

+

35

81

+

81

+

Cl Br-MH ], 436 [ Cl Br-MH ], 436 [ Cl Br-MH ], 434

155.4 (C ), 160.2 (C ); MS (ESI) m/z 436 [ Br-MH ]; HRMS

q q

+ +

79

+

Cl Br-MH ]; HRMS (ESI) calcd for (C H BrClN O )

(ESI) calcd for C H BrN O [M +Na ]: 456.0318, found:

22 16 3 2

19

17

3

2 2

+

M +Na ]: 891.0258, found: 891.0243.

456.0309.

4

1

.1.29 Methyl

3-(3-bromophenyl)-1-(4-bromophenyl)-1H-

4.1.31 Methyl 1-(4-iodophenyl)-3-(4-cyanophenyl)-1H-1,2,4-

triazole-5-carboxylate (6l) and methyl 1-(4-iodophenyl)-5-(4-

cyanophenyl)-1H-1,2,4-triazole-3-carboxylate (5l) are prepared

from (4-cyanobenzylidene-amino) acetic acid methyl ester (3k)

,2,4-triazole-5-carboxylate (6j) and methyl 5-(3-bromophenyl)-

-(4-bromophenyl)-1H-1,2,4-triazole-3-carboxylate (5j) are

prepared from (3-bromobenzylidene-amino) acetic acid methyl

ester (3i) (566 µmol, 150 mg) and tert-butyl 2-(4-

(742 µmol,

150 mg)

and

tert-butyl

2-(4-

bromophenyl)azocarboxylate

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 100:1) to give the title

compounds 6j (128 µmol, 55.9 mg, 23%) and 5j (286 µmol,

(1b)

(1.11 mmol,

317 mg)

iodophenyl)azocarboxylate (1c) (1.19 mmol, 395 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 100:1) to give the title compounds 6l (274 µmol,

118 mg, 37%) and 5l (453 µmol, 195 mg, 61%) as pale yellow

solids. Methyl 1-(4-iodophenyl)-3-(4-cyanophenyl)-1H-1,2,4-

1

25 mg, 52%) as white solids. Methyl 3-(3-bromophenyl)-1-(4-

bromophenyl)-1H-1,2,4-triazole-5-carboxylate (6j):₁R = 0.9

triazole-5-carboxylate (6l): R = 0.8 (dichloromethane / ethyl

f

1

(

dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 3.98 (s,

3

600 MHz, CDCl ) δ 3.97 (s, 3 H), 7.33 (t, J = 8.0 Hz, 1 H), 7.40

3 H), 7.26 (d, J = 8.7 Hz, 2 H), 7.76 (d, J = 8.7 Hz, 2 H), 7.88 (d,

3

13

d, J = 8.8 Hz, 2 H), 7.57 (ddd, J = 1.1 Hz, J = 1.8 Hz,

J = 8.7 Hz, 2 H), 8.30 (d, J = 8.7 Hz, 2 H); C NMR (91 MHz,

CDCl ) δ 53.5 (CH ), 95.8 (C ), 113.6 (C ), 118.5 (C ), 127.2

J = 8.0 Hz, 1 H), 7.66 (d, J = 8.8 Hz, 2 H), 8.11 (ddd, J = 1.1 Hz,

3

q

13

J = 1.8 Hz, J = 8.8 Hz, 1 H), 8.36 (t, J = 1.8 Hz, 1 H); C NMR

(2 × CH), 127.3 (2 × CH), 132.6 (2 × CH), 133.7 (C ), 137.3

q

(

91 MHz, CDCl ) δ 53.4 (CH ), 122.9 (CH), 124.0 (CH), 125.3

(C ), 138.3 (2 × CH), 145.6 (C ), 157.6 (C ), 160.7 (C ); MS

3

q

+

CH), 127.3 (2 × CH), 129.7 (C ), 130.2 (CH), 131.4 (C ), 132.2

(ESI) m/z 431 [MH ]; HRMS (ESI) calcd for C H IN O

17 11 4 2

+ +

q

2 × CH), 133.1 (C ), 136.7 (C ), 145.3 (C ), 157.7 (C ), 161.0

[M +Na ]: 452.9819, found: 452.9809. Methyl 1-(4-iodophenyl)-

q

81

79

+

C ); MS (ESI) m/z 438 [ Br Br-MH ]; HRMS (ESI) calcd for

5-(4-cyanophenyl)-1H-1,2,4-triazole-3-carboxylate (5l): R = 0.5

q

f

+

1

C H Br N O [M +Na ]: 459.9091, found: 459.9082. Methyl 5-

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

1

6

11

2

3

2

(

3-bromophenyl)-1-(4-bromophenyl)-1H-1,2,4-triazole-3-

carboxylate (5j): R = 0.6 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 4.07 (s,

(600 MHz, CDCl ) δ 4.05 (s, 3 H), 7.12 (d, J = 8.7 Hz, 2 H), 7.67

3

(d, J = 8.8 Hz, 2 H), 7.68 (d, J = 8.8 Hz, 2 H), 7.82 (d,

f

1

13

J = 8.7 Hz, 2 H); C NMR (151 MHz, CDCl ) δ 53.1 (CH ), 95.9

3

H), 7.22 (t, J = 8.0 Hz, 1 H), 7.28-7.32 (m, 3 H), 7.59-7.64 (m,

H), 7.88 (t, J = 1.8 Hz, 1 H); C NMR (151 MHz, CDCl₃)

(C ), 114.7 (C ), 117.7 (C ), 127.0 (2 × CH), 129.6 (2 × CH),

q q q

13

130.6 (C ), 132.5 (2 × CH), 136.7 (C ), 139.1 (2 × CH), 153.7

q q

+

δ 53.0 (CH ), 122.9 (CH), 124.0 (CH), 126.9 (CH), 127.3

(C ), 154.8 (C ), 159.8 (C ); MS (ESI) m/z 431 [MH ]; HRMS

q q q

+

3

(2 × CH), 128.3 (C ), 130.1 (CH), 132.2 (C ), 132.9 (2 × CH),

(ESI) calcd for C H IN O [MH ]: 430.9999, found: 430.9996.

17 11 4 2

q

1

33.9 (C ), 136.1 (C ), 154.1 (C ), 154.5 (C ), 160.0 (C ); MS

q q q q q

81 + 81 79 +

(ESI) m/z 440 [ Br -MH ], 438 [ Br Br-MH ]; HRMS (ESI)

4.1.32 Methyl 3-(4-bromophenyl)-1-(4-iodophenyl)-1H-1,2,4-

triazole-5-carboxylate (6m) and methyl 5-(4-bromophenyl)-1-(4-

iodophenyl)-1H-1,2,4-triazole-3-carboxylate (5m) are prepared

from (4-bromobenzylidene-amino) acetic acid methyl ester (3f)

2

+

calcd for C H Br N O [M +Na ]: 459.9091, found: 459.9079.

