Oxidative cyclization of 1-(pyridin-2-yl)guanidine derivatives: A synthesis of [1,2,4]triazolo[1,5-a]pyridin-2-amines and an unexpected synthesis of [1,2,4]triazolo[4,3-a]pyridin-3-amines

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Oxidative Cyclization of 1-(Pyridin-2-

yl)guanidine Derivatives: A Synthesis of

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[

1,2,4]Triazolo[1,5-a]pyridin-2-amines and

An Unexpected Synthesis of

1,2,4]Triazolo[4,3-a]pyridin-3-amines

[

Kazuhisa Ishimoto, Toshiaki Nagata, Mika Murabayashi and Tomomi Ikemoto

Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85,

Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Oxidative Cyclization of 1-(Pyridin-2-yl)guanidine Derivatives: A Synthesis of

[

1,2,4]Triazolo[1,5-a]pyridin-2-amines and An Unexpected Synthesis of

1,2,4]Triazolo[4,3-a]pyridin-3-amines

Kazuhisa Ishimoto∗ , Toshiaki Nagata, Mika Murabayashi and Tomomi Ikemoto

Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi

2

-chome, Yodogawa-ku, Osaka 532-8686, Japan

ARTICLE INFO

ABSTRACT

Article history:

Received

Received in revised form

Accepted

Oxidative cyclization of 1-(pyridin-2-yl)guanidine derivatives using N-chlorosuccinimide and

aqueous potassium carbonate has been investigated. Chlorination of 1-(5-nitropyridin-2-

yl)guanidine by N-chlorosuccinimide in methanol followed by addition of aqueous potassium

carbonate gave rise to cyclization and afforded 6-nitro-[1,2,4]triazolo[1,5-a]pyridin-2-amine in

one-pot. In the course of studying the scope and limitation of the reaction, it was found that

some of the examined 1-(pyridin-2-yl)guanidine derivatives gave not only the desired

Available online

Keywords:

oxidative cyclization

one-pot reaction

[

1,2,4]triazolo[1,5-a]pyridin-2-amines but also unexpected [1,2,4]triazolo[4,3-a]pyridin-3-amine

products. As plausible reaction mechanisms of this oxidative cyclization, diazirine formation

and nitrene formation are presented.

1

-(pyridin-2-yl)guanidine derivatives

2

[

1,2,4]triazolo[1,5-a]pyridin-2-amines

1,2,4]triazolo[4,3-a]pyridin-3-amines

1

. Introduction

flammability of H S generated during the reaction, and an

2

alternative convenient synthesis of 3 was highly desired.

N-fused heterocycles are one of the important classes of

molecules that are found in a variety of natural products and

biologically active compounds. Among a diverse array of N-

fused

heterocycles,

[1,2,4]triazolo[1,5-a]pyridin-2-amine

derivatives have attracted much attention due to their significant

bioactivities in the field of pharmaceuticals. In fact, a large

number of compounds that contain

a [1,2,4]triazolo[1,5-

a]pyridin-2-amine core have been recently reported as drug

1

2

candidates, including PI3Kγinhibitors, JAK2 inhibitors, CRK3

3

4

inhibitors,₅DNA gyrase /topoisomerase IV inhibitors, PDE10A

inhibitors, TYK2 inhibitors, and Src kinase inhibitors .

6

7

The most common synthetic approach to [1,2,4]triazolo[1,5-

8

a]pyridin-2-amines 3 is described in Scheme 1. The reaction of

Scheme 1. The most common synthetic approach to

2

-aminopyridines 1 with ethoxycarbonyl isothiocyanate gives

[

1,2,4]triazolo[1,5-a]pyridin-2-amines 3

thioureas 2, which are treated with NH OH, hydrochloric acid

2

and diisopropylethylamine (DIPEA) to give 3 in good to

9

excellent yield, accompanied by evolution of H S and CO . This

2. Results and discussion

2

synthesis is so robust that it was applicable to our multi-hundred

gram scale synthesis of an intermediate for a VEGFR-2 kinase

inhibitor. However, despite the good yield and robustness, the

synthesis suffered from the odor, toxicity, corrosivity, and

Grenda et al. reported that N-(pyridin-2-yl)benzimidamide

was subjected to chlorination when treated with aqueous NaOCl

and 1 M HCl, and treatment of the obtained N-chloroamidine

10

with aqueous Na CO₃gave rise to cyclization to afford

2

—

——

∗

Corresponding author. Tel.: +81-6-6300-6797; fax: +81-6-6300-6251; e-mail: kazuhisa.ishimoto@takeda.com