16

11

2

3

2

4

1

.1.30 Methyl 3-([1,1'-biphenyl]-4-yl)-1-(4-bromophenyl)-1H-

,2,4-triazole-5-carboxylate (6k) and methyl 5-([1,1'-biphenyl]-

(566 µmol,

150 mg)

and

tert-butyl

2-(4-

1

iodophenyl)azocarboxylate (1c) (1.13 mmol, 375 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 100:1) to give the title compounds 6m (122 µmol,

338 mg) according to general procedure GP 2. The crude

ACCEPTED MANUSCRIPT

product is subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 100:1 → 50:1) to give the title

compounds 6o (234 µmol, 80.9 mg, 33%) and 5o (156 µmol,

53.9 mg, 22%) as pale yellow solids. Methyl 3-(4-chlorophenyl)-

5

9.1 mg, 22%) and 5m (329 µmol, 159 mg, 58%) as white solids.

Methyl 3-(4-bromophenyl)-1-(4-iodophenyl)-1H-1,2,4-triazole-

-carboxylate (6m): ₁R = 0.8 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 3.96 (s,

1-(4-fluoro-2-methylphenyl)-1H-1,2,4-triazole-5-carboxylate

1

5

(6o): R = 0.8 (dichloromethane / ethyl acetate = 100:1) (UV); H

f

NMR (360 MHz, CDCl ) δ 2.10 (s, 3 H), 3.93 (s, 3 H), 7.02-7.06

3

H), 7.26 (d, J = 8.7 Hz, 2 H), 7.59 (d, J = 8.7 Hz, 2 H), 7.86 (d,

(m, 1 H), 7.08-7.10 (m, 1 H), 7.27 (dd, J_H_F= 5.2 Hz, J = 8.7 Hz,

13

J = 8.7 Hz, 2 H), 8.06 (d, J = 8.7 Hz, 2 H); C NMR (91 MHz,

CDCl ) δ 53.4 (CH ), 95.5 (C ), 124.5 (C ), 127.4 (2 × CH),

1 H), 7.44 (d, J = 8.8 Hz, 2 H), 8.14 (d, J = 8.8 Hz, 2 H);

C

NMR (91 MHz, CDCl ) δ 17.5 (d, J = 1.5 Hz, CH ), 53.3

3

q

3

CF

3

1

28.3 (2 × CH), 128.5 (C ), 131.9 (2 × CH), 137.4 (C ), 138.2

(CH ), 113.7 (d, J = 23.1 Hz, CH), 117.7 (d, J_C_F= 22.8 Hz,

q

3 CF

(

[

2 × CH), 145.2 (C ), 157.7 (C ), 161.5 (C ); MS (ESI) m/z 486

CH), 128.1 (2 × CH), 128.1 (C ), 128.7 (d, J = 9.4 Hz, CH),

q CF

q

81

+

79

+

Br-MH ], 484 [ Br-MH ]; HRMS (ESI) calcd for

129.0 (2 × CH), 133.3 (d, J_C_F= 3.2 Hz, C ), 136.1 (C ), 137.7 (d,

q q

+

C H BrIN O [M +Na ]: 505.8972, found: 505.8961. Methyl 5-

J_C_F= 8.9 Hz, C ), 146.1 (C ), 157.4 (C ), 161.6 (C ), 163.2 (d,

q q q q

37 + 35

16

11

3

2

(

4-bromophenyl)-1-(4-iodophenyl)-1H-1,2,4-triazole-3-

carboxylate (5m): R = 0.5 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 4.06 (s,

J_C_F= 250.3 Hz, C ); MS (ESI) m/z 348 [ Cl-MH ], 346 [ Cl-

q

+ + +

MH ]; HRMS (ESI) calcd for C H ClFN O [M +Na ]:

f

17 13

3

2

1

368.0573, found: 368.0556. Methyl 5-(4-chlorophenyl)-1-(4-

3

H), 7.16 (d, J = 8.8 Hz, 2 H), 7.42 (d, J = 8.8 Hz, 2 H), 7.54 (d,

fluoro-2-methylphenyl)-1H-1,2,4-triazole-3-carboxylate

(5o):

13

1

J = 8.8 Hz, 2 H), 7.81 (d, J = 8.8 Hz, 2 H); C NMR (151 MHz,

CDCl ) δ 53.0 (CH ), 95.4 (C ), 125.3 (C ), 125.7 (C ), 127.0

R = 0.5 (dichloromethane / ethyl acetate = 100:1) (UV);

H

f

NMR (360 MHz, CDCl ) δ 1.96 (s, 3 H), 4.06 (s, 3 H), 7.06 (d,

3

q

3

(

[

2 × CH), 130.5 (2 × CH), 132.1 (2 × CH), 136.9 (C ), 138.6

J = 8.8 Hz, 2 H), 7.28-7.33 (m, 3 H),7.48 (d, J = 8.8 Hz, 2 H);

q

13

2 × CH), 154.5 (C ), 154.7 (C ), 160.0 (C ); MS (ESI) m/z 486

C NMR (91 MHz, CDCl ) δ 17.5 (d, J = 1.5 Hz, CH ), 53.0

q

3 CF 3

8

1

+

79

+

Br-MH ], 484 [ Br-MH ]; HRMS (ESI) calcd for

(CH ), 114.5 (d, J = 23.1 Hz, CH), 118.3 (d, J_C_F= 22.8 Hz,

3 CF

+

C H BrIN O [M +Na ]: 505.8972, found: 505.8951.

CH), 129.2 (2 × CH), 129.3 (d, J_C_F= 9.4 Hz, CH), 129.5 (C_q),

29.5 (2 × CH), 132.9 (d, J_C_F= 3.5 Hz, C ), 137.3 (C ), 137.9 (d,

1

6

11

3

2

1

q

4

.1.33 Methyl 3-(3-bromophenyl)-1-(4-iodophenyl)-1H-1,2,4-

J_C_F= 8.9 Hz, C ), 154.5 (C ), 155.5 (C ), 160.2 (C ), 163.3 (d,

q q q q

37 + 35

triazole-5-carboxylate (6n) and methyl 5-(3-bromophenyl)-1-(4-

iodophenyl)-1H-1,2,4-triazole-3-carboxylate (5n) are prepared

from (3-bromobenzylidene-amino) acetic acid methyl ester (3i)

J_C_F= 251.7 Hz, C ); MS (ESI) m/z 348 [ Cl-MH ], 346 [ Cl-

q

+ + +

MH ]; HRMS (ESI) calcd for C H ClFN O [M +Na ]:

17

13

3

2

368.0573, found: 368.0557.

(566 µmol,

150 mg)

and

tert-butyl

2-(4-

iodophenyl)azocarboxylate (1c) (1.13 mmol, 375 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 100:1) to give the title compounds 6n (147 µmol,

4.1.35 3-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-

triazole (7) and methyl 5-(4-chlorophenyl)-1-(2,4-

dichlorophenyl)-1H-1,2,4-triazole-3-carboxylate (5p) are

prepared from (4-chlorobenzylidene-amino) acetic acid methyl

7

1.2 mg, 26%) and 5n (326 µmol, 158 mg, 58%) as white solids.