2

Tetrahedron

MAla

11

[

1,2,4]triazolo[1,5-a]pyridine. On the basis

A

of

C

th

C

ei

E

r w

P

o

T

rk

E

, w

D

e

N

yer

U

w

S

as

C

a

R

na

I

lyzed by HPLC using an authentic sample, which

P

T

thought that could be synthesized from 1-(pyridin-2-

3

showed that 3a was obtained in 79% yield.

yl)guanidines 5 using a similar reaction (Scheme 2). The

guanidines 5 were envisaged to be prepared by S Ar reaction of

N

2

-halopyridines 4 with guanidine. It was assumed that oxidation

of 5 would give intermediate 6, and treatment of 6 with a base

would lead to cyclization and afford 3. To the best of our

knowledge, oxidation of 5 followed by ring closure with a base

has not been hitherto reported. Thus, in order to verify our

concept, we first investigated chlorination of a known compound

12

Figure 1. Structure determination of 6a

1

-(5-nitropyridin-2-yl)guanidine 5a (Table 2, entry 1) using N-

chlorosuccinimide (NCS) and ring closure of the obtained

chlorinated intermediate 6a by aqueous K CO (Scheme 3, (a)).

With this promising result in hand, optimization of the

reaction condition was conducted through a screening of

oxidizing agents, bases and solvents (Table 1). Among the

screened chlorinating agents, t-BuOCl gave 3a in good yield

comparable to NCS (80%, entry 5). Other chlorinating agents

such as aqueous NaOCl, chloramine-T, trichloroisocyanuric acid

2

3

(

TCCA), 1,3-dichloro-5,5-dimethylhydantoin (NDDH) all

decreased the yield (entries 1–4). The use of other oxidizing

agents was also examined. While N-bromosuccinimide (NBS)

gave the product in low yield (14%, entry 6), N-iodosuccinimide

(NIS) did not give the product (entry 7). Taking ease of handling

and price of the reagent into consideration, NCS was selected as

the oxidizing agent for further optimization.

Organic bases such as pyridine, triethylamine and DBU gave

Scheme 2. Proposed synthesis of 3 from 1-(pyridin-2-

yl)guanidines 4

the product in lower yield than aqueous K CO (entries 8–10).

2

3

Interestingly, solid K CO gave the product in lower yield (34%,

2

3

entry 11) than aqueous K CO . The use of 1M NaOH gave the

When a slurry of 5a in MeCN was treated with 1.1 equiv of

NCS at 40 ºC, generation of yellow solids was observed in a few

minutes. After cooling to room temperature, the yellow solids

were isolated by filtration. HRMS and NMR analysis revealed

that the structure of the obtained compound was not 6b but 6a

2

3

product in comparable yield to aqueous K CO (77%, entry 12),

2

3

whereas the use of aqueous KOAc largely decreased the yield

5%, entry 13). These results indicate that the use of a strong

(

inorganic base and the presence of H O are essential for high

2

13,14

conversion of 6a to 3a.

(

Figure 1).

Fortunately, ring closure of 6a proceeded

smoothly in MeCN by addition of 2.1 equiv of K CO in H O at

2

3

2

It was found that alcohol solvents could also be used for this

one-pot process (entries 14–16). When alcohol solvents were

used for the reaction, precipitation of the product was observed

after addition of aqueous K CO . Following further addition of

4

0 °C, affording 3a in 93% yield. Compound 3a was also

synthesized from 2-amino-5-nitropyridine according to the

procedure described in Scheme 1 (See Experimental Section),

and we confirmed that the spectral data of 3a prepared by these

2

3

H O to the reaction mixture, 3a was easily isolated by filtration.

2

15

two methods was identical.

The best yield (87% isolated yield) was achieved when MeOH

was used as the solvent (entry 14).

For the synthesis of 3a, it was possible to use MeCN as the

solvent for both the chlorination of 5a and the ring closure of 6a.