Methyl 3-(3-bromophenyl)-1-(4-iodophenyl)-1H-1,2,4-triazole-

-carboxylate (6n): ₁R = 0.8 (dichloromethane / ethyl

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 3.97 (s,

ester (3a) (236 µmol, 50 mg) and tert-butyl 2-(2,4-

dichlorophenyl)azocarboxylate

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

(1e) (472 µmol, 130 mg)

5

f

3

(

H), 7.26 (d, J = 8.8 Hz, 2 H), 7.33 (t, J = 7.9 Hz, 1 H), 7.57

ddd, J = 1.4 Hz, J = 2.0 Hz, J = 7.9 Hz, 1 H), 7.87 (d,

J = 8.8 Hz, 2 H), 8.10-8.12 (m, 1 H), 8.36 (t, J = 1.7 Hz, 1 H);

dichloromethane / ethyl acetate = 100:1 → 50:1) to give the title

compounds 7 (234 µmol, 80.9 mg, 32%) and 5p (156 µmol,

53.9 mg, 40%) as white solids. 3-(4-Chlorophenyl)-1-(2,4-

13

C NMR (91 MHz, CDCl ) δ 53.4 (CH ), 95.6 (C ), 122.9 (C ),

dichlorophenyl)-1H-1,2,4-triazole

(dichloromethane / ethyl acetate = 100:1) (UV);

(7):

R = 0.9

NMR

3

q

f

1

25.3 (CH), 127.4 (2 × CH), 129.7 (CH), 130.2 (CH), 131.4 (C_q),

33.1 (CH), 137.4 (C ), 138.3 (2 × CH), 145.2 (C ), 157.7 (C ),

H

(600 MHz, CDCl ) δ 7.42-7.45 (m, 3 H), 7.60 (d, J = 2.2 Hz,

q

3

8

1

+

79

+

61.1 (C ); MS (ESI) m/z 486 [ Br-M ], 484 [ Br-M ]; HRMS

1 H), 7.63 (d, J = 8.6 Hz, 1 H), 8.12 (d, J = 8.8 Hz, 2 H), 8.55 (s,

q

+

13

(ESI) calcd for C H BrIN O [M +Na ]: 505.8972, found:

1 H); C NMR (91 MHz, CDCl ) δ 127.9 (2 × CH), 128.3 (CH),

16

11

3

2

3

5

1

05.8962. Methyl 5-(3-bromophenyl)-1-(4-iodophenyl)-1H-

128.4 (CH), 128.7 (C ), 128.9 (2 × CH), 129.0 (C ), 130.6 (CH),

q

,2,4-triazole-3-carboxylate

(5n):

R = 0.5

NMR

133.5 (C ), 135.6 (C ), 135.7 (C ), 145.3 (C ), 162.1 (C ); MS

q q q q q

37 35 + 37 35 +

f

1

(

dichloromethane / ethyl acetate = 100:1) (UV);

600 MHz, CDCl ) δ 4.05 (s, 3 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.21

t, J = 7.9 Hz, 1 H), 7.30 (ddd, J = 1.1 Hz, J = 1.7 Hz, J = 7.9 Hz,

H

(ESI) m/z 328 [ Cl - Cl-MH ], 326 [ Cl- Cl -MH ]; HRMS

2 2

+

(ESI) calcd for C H Cl N [MH ]: 323.9857, found: 323.9839.

14 8 3 3

3

Methyl

5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-1,2,4-

1

H), 7.59 (ddd, J = 1.1 Hz, J = 2.0 Hz, J = 7.9 Hz, 1 H), 7.80 (d,

triazole-3-carboxylate (5p): R = 0.5 (dichloromethane / ethyl

f

13

1

J = 8.8 Hz, 2 H), 7.86 (d, J = 1.7 Hz, 1 H); C NMR (91 MHz,

CDCl ) δ 53.1 (CH ), 95.5 (C ), 123.0 (C ), 126.9 (2 × CH),

1

MS (ESI) m/z 486 [ Br-MH ], 484 [ Br-MH ]; HRMS (ESI)

calcd for C H BrIN O [M +Na ]: 505.8972, found: 505.8959.

acetate = 100:1) (UV); H NMR (600 MHz, CDCl ) δ 4.20 (s,

3

3 H), 7.49 (d, J = 8.8 Hz, 2 H), 7.60 (dd, J = 2.1 Hz, J = 8.5 Hz,

3

q

1

3

27.3 (CH), 128.3 (C ), 130.0 (CH), 132.2 (CH), 133.9 (CH),

1 H), 7.61-7.63 (m, 3 H), 7.71 (d, J = 2.1 Hz, 1 H); C NMR

(91 MHz, CDCl ) δ 53.0 (CH ), 124.7 (C ), 128.6 (CH), 129.2

q

36.9 (C ), 138.9 (2 × CH), 154.1 (C ), 154.6 (C ), 160.1 (C );

q

3

q

81

+

79

+

(2 × CH), 129.5 (2 × CH), 130.0 (CH), 130.8 (CH), 132.7 (C_q),

134.1 (C ), 137.4 (C ), 137.6 (C ), 154.9 (C ), 156.2 (C ), 160.0

+

16

11

3

2

q

35

+

(

C ); MS (ESI) m/z 383 [ Cl-MH ]; HRMS (ESI) calcd for

q

+ +

4

1

.1.34 Methyl 3-(4-chlorophenyl)-1-(4-fluoro-2-methylphenyl)-

H-1,2,4-triazole-5-carboxylate (6o) and methyl 5-(4-

C H Cl N O [M +Na ]: 403.9731, found: 403.9718.

16 10 3 3 2

chlorophenyl)-1-(4-fluoro-2-methylphenyl)-1H-1,2,4-triazole-3-

carboxylate (5o) are prepared from (4-chlorobenzylidene-amino)

acetic acid methyl ester (3a) (709 µmol, 150 mg) and tert-butyl

4.1.36 Methyl

fluorophenoxy)phenyl)-1H-1,2,4-triazole-5-carboxylate (6q) and

methyl 5-(4-chlorophenyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-

1,2,4-triazole-3-carboxylate (5q) are prepared from (4-

3-(4-chlorophenyl)-1-(4-(4-

2

-(4-fluoro-2-methylphenyl)azocarboxylate (1d) (1.42 mmol,

1

2

chlorobenzylidene-amino) acetic acid methyl ester (3a)

triazole-3-carboxylate (5s) are prepared from (4-

ACCEPTED MANUSCRIPT

(472 µmol, 100 mg) and tert-Butyl 2-(4-(4-fluorophenoxy)-

chlorobenzylidene-amino) acetic acid tert-butyl ester (3a)

(591 µmol, 150 mg) and tert-butyl 2-(3-methoxy-4-

phenyl)azocarboxylate (1f) (945 µmol, 300 mg) according to

general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 50:1 → 20:1) to give the title compounds 6q

nitrophenyl)azocarboxylate (1h) (1.18 mmol, 332 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 100:1) to give the title compounds 6s (142 µmol,