These results led us to explore the possibility of a convenient

one-pot synthesis of 3a from 5a in MeCN (Scheme 3, (b)). After

5

a was reacted with 1.1 equiv of NCS in MeCN at 40 °C for 15

min, 2.1 equiv of K CO in H O was added, and the mixture was

2

3

2

stirred for 30 min at the same temperature. Following extraction

with EtOAc and washing with 10% aqueous NaCl, the organic

Scheme 3. Synthesis of 3a from 5a via 6a

3

Table 1. Optimization of the reaction conditio

pot synthesis of 3a

A

n

C

fo

C

r t

E

he

P

o

T

ne

E

-

D MANUSCRIPT

2

A

32

4

b

5b

5c

3

4

5

B

39

47

12

4

c

4

d

5

d

a

oxidizing

yield

(%)

41

42

69

42

80

13

0

entry

solvent

base

CO

agent

4

e

5e

1

2

3

4

5

6

7

8

9

aq NaOCl

chloramine-T

MeCN

MeOH

EtOH

aq K

2

3

2

CO

3

6

7

C

B

39

c

b

4f

c

TCCA

2

5f

NDDH

t-BuOCl

NBS

NIS

2

N

47

F3C

Cl

2

4

g

5g

2

8

9

D

37

NCS

pyridine

32

15

51

34

77

5

h

5

h

triethylamine

DBU

1

0

1

2

3

4

5

6

C

B

36

50

2 3

K CO

4

i

5i

1M NaOH

aq KOAc

1

0

c

aq K

2

CO

3

87

4

j

5

j

c

2

74

c

i-PrOH

2

68

a

b

c

11

B

58

57

HPLC assay yield.

.37 equiv of TCCA was used for the reaction.

Isolated yield.

4

k

0

5k

1

2

C

4

m

5

m

In order to study the scope and limitation of the reaction, a

series of 1-(pyridin-2-yl)guanidine derivatives 5b–5m were

a

Reaction conditions described in the table are as follows:

prepared by S Ar reaction of 2-halopyridine derivatives 4 with

guanidine carbonate or guanidine hydrochloride as described in

Scheme 2 (Table 2). Although many kinds of 2-halopyridines

N

A guanidine hydrochloride (10 equiv), K CO (15 equiv), t-

BuOH, reflux.

2

3

^B^g^u^aⁿⁱ^dⁱⁿ^e^c^a^r^b^oⁿ^a^t^e⁽³^e^q^uⁱ^v⁾^,^K^C^O3 (5 equiv), 1-

were examined, the S Ar reaction proceeded only when 2-

2

N

methylpyrrolidin-2-one (NMP), 120–140 °C.

halopyridines possessed electron withdrawing groups (entries 1–

9

). Due to the low solubility of 5 in common organic solvents,

C guanidine carbonate (1 equiv), K CO (3 equiv), NMP,

00–120 °C.

2

3

isolation of 5 required a rather troublesome work-up and 5 was

obtained in low to moderate yields.

1

D guanidine carbonate (3 equiv), K CO₃(5 equiv), N,N-

2

dimethylacetamide, 120 °C.

b

Table 2. Preparation of 1-(pyridin-2-yl)guanidine derivatives 5

Isolated yield.

c

0

.9 NMP solvate was obtained.

b

reaction

yield

(%)

entry

1

substrate

product

a

condition

With these substrates in hand, the one-pot oxidative

cyclization was applied to compounds 5b–5m (Table 3). When 1-

3-nitropyridin-2-yl)guanidine 5b was subjected to the above-

mentioned one-pot chlorination-cyclization procedure, the

product precipitated in the reaction mixture. After addition of

A

25

(

4

a

5

a

4

Tetrahedron

in MANUSCRIPT5b

H O to the reaction mixture, 3b was isolate

A

d

C

by

C

f

E

ilt

P

ra

T

tio

E

n

D

3b

7b

2

8

6% yield (entry 1).

b

8

6%

N.D.