61.1 mg, 24%) and 5s (263 µmol, 113 mg, 47%) as pale orange

(

89.0 µmol, 37.7 mg, 19%) and 5q (260 µmol, 110 mg, 55%) as

pale orange solids. Methyl 3-(4-chlorophenyl)-1-(4-(4-

fluorophenoxy)phenyl)-1H-1,2,4-triazole-5-carboxylate (6q):

R = 0.6 (dichloromethane / ethyl acetate = 50:1) (UV); H NMR

solids.

nitrophenyl)-1H-1,2,4-triazole-5-carboxylate

(dichloromethane / ethyl acetate = 100:1) (UV);

Tert-butyl

3-(4-chlorophenyl)-1-(3-methoxy-4-

1

(6s): ₁R = 0.8

f

(

600 MHz, CDCl ) δ 3.97 (s, 3 H), 7.05-7.11 (m, 6 H), 7.42-7.47

H

NMR

3

13

(m, 4 H), 8.14 (d, J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl₃)

(600 MHz, CDCl ) δ 1.52 (s, 9 H), 4.02 (s, 3 H), 7.18 (dd,

3

δ 53.3 (CH ), 116.7 (d, J = 23.4 Hz, 2 × CH), 117.7 (2 × CH),

J = 2.1 Hz, J = 8.6 Hz, 1 H), 7.29 (d, J = 2.1 Hz, 1 H), 7.44 (d,

J = 8.8 Hz, 2 H), 8.00 (d, J = 8.6 Hz, 1 H), 8.13 (d, J = 8.8 Hz,

3

CF

1

J

21.5 (d, J_C_F= 8.3 Hz, 2 × CH), 127.3 (2 × CH), 128.1 (2 × CH),

13

28.2 (C ), 128.9 (2 × CH), 132.5 (C ), 136.1 (C ), 145.2 (C ),

2 H); C NMR (91 MHz, CDCl ) δ 27.8 (3 × CH ), 57.0 (CH ),

q

3 3 3

51.7 (d, J_C_F= 2.7 Hz, C ), 157.8 (C ), 159.1 (C ), 159.4 (d,

85.5 (C ), 111.3 (CH), 117.3 (CH), 126.2 (CH), 127.9 (C ), 128.1

q q

q

35

= 243.2 Hz, C ), 161.2 (C ); MS (EI) m/z 423 (100) [ Cl-

(2 × CH), 129.0 (2 × CH), 136.4 (C ), 139.6 (C ), 142.3 (C ),

CF

q

q q q

+

M ], 202 (13), 201 (93), 200 (22), 149 (11), 95 (17), 90 (27), 75

147.1 (C ), 153.4 (C ), 156.3 (C ), 161.6 (C ); MS (ESI) m/z 433

q q q q

37 + 35 + 37 + 35

+

(10), 63 (10); HRMS (EI) calcd for C H ClFN O [M ]:

[ Cl-MH ], 431 [ Cl-MH ], 333 [ Cl-MH -Boc], 331 [ Cl-

+ + +

22

15

3

4

23.0786, found: 423.0785. Methyl 5-(4-chlorophenyl)-1-(4-(4-

(5q):

R = 0.3 (dichloromethane / ethyl acetate = 50:1) (UV); H NMR

MH -Boc]; HRMS (ESI) calcd for (C H ClN O ) [M +Na ]:

20 19 4 5 2

fluorophenoxy)phenyl)-1H-1,2,4-triazole-3-carboxylate

883.1980, found: 883.1985. Tert-butyl 5-(4-chlorophenyl)-1-(3-

1

methoxy-4-nitrophenyl)-1H-1,2,4-triazole-3-carboxylate

R = 0.5 (dichloromethane / ethyl acetate = 100:1) (UV);

f

(5s):

f

1

(

600 MHz, CDCl ) δ 4.04 (s, 3 H), 7.00 (d, J = 9.0 Hz, 2 H), 7.03

H

3

(dd, J_H_F= 4.5 Hz, J = 9.2 Hz, 2 H), 7.09 (dd, J_H_F= 8.0 Hz,

NMR (600 MHz, CDCl ) δ 1.67 (s, 9 H), 3.92 (s, 3 H), 6.92 (dd,

3

J = 9.2 Hz, 2 H), 7.32 (d, J = 9.0 Hz, 2 H), 7.35 (d, J = 8.8 Hz,

J = 2.1 Hz, J = 8.7 Hz, 1 H), 7.25 (d, J = 2.1 Hz, 1 H), 7.40 (d,

J = 8.7 Hz, 2 H), 7.49 (d, J = 8.7 Hz, 2 H), 7.87 (d, J = 8.7 Hz,

13

2

H), 7.51 (d, J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl₃)

13

δ 52.9 (CH ), 116.8 (d, J = 23.5 Hz, 2 × CH), 118.2 (2 × CH),

1 H); C NMR (91 MHz, CDCl ) δ 28.1 (3 × CH ), 57.0 (CH ),

3

CF

3

1

21.5 (d, J_C_F= 8.4 Hz, 2 × CH), 125.1 (C ), 127.1 (2 × CH),

83.8 (C ), 110.6 (CH), 116.6 (CH), 125.1 (C ), 126.7 (CH), 129.3

(2 × CH), 130.5 (2 × CH), 137.6 (C ), 139.4 (C ), 141.6 (C ),

q q q

q

29.0 (2 × CH), 130.3 (2 × CH), 132.0 (C ), 137.0 (C ), 151.4 (d,

q

J_C_F= 2.7 Hz, C ), 154.2 (C ), 154.6 (C ), 159.1 (C ), 159.5 (d,

153.8 (C ), 154.7 (C ), 156.2 (C ), 158.7 (C ); MS (ESI) m/z 433

q q q q

37 + 35 +

q

37

+

J_C_F= 243.6 Hz, C ), 160.2 (C ); MS (EI) m/z 425 (24) [ Cl-M ],

[ Cl-MH ], 431 [ Cl-MH ]; HRMS (ESI) calcd for

+ +

q

35

+

35

+

4

2

24 (15) [ Cl-MH ], 423 (62) [ Cl-M ], 202 (14), 201 (100),

00 (14), 95 (17), 90 (18); HRMS (EI) calcd for C H ClFN O

3

(C H ClN O ) [M +Na ]: 883.1980, found: 883.1972.

20 19 4 5 2

22

15

3

+

[

M ]: 423.0786, found: 423.0786.

4.1.39 Methyl 1-(4-bromophenyl)-3-(thiophen-2-yl)-1H-1,2,4-

triazole-5-carboxylate (12) and methyl 1-(4-bromophenyl)-5-

(thiophen-2-yl)-1H-1,2,4-triazole-3-carboxylate (11) are prepared

from methyl-2-((thiophen-2-ylmethylene)amino)acetate (10)

4

.1.37 3-(4-chlorophenyl)-1-(4-nitrophenyl)-1H-1,2,4-triazole

(

8) and methyl 5-(4-chlorophenyl)-1-(4-nitrophenyl)-1H-1,2,4-

triazole-3-carboxylate (5r) are prepared from (4-

chlorobenzylidene-amino) acetic acid methyl ester (3a)

238 µmol, 60.0 mg) and tert-butyl 2-(4-

(546 µmol,

100 mg)

and

tert-butyl

2-(4-

bromophenyl)azocarboxylate

(1b)

(1.09 mmol,

310 mg)

(

according to general procedure GP 2. The crude product is

subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 100:1) to give the title

compounds 12 (131 µmol, 47.7 mg, 24%) and 11 (278 µmol,

101 mg, 51%) as white solids. Methyl 1-(4-bromophenyl)-3-

nitrophenyl)azocarboxylate (1g) (566 µmol, 142 mg) according

to general procedure GP 2. The crude product is subjected to

column chromatography (silica gel, dichloromethane / ethyl

acetate = 50:1) to give the title compounds 8 (48.1 µmol,

1

4.5 mg, 17%) and 5r (90.6 µmol, 32.5 mg, 32%) as an orange

(thiophen-2-yl)-1H-1,2,4-triazole-5-carboxylate (12):₁R = 0.8

f

solid. 3-(4-chlorophenyl)-1-(4-nitrophenyl)-1H-1,2,4-triazole (8):

R = 0.5 (dichloromethane / ethyl acetate = 50:1) (UV); H NMR

(dichloromethane / ethyl acetate = 100:1) (UV);

H

NMR

1

(360 MHz, CDCl ) δ 3.96 (s, 3 H), 7.13 (dd, J = 3.7 Hz,

f

3

(

600 MHz, CDCl ) δ (ppm) = 7.47 (d, J = 8.7 Hz, 2 H), 7.97 (d,

J = 5.0 Hz, 1 H), 7.40 (d, J = 8.9 Hz, 2 H), 7.41 (dd, J = 1.2 Hz,

J = 5.0 Hz, 1 H), 7.65 (d, J = 8.9 Hz, 2 H), 7.83 (dd, J = 1.2 Hz,

3

J = 9.2 Hz, 2 H), 8.15 (d, J = 8.7 Hz, 2 H), 8.42 (d, J = 9.2 Hz,

2

1

13

H), 8.71 (s, 1 H). Methyl 5-(4-chlorophenyl)-1-(4-nitrophenyl)-

J = 3.7 Hz, 1 H); C NMR (91 MHz, CDCl ) δ 53.4 (CH ), 123.9

3 3

H-1,2,4-triazole-3-carboxylate

(5r):

R = 0.3

NMR

(C ), 127.4 (2 × CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 132.0

f

q

1

(

dichloromethane / ethyl acetate = 50:1) (UV);

600 MHz, CDCl ) δ 4.06 (s, 3 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.46

d, J = 8.8 Hz, 2 H), 7.61 (d, J = 9.1 Hz, 2 H), 8.32 (d,

H

(C ), 132.2 (2 × CH), 136.6 (C ), 144.9 (C ), 157.6 (C ), 158.6

q

81

+

79

+

(C ); MS (ESI) m/z 366 [ Br-MH ], 364 [ Br-MH ]; HRMS

3

q

+

(ESI) calcd for C H BrN O S [MH ]: 363.9749, found:

14

10

3

2

13

J = 9.2 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 53.2 (CH ), 124.6

363.9741. Methyl 1-(4-bromophenyl)-5-(thiophen-2-yl)-1H-

3

(

[

(

C ), 125.1 (2 × CH), 125.9 (2 × CH), 129.5 (2 × CH), 130.4

1,2,4-triazole-3-carboxylate

(dichloromethane / ethyl acetate = 100:1) (UV);

(11):

R = 0.5

NMR

q

f

1

2 × CH), 137.9 (C ), 141.9 (C ), 147.9 (C ), 155.1 (C ), 155.1

H

q

37

+

C ), 159.8 (C ); MS (EI) m/z 360 (35) [ Cl-M ], 359 (19)

(360 MHz, CDCl ) δ 4.04 (s, 3 H), 7.01 (dd, J = 3.8 Hz,

q

3

+

35

+

MH ], 358 (100) [ Cl-M ], 221 (72), 137 (10), 136 (29), 111

10), 90 (52), 89 (18), 80 (14), 76 (18), 75 (16), 64 (11), 63 (29),

J = 5.1 Hz, 1 H), 7.23 (dd, J = 1.2 Hz, J = 3.8 Hz, 1 H), 7.37 (d,

J = 8.8 Hz, 2 H), 7.45 (dd, J = 1.2 Hz, J = 5.1 Hz, 1 H), 7.68 (d,

13

5

9 (50), 50 (12), 39 (15), 30 (52), 28 (11); HRMS (EI) calcd for

J = 8.8 Hz, 2 H); C NMR (91 MHz, CDCl ) δ 52.9 (CH ), 124.7

3 3

+

C H ClN O [M ]: 358.0469, found: 358.0470.

(C ), 127.6 (C ), 127.7 (CH), 128.1 (2 × CH), 130.0 (CH), 130.2

q q

16

11

4

(

CH), 132.9 (2 × CH), 136.0 (C ), 151.3 (C ), 154.3 (C ), 160.0

q

81

+

79

+

4

.1.38 Tert-butyl

nitrophenyl)-1H-1,2,4-triazole-5-carboxylate (6s) and tert-butyl

-(4-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-

3-(4-chlorophenyl)-1-(3-methoxy-4-

(C ); MS (ESI) m/z 366 [ Br-MH ], 364 [ Br-MH ]; HRMS

(ESI) calcd for C H BrN O S [MH ]: 363.9749, found:

q

+

14

10

3

2

5

363.9754.

1

3

under nitrogen is cooled to -15 °C and treated with 1,8-

ACCEPTED MANUSCRIPT

4

.1.40 3-(4-Chlorophenyl)-1-(4-fluorophenyl)-1H-1,2,4-

diazabicyclo[5.4.0]undec-7-ene (200 µmol, 30.0 µL) and stirred

for 45 minutes. Tert-butyl 2-(3-methoxy-4-nitrophenyl)-

azocarboxylate (1h) (400 µmol, 113 mg) is added and the

reaction is stirred for 30 minutes. Manganese dioxide (800 µmol,

70 mg) is added, the cooling is removed and the reaction is

stirred for four hours at ambient air. Trifluoroacetic acid

(4.00 mmol, 300 µL) is added and the reaction is stirred for one

hour. After addition of a saturated aqueous solution of potassium

carbonate (40 mL), the mixture is filtered and then extracted with

dichloromethane (4 × 30 mL). The combined organic phases are

washed with a saturated aqueous solution of sodium chloride

(20 mL) and dried over sodium sulfate. The triazoles 5i

(98.0 µmol, 42.3 mg, 49%) and 6i (26.0 µmol, 11.2 mg, 13%) are

determined with an internal standard 1,3,5-trimethoxybenzene.

The 1,2,4-triazoles 5s and 6s cannot be identified.

triazole (9). A solution of methyl 3-(4-chlorophenyl)-1-(4-

fluorophenyl)-1H-1,2,4-triazole-5-carboxylate (6a) (19.6 µmol,

.50 mg) in acetonitrile (1.0 mL) and is treated with concentrated

hydrochloric acid (2.0 mL) and heated to reflux for four hours at

0° C. After cooling to room temperature water (2.0 mL) is

added. The composite is extracted with diethyl ether (3 × 15 mL).