The reaction of 1-(3-chloropyridin-2-yl)guanidine 5c, in

contrast, gave a completely different result from the results of the

reactions of 5a and 5b (entry 2). When 5c was treated with 1.1

equiv of NCS, chlorination proceeded smoothly to give a single

chlorinated product. However, treatment of the chlorinated

intermediate with aqueous K CO unexpectedly gave two main

2

3

4

3c

7

c

5

c

2

7%

1

9%

2

3

products with several kinds of byproducts. After isolation by

column chromatography, the two products were analyzed by

HRMS and NMR. Interestingly, HRMS analysis showed that the

two compounds have the same accurate molecular mass

3

d

7

d

5

d

1

trace

corresponding to molecular formula C H ClN . In addition, H

50%

6

5

4

NMR spectra of the two compounds showed a similar coupling

pattern: one triplet-like peak and two doublet-like peaks in the

aromatic region, and one peak corresponding to NH protons,

2

whereas the chemical shifts of the corresponding peaks in the two

compounds were different. These results implied that treatment

of the chlorinated intermediate with aqueous K CO gave not

3

e

7

e

5e

4

4%

2

3

20%

only the desired 3c but a compound having a similar structure to

c via an unexpected reaction pathway. Subsequent two-

3

dimensional NMR experiments such as HMBC and NOESY

spectra indicated that the structure of the unexpected product was

c

5

3

f

7

f

16

5f

2

3%

7

c depicted in Figure 2. The structures of 3c and 7c obtained in

5

2%

this one-pot oxidative cyclization were confirmed by comparing

the spectral data with that of 3c and 7c prepared according to

8, 17

known procedures (Scheme 4).

6

7

3

g

7

g

In the case of 1-(5-chloropyridin-2-yl)guanidine 5d,

compound 7d was obtained as the main product in 50% yield

with a trace amount of 3d (entry 3). Then 1-(pyridin-2-

5g

1

6%

50%

yl)guanidines bearing a CF group at three different positions

3

were subjected to the reaction. Compound 5e bearing a 3-CF₃

group gave 3e as the main product in 44% yield and 7e as the

minor product in 20% yield, respectively (entry 4). On the other

hand, in the case of the 4-CF and 5-CF derivatives, compound 7

3

h

7h

5

h

N.D.

3

became the main product. Compound 5f gave 7f in 52% yield

entry 5), and 5g gave 7g in 50% yield (entry 6), respectively.

Interestingly, the reaction of 5h bearing a 2-F group gave neither

h nor 7h (entry 7). Although the chlorination of 5h proceeded

cleanly, addition of aqueous K CO made the reaction mixture a

(

8

9

3

i

3

7i

5

i

57%

2

3

9%

dark purple solution, and generation of several kinds of

unidentified products was observed. Compound 5i bearing a 3-Cl

group and a 5-CF group gave 3i as the main product in 57%

3

yield (entry 8).

7

j

5

j

3j

The reaction was also applied to guanidines containing a

bicyclic ring such as 1-(quinolin-2-yl)guanidine 5j and 1-

3

9%

2

0%

(isoquinolin-1-yl)guanidine 5k. Fortunately, both 5j and 5k were

successfully chlorinated by NCS, and treatment with aqueous

K CO gave tricyclic compounds. When 5j was subjected to the

2

3

1

0

1

7

k

reaction, 7j was obtained as the main product in 39% yield (entry

). On the other hand, the reaction of 5k gave 3k as the main

product in 35% yield (entry 10). Unfortunately, in the case of 1-

benzo[d]oxazol-2-yl)guanidine 5m, the cyclized products were

3

k

9

13%

5

k

3

5%

(

not obtained (entry 11).

1

3

m

7

m

5

m

Table 3. One-pot oxidative cyclization of 1-(pyridin-2-

N.D.

a

yl)guanidine derivatives 5

a

The substrates in MeOH were treated with 1.1 equiv of NCS

at 40 °C for 15 min. Then 2.1 equiv of K CO in H O was added,

and the reaction mixture was stirred at 40 °C for 30 min.

2

3

2

entry

1

substrate

product

b

Not Detected.

c

0

.9 NMP solvate of 5f was used as the substrate.

5

ACCEPTED MANUSCRIPT

In the case of 5, an electron deficient pyridine ring is thought

to increase acidity of the neighboring NH proton, which would

cause base promoted formation of diazirine 12 via 11 (Scheme 6,

(a)). Ring opening of 12 is assumed to proceed in two different

pathways. The attack of a nitrogen atom of a pyridine ring to the

nitrogen atom of the diazirine would give 3 via N-N bond

cleavage (path A), while the attack of the nitrogen atom of the

pyridine ring to the carbon atom of the C=N double bond of the

diazirine would give 7 via C-N bond cleavage (path B).