The combined organic phases are washed with a saturated

aqueous solution of sodium chloride and dried over sodium

sulfate. The title compound 9 is identified as a white solid

6

8

(

19.6 µmol, 5.40 mg, quant.): R = 0.5 (dichloromethane / ethyl

f

1

acetate = 50:1) (UV); H NMR (600 MHz, CDCl ) δ 7.22 (dd,

3

J_H_F= 8.0 Hz, J = 9.0 Hz, 2 H), 7.44 (d, J = 8.5 Hz, 2 H), 7.71

dd, J_H_F= 4.6 Hz, J = 9.0 Hz, 2 H), 8.12 (d, J = 8.5 Hz, 2 H),

(

8

13

.51 (s, 1 H);

C NMR (91 MHz, CDCl₃) δ 116.7 (d,

J_C_F= 23.2 Hz, 2 × CH), 121.9 (d, J_C_F= 8.5 Hz, 2 × CH), 125.5

C ), 127.8 (2 × CH), 128.9 (2 × CH), 129.0 (C ), 133.3 (d,

(

Experiment (2): A mixture of (4-chlorobenzylideneamino)acetic

q

J_C_F= 3.1 Hz, C ), 135.6 (C ), 141.6 (d, J = 1.6 Hz, CH), 162.0

acid tert-butyl ester (3c) (200 µmol, 50.0 mg, from GP 1), tert-

q

CF

(d, J_C_F= 248.6 Hz, C_q).

butyl

2-(3-methoxy-4-nitrophenyl)-azocarboxylate

(1h)

(400 µmol, 113 mg) and molecular sieve (4 Å, 200 mg) in dry

4

.1.41 Methyl (E)-N-[(tert-butyl)methylene]glycinate (13) is

acetonitrile (2.5 mL) under nitrogen is cooled to -15 °C and

treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (200 µmol,

30.0 µL) and stirred for 45 minutes. Tert-butyl 2-(4-

bromophenyl)azocarboxylate (1b) (400 µmol, 114 mg) is added

and the reaction is stirred for 30 minutes. Manganese dioxide

(800 µmol, 70 mg) is added, the cooling is removed and the

reaction is stirred for four hours at ambient air. Trifluoroacetic

acid (4.00 mmol, 300 µL) is added and the reaction is stirred for

one hour. After addition of a saturated aqueous solution of

potassium carbonate (40 mL), the mixture is filtered and then

extracted with dichloromethane (4 × 30 mL). The combined

organic phases are washed with a saturated aqueous solution of

sodium chloride (20 mL) and dried over sodium sulfate. The

triazoles 5s (112 µmol, 48.3 mg, 56%) and 6s (43.2 µmol,

18.6 mg, 22%) are determined with an internal standard 1,3,5-

trimethoxybenzene. The 1,2,4-triazoles 5i and 6i cannot be

identified.

prepared from glycine ethyl ester hydrochloride (5.74 mmol,

21 mg) and pivaldehyde (4.59 mmol, 500 µL) according to

general procedure GP 1. The title compound 13 is identified as a

colorless oil 4.22 mmol, 664 mg, ₁92%): R = 0.2

chloroform / methanol = 20:1) (KMnO ); H NMR (360 MHz,

7

f

(

4

CDCl ) δ 1.11 (s, 9 H), 3.74 (s, 3 H), 4.16 (d, J = 1.1 Hz, 2 H),

7

3

.56 (t, J = 1.2 Hz, 1 H).

4

.1.42 1-(tert-Butyl) 5-methyl 2-(4-bromophenyl)-3-(tert-

butyl)-2,3-dihydro-1H-1,2,4-triazole-1,5-dicarboxylate (14) and

methyl 1-(4-bromophenyl)-5-(tert-butyl)-1H-1,2,4-triazole-3-

carboxylate (15) are prepared from methyl (E)-N-[(tert-

butyl)methylene]glycinate (13) (636 µmol, 100 mg) and tert-

butyl 2-(4-bromophenyl)azocarboxylate (1b) (1.27 mmol,

3

62 mg) according to general procedure GP 2. The crude product

is subjected to column chromatography (silica gel,

dichloromethane / ethyl acetate = 100:1 → 20:1) to give the title

compounds 14 (290 µmol, 128 mg, 46%) and 15 (69.9 µmol,

Experiment (3): A mixture of (4-fluorobenzylideneamino)acetic

acid methyl ester (3h) (256 µmol, 50.0 mg, from GP 1), tert-

butyl 2-(4-bromophenyl)azocarboxylate (1b) (512 µmol, 146 mg)

and molecular sieve (4 Å, 200 mg) in dry acetonitrile (2 mL)

under nitrogen is cooled to -15 °C and treated with 1,8-

diazabicyclo[5.4.0]undec-7-ene (256 µmol, 40.0 µL) and stirred

for 45 minutes. Diethyl azodicarboxylate (512 µmol, 223 µL,

40% in toluene) is added and the reaction is stirred for 30

minutes. Manganese dioxide (1.02 mmol, 88.7 mg) is added, the

cooling is removed and the reaction is stirred for four hours at

ambient air. Trifluoroacetic acid (5.12 mmol, 400 µL) is added

and the reaction is stirred for one hour. After addition of a

saturated aqueous solution of potassium carbonate (40 mL), the

mixture is filtered and then extracted with dichloromethane

(4 × 30 mL). The combined organic phases are washed with a

saturated aqueous solution of sodium chloride (20 mL) and dried

over sodium sulfate. The triazoles 5h (128 µmol, 48.2 mg, 50%)