Figure 2. Structure determination of 7c

In Table 3, the substrates having an electron withdrawing

group at 3-position of the pyridine ring (5b, 5c, 5e) gave 3 as the

major product. Meanwhile, while 5d and 5f, which have an

electron withdrawing group at 5-position, mainly gave 7,

compound 5a with a strong electron withdrawing group (NO ) at

-position gave exclusively compound 3. Interestingly, although

compound 5f gave mainly compound 7, compound 5i, which

have one more additional electron withdrawing group (Cl) at 3-

position, showed a different reactivity from 5f and gave mainly

compound 3. These results may indicate that the type, position

An alternative possible reaction mechanism is the one

22

involving nitrene formation (Scheme 6, (b)). Anion 11 could

generate nitrene 13 by loss of a chlorine atom, and ring closure of

11

13 would give 3 (path C). At the same time, there is a

possibility that nitrene 14, which is an isomer of 13, could give

2

5

23, 24

carbodiimide 15 via Curtius-type rearrangement.

The attack

of the nitrogen atom of the pyridine ring to the carbon atom of

the carbodiimide would give 7 (path D).

At present, it is difficult to predict which reaction pathway

mainly works in each substrate. Further detailed investigation is

required to elucidate the factors (substituent, oxidizing agent,

temperature, base and solvent) that control the dominant reaction

pathway.

18

and number of substituents affect the reaction pathway.

As mentioned previously, oxidation of 1-(pyridin-2-

yl)guanidine derivatives 5 and their ring closure with a base has

not been previously reported. Meanwhile, a literature survey

shows that treatment of amidines with aqueous NaOCl/NaOBr

gives 3-halo-3-substituted diazirines via an interesting reaction

3

. Conclusions

19

mechanism (Scheme 5). In this diazirine formation reported

We have shown that chlorination of 1-(5-nitropyridin-2-

yl)guanidine 5a by NCS followed by treatment with aqueous

first by Graham, intermediates other than N-chloro and N,N'-

20

dichloroamidines have not been directly observed. Thus, it is

not clear whether the diazirine formation proceeds via direct

displacement of a halogen atom with a nitrogen anion or via

formation of iminonitrene. Moss et al. intensively studied this

reaction and reported that dichlorination of amidines is

prerequisite for the base promoted diazirine formation, while N-

K CO₃gives rise to cyclization and affords 6-nitro-

2

[

1,2,4]triazolo[1,5-a]pyridin-2-amine 3a. It was possible to

conduct this reaction sequence in one-pot by using MeOH as the

solvent. In the course of studying the scope and limitation of this

one-pot oxidative cyclization, it was found that some of the 1-

(pyridin-2-yl)guanidine derivatives

5

gave not only

21

chloro and N,N',N'-trichloroamidines did not afford diazirine.

[

1,2,4]triazolo[1,5-a]pyridin-2-amines 3 but [1,2,4]triazolo[4,3-

Probably, the second chlorination of a NH group would be

2

a]pyridin-3-amines 7. Although we proposed plausible reaction

mechanisms based on the diazirine formation and the nitrene

formation, the precise reaction mechanism remains to be

elucidated. A more detailed study on this reaction is to be

performed in the future.

essential because the chlorine atom acts as an electron

withdrawing group and promotes deprotonation of the NH proton

by a base.

X

R

X

R

NH

NH2

NaOX

N

NaOX

N

H

R

NH₂

N

X

(

X=Cl. Br)

OH

X

R

N

N N

N

R

N

X

R

X

R

X

Scheme 5. Formation of 3-halo-3-substituted diazirines by

Graham's procedure (ref 19)

6

Tetrahedron

ACCEPTED MANUSCRIPT

Scheme 4. Preparation of 3c and 7c according to known procedures

Scheme 6. Plausible reaction mechanisms of the oxidative cyclization of 5

7

1

orange solid (1.16 g, 25%). mp 228 °C; H NMR (500 MHz,

4

. Experimental section

ACCEPTED MANUSCRIPT

DMSO-d ) δ 6.58 (d, J = 9.5 Hz, 1H), 7.30 (br s, 4H), 8.10 (dd, J

9.3, 3.0 Hz, 1H), 8.93 (d, J = 2.8 Hz, 1H); C NMR (125 MHz,

6

13

4

.1. General

=

DMSO-d ) δ 118.0, 131.3, 134.8, 144.6, 159.7, 167.2; IR (ATR)