and 6h (38.4 µmol, 14.4 mg, 15%) are determined with an

internal standard 1,3,5-trimethoxybenzene. 1,2,4-Triazolines

2

(

1

3.7 mg, 11%) as pale brown solids. 1-(tert-Butyl) 5-methyl 2-

4-bromophenyl)-3-(tert-butyl)-2,3-dihydro-1H-1,2,4-triazole-

,5-dicarboxylate (14): R = 0.3 (dichloromethane / ethyl

f

1

acetate = 100:1) (UV); H NMR (360 MHz, CDCl ) δ 0.94 (s,

9

J = 9.0 Hz, 2 H), 7.44 (d, J = 9.0 Hz, 2 H); C NMR (91 MHz,

CDCl ) δ 25.4 (3 × CH ), 28.1 (3 × CH ), 35.8 (CH), 53.5 (CH ),

3

H), 1.46 (s, 9 H), 3.89 (s, 3 H), 5.57 (s, 1 H), 7.17 (d,

13

3

8

1

3.3 (C ), 94.0 (C ), 118.9 (C ), 123.1 (2 × CH), 131.9 (2 × CH),

q q q

41.9 (C ), 150.5 (C ), 158.5 (C ), 159.5 (C ); MS (ESI) m/z 442

q

8

1

+

81

+

[

Br-MH ], 384 [ Br-M -C(CH ) ]; HRMS (ESI) calcd for

3 3

+

C H BrN O [MH ]: 440.1180, found: 440.1173. Methyl 1-(4-

1

9

26

3

4

bromophenyl)-5-(tert-butyl)-1H-1,2,4-triazole-3-carboxylate

15): R = 0.4 (dichloromethane / ethyl acetate = 100:1) (UV); H

1

(

f

NMR (600 MHz, CDCl ) δ 1.45 (s, 9 H), 3.92 (s, 3 H), 7.35 (d,

J = 8.8 Hz, 2 H), 7.63 (d, J = 8.8 Hz, 2 H); C NMR (91 MHz,

CDCl ) δ 29.5 (3 × CH ), 53.2 (CH ), 85.3 (C ), 123.5 (C ), 127.3

3

13

3

q

(2 × CH), 132.1 (2 × CH), 137.0 (C ), 144.4 (C ), 158.1 (C ),

q

8

1

+

79

+

1

72.4 (C ); MS (ESI) m/z 340 [ Br-MH ], 338 [ Br-MH ];

q

+

1

HRMS (ESI) calcd for C H BrN O [MH ]: 338.0492, found:

cannot be identified in the crude H-NMR.

14

16

3

2

3

38.0499.

Experiment (4): A mixture of (4-fluorobenzylideneamino)acetic

acid methyl ester (3h) (256 µmol, 50 mg, from GP 1), tert-butyl

2-(4-bromophenyl)azocarboxylate (1b) (512 µmol, 146 mg),

diethyl azodicarboxylate (512 µmol, 223 µL, 40% in toluene) and

molecular sieve (4 Å, 200 mg) in dry acetonitrile (2 mL) under

nitrogen is cooled to -15 °C and treated with 1,8-

Description of competition experiments (Scheme 4)

Experiment (1): A mixture of (4-chlorobenzylideneamino)acetic

acid tert-butyl ester (3c) (200 µmol, 50.0 mg, from GP 1), tert-

butyl 2-(4-bromophenyl)azocarboxylate (1b) (400 µmol, 114 mg)

and molecular sieve (4 Å, 200 mg) in dry acetonitrile (2.5 mL)

1

4

diazabicyclo[5.4.0]undec-7-ene (265 µmol, 40.0 µL) and stirred

for 45 minutes. Manganese dioxide (1.02 mmol, 70.0 mg) is

added, the cooling is removed and the reaction is stirred for four

hours at ambient air. Trifluoroacetic acid (5.12 mmol, 400 µL) is

added and the reaction is stirred for one hour. After addition of a

saturated aqueous solution of potassium carbonate (40 mL), the

mixture is filtered and then extracted with dichloromethane

saturated aqueous solution of sodium chloride (20 mL) and

ACCEPTED MANUSCRIPT

dried over sodium sulfate. The reaction gives a complex mixture,

no 1,2,4-triazoles or 1,2,4-triazolines could be identified.

(4 × 30 mL). The combined organic phases are washed with a

1

3. (a) Tšubrik, O.; Kisseljova, K.; Mäeorg, U. Synlett 2006, 15, 2391.

b) Tšubrik, O.; Sillard, R.; Mäeorg, U. Synthesis 2006, 5, 843. (c)

(

Zhu, M.; Zheng, N. Synthesis 2011, 14, 2223. (d) Jurberg, I. D.;

Gagosz, F. J. Organomet. Chem. 2011, 696, 37. (e) Kisseljova, K.;

Tšubrik, O.; Sillard, R.; Mäeorg, S.; Mäeorg, U. Org. Lett. 2006,

Acknowledgments

8

1

, 43. (f) Forchiassin, M.; Risaliti, A.; Russo, C. Tetrahedron

981, 37, 2921. (g) Ballaben, E.; Forchiassin, M.; Nitti, P.; Russo,

The authors would like to thank the Deutsche Forschungs-

gemeinschaft (DFG) for financial support of this project within

the grants HE5413/3-1 and GRK1910/B3. The experimental

assistance of Christian Hühndorf is gratefully acknowledged.

C. Gazz. Chim. Ital. 1993, 123, 387.

14. Sapountzis, I.; Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 897.

15. Cycloaddition of ketenes with N-benzoyldiazenes catalyzed by N-

heterocyclic carbenes, see: Huang, X.-L.; He, L.; Shao, P.-L. Ye,

S. Angew. Chem. Int. Ed. 2009, 48, 192.

6. Michels, G.; Mynott, R.; Regitz, M. Chem. Ber. 1988, 121, 357.

7. (a) Kato, T.; Sato, M. J. Org. Chem. 1974, 39, 3305. (b) Kerber, R.

B.; Ryan, T. J.; Hsu, S. D. J. Org. Chem. 1974, 39, 1215.

18. Monge, D.; Jensen, K. D.; Marin, I.; Jørgensen, K. A. Org. Lett.

2011, 13, 328.

19. Hong, D.; Zhu, Y.; Lin, X.; Wang, Y. Tetrahedron 2011, 67, 650.

20. Wang, Q.-L.; Fu, J.-Y.; Peng, L.; Yang, Q.-C.; Jia, L.-N.; Luo, X.-

Y.; Gui, Y.-Y.; Tian, F.; Wang, W.; Xu, X.-Y.; Wang, L.-X.

Tetrahedron Lett. 2012, 53, 2985.

21. For further cycloaddition reactions to azodiesters, see: (a) Nair, V.;

Mathew, S. M.; Biju, A. T.; Suresh, E. Angew. Chem. Int. Ed.

2007, 46, 2070. (b) Shen, L.-T.; Sun, L.-H.; Ye, S. J. Am. Chem.

Soc. 2011, 133, 15894.

22. The experiments with 2-isocyano-3-phenylpropanoate and 1b were

carried out under conditions reported in ref. 18. No triazoles or

References and notes

1

.

Reviews on uses preparation of 1,2,4-triazoles: (a) Al-Masoudi,

A.; Al-Soud, Y. A.; Al-Salihi, N. J.; Al-Masoudi, N. A. Chem.

Heterocycl. Compd. 2006, 42, 1377. (b) Shalini, K.; Kumar, N.;

Drabu, S.; Sharma, P. K.; Beilstein J. Org. Chem. 2011, 7, 668. (c)

Klingele, M. H.; Brooker, S. Coord. Chem. Rev. 2003, 241, 119.

Rilmazafone: Koike, M.; Norikuram, R.; Iwatani, K.; Sugeno, K.;

Takahashi, S.; Nakagawa, Y. Xenobiotika 1988, 18, 257.

Flupoxam: Shida, T.; Arabori, H.; Watanabe, T.; Kubota, Y.;

Ichinose, I.; Kanda, Y.; Yamazaki, S.; Shinkawa, H.

EP0282303A1, 1988 (Chem. Abstr. 1989, 110, 95247p).

2

3

.

4

5

.

Potts, K. T. Chem. Rev. 1961, 61, 87.

For a review article see: Moulin, A.; Bibian, M.; Blayo, A.-L.; El

Habnouni, S.; Martinez, J.; Fehrentz, J.-A. Chem. Rev. 2010, 110,

1

triazolines could be detected by H NMR analysis of the reaction

mixtures.

1

809.

6

.

For recent examples, see: (a) Siddaiah, V.; Basha, G. M.;

Srinuvasarao, R.; Yadav, S. K. Catal. Lett. 2011, 141, 1511. (b)

Bibian, M.; Blayo, A.-L.; Moulin, A.; Martinez, J.; Fehrentz, J.-A.

Tetrahedron Lett. 2010, 51, 2660. (c) Bekircan, O.; Bektas, H.

Molecules 2006, 11, 469. Milcent, R.; Redeuilh, C. J. Heterocycl.

Chem. 1977, 14, 53. (d) Castanedo, G. M.; Seng, P. S.; Blaquiere,

N.; Trapp, S.; Staben, S. T. J. Org. Chem. 2011, 76, 1177. (e) Lee,

J.; Hong, M.; Jung, Y.; Cho, E. J.; Rhee, H. Tetrahedron 2012, 68,

23. The presence of a triazoline was assumed due to a 1H-NMR

singlett signal around 5.70 ppm.

24. Related experiments indicated that the presence of the oxidant

MnO₂alone is not sufficient to achieve Boc-cleavage and

aromatization.

2

5. (a) Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765. (b)

Kudryavtsev, K. V.; Ivantcova, P. M.; Churakov, A. V.;

Wiedmann, S.; Luy, B.; Muhle-Goll, C.; Zefirov, N. S.; Bräse, S.

Angew. Chem. Int. Ed. 2013, 52, 12736.

6. The formation of triazole 8 can be explained by an increased

reactivity of the tert-butyl ester on the triazoline stage of the

reaction while the decarboxylation of 6p forming product 7 might

be favored due to steric reasons.

7. The position of the double bond in triazoline 14 was determined

by HSQC and HMBC experiments.

8. The reaction of azocarboxylate 1b and glycine imine 13 further

gave 11% of 1-(tert-butyl) 2-(4-bromophenyl)-3-(tert-butyl)-2,3-

dihydro-1H-1,2,4-triazole-1-carboxylate, resulting from methyl

ester cleavage and decarboxylation of 14.

2

045.

7

8

.

(a) Xie, R.; Liu, X.; Mai, C.; Liu, Z. Int. J. Org. Chem. 2013, 3,

2

3

2

5. (b) Stocks, M. J.; Cheshire, D. R.; Reynolds, R. Org. Lett.

004, 6, 2969.

For recent syntheses of 1,3-, 1,5- and 3,5-disubstituted 1,2,4-

triazoles, see: 1,3: (a) Tam, A.; Armstrong, I. S.; La Cruz, T. E.

Org. Lett. 2013, 15, 3586. 1,5: (b) Xu, Y.; McLaughlin, M.;

Bolten, E. N.; Reamer, R. A. J. Org. Chem. 2010, 75, 8666. 3,5:

2

(c) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. 2009, 131, 15080.

9

1

.

For a recently developed four-component reaction to access

triazoles via acylhydrazones, see: (a) Staben, S. T.; Blaquiere, N.

Angew. Chem. Ind. Ed. 2010, 49, 325. For other condensation

reactions for 1,2,4-triazols, see: (b) Heckdorn, R. Helv. Chim. Acta

2

3

9. For the addition (and cycloaddition) of deprotonated glycine

imines to enones, see: Zhang, Y.; Pan, L.; Xu, X.; Liu, Q. RSC

Adv. 2012, 2, 5138.

0. For the regioselectivity in cycloadditions of nitrile oxides to

Michael systems, see: Mayo, P.; Hecnar, T.; Tam, W. Tetrahedron

1

987, 70, 2118.

0. (a) Tseng, W.-C.; Wang, L.-Y.; Wu, T.-S.; Wong, F. F.

Tetrahedron 2011, 67, 5339. (b) Wang, L.-Y.; Tsai, H. J.; Lin, H.-

Y.; Kaneko, K.; Cheng, F.-Y.; Shih, H.-S.; Wong, F. F.; Huang, J.-

J. RSC Adv. 2014, 4, 14215. (c) Wang, L.-Y.; Tseng, W.-C.; Wu,

T.-S.; Kaneko, K.; Takayama, H.; Kimura, M.; Yang, W.-C.; Wu,

J. B.; Juang, S.-H.; Wong, F. F. Bioorg. Med. Chem. Lett. 2011,

2

001, 57, 5931.

1. References for known compounds 1a, f, g: (a) Jasch, H.; Höfling,

S. B.; Heinrich, M. R. J. Org. Chem. 2012, 77, 1520. Compound

1

3

c: (b) Zhu, M.; Zheng, N. Synthesis 2011, 14, 2223. Compounds

a, d, f, 10 and 13: (c) Robles-Machín, R.; López-Pérez, A.;

2

1, 5358. (d) For a general overview, see: Huisgen, R. in 1,3-

Dipolar Cycloaddition Chemistry, Padwa, A., Ed., Wiley-

Interscience, New York 1984, 176.

González-Esguevillas, M.; Adrio, J.; Carretero, J. C. Chem. Eur. J.

010, 16, 9864. Compound 3b: (d) Patrick, T. B.; Shadmehr, M.;

Khan, A. H.; Singh, R. K.; Asmelash, B. J. Fluorine Chem. 2012,

43, 109. Compounds 3c,h,k: (e) Mazaleyrat, J.-P.; Goubard, Y.;

2

1

1. (a) Höfling, S. B.; Bartuschat, A. L.; Heinrich, M. R. Angew.

Chem. Int. Ed. 2010, 49, 9769. (b) Jasch, H.; Höfling, S.; Heinrich,

M. R. J. Org. Chem. 2012, 77, 1520. (c) Fehler, S.; Pratsch, G.;

Heinrich, M. R. Angew. Chem. Int. Ed. 2014, 53, 11361.

2. For an application in F-radiochemistry, see: Fehler, S.; Höfling,

S.; Bartuschat, A.; Maschauer, S.; Tschammer, N.; Hübner, H.;

Gmeiner, P.; Prante, O.; Heinrich, M. R. Chem. Eur. J. 2014, 20,

1

Azzini, M.-V.; Wakselman, M.; Peggion, C.; Formaggio, F.;

Toniolo, C. Eur. J. Org. Chem. 2002, 1232. Compound 3i: (f) Gu,

X.; Xu, Z.-J.; Lo, V. K.-Y.; Che, C.-M. Synthesis 2012, 3307.

1

8

3

70.

1

5

Supplementary Material

ACCEPTED MANUSCRIPT

1

13

Copies of H and C-NMR spectra of the new triazoles or

triazolines 5-7, 11, 12, 14 and 15.

Article Doi

Cycloaddition reactions of glycine imine anions to phenylazocarboxylic esters - A new access to 1,3,5-trisubstituted 1,2,4-triazoles

DOI: 10.1016/j.tet.2015.04.078

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Full text of DOI:10.1016/j.tet.2015.04.078

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