6

All materials were purchased from commercial suppliers and

3

1

406, 3033, 1664, 1599, 1563, 1509, 1461, 1412, 1313, 1262,

111, 992, 947, 934, 864, 836, 771, 726, 713, 531, 496, 452, 420

used without any additional purification. NH silica gel

CHROMATOREX) was purchased from Fuji Silysia Chemical

Ltd. Melting points were determined on a Büchi Melting Point B-

40 and on a Stanford Research Systems OptiMelt MPA 100,

(

−1

+

cm ; HRMS-ESI (m/z): [M + H] calcd for C H N O ,

6

8

5

2

1

82.0678; found, 182.0673.

5

1

13

and are uncorrected unless otherwise noted. H and C NMR

spectra were recorded on BRUKER AVANCE 500

4.3.2. 1-(3-Nitropyridin-2-yl)guanidine (5b)

a

To a suspension of 2-chloro-3-nitropyridine 4b (5.00 g, 31.5

mmol) and guanidine hydrochloride (30.1 g, 315 mmol) in t-

BuOH (150 mL) was added K CO (65.4 g, 473 mmol), and the

spectrometer and on a BRUKER AVANCE 600 spectrometer

with tetramethylsilane as an internal standard. Chemical shifts

are shown in ppm. HPLC analysis of the compounds and reaction

2

3

mixture was refluxed for 40 h. The solvent was removed by

evaporation, and EtOAc (500 mL) was added to the residue. The

suspension was filtered through a pad of NH silica gel, and the

pad was washed with EtOAc (2 × 100 mL). The combined filtrate

was washed with saturated brine (3 × 15 mL) and 10% aqueous

NaCl (2 × 15 mL), and concentrated in vacuo. The resulting

solids were suspended in EtOAc/hexane (1:2, 45 mL) and stirred

at 50 °C for 1 h. The mixture was cooled to room temperature

and stirred for 1 h, and then filtrated to give the crude product

(3.99 g). The crude product (1.00 g) was suspended in

EtOAc/hexane (1:2, 9 mL), and the mixture was stirred at 50 °C

for 30 min. The mixture was cooled to room temperature and

stirred for 1 h, and then filtrated to give 5b as a yellow solid (462

monitoring was carried out on a Shimadzu LC-2010C . High-

HT

resolution mass spectrometry (HRMS) data was obtained on a

Shimadzu Prominence UFLC system with a Thermofisher LTQ

Orbitrap Discovery. IR spectra were recorded on a Thermo

Electron FT-IR Nicolet 4700 (ATR). Elemental analyses were

recorded on an Elementar vario MICRO cube. HPLC conditions

are as follows: Inertsil ODS-3 column, 5 µm, 250 mm × 4.6 mm

i.d.; UV detector at 254 nm; isocratic elution with CH CN/50

3

mM aqueous KH PO (pH 7) (30:70) at 1.0 mL/min flow rate;

2

4

column temperature: 25 °C. Retention times: 5a (3.9 min), 3a

4.9 min).

(

4

.2. General procedure for the one-pot oxidative cyclization

25

1

mg, 32%). mp 140–141 °C (lit. mp 143–144 °C); H NMR (500

MHz, DMSO-d ) δ 6.73 (dd, J = 7.6, 5.0 Hz, 1H), 6.96 (br s, 4H),

7.86 (dd, J = 7.9, 1.9 Hz, 1H), 8.21 (dd, J = 4.7, 1.9 Hz, 1H);

NMR (125 MHz, DMSO-d ) δ 111.9, 130.8, 140.3, 148.8, 154.7,

To a solution of 1-(3-chloropyridin-2-yl)guanidine 5c (1.00 g,

.86 mmol) in MeOH (100 mL) was added N-chlorosuccinimide

861 mg, 6.45 mmol) at 40 °C, and the mixture was stirred at the

6

13

5

(

C

6

same temperature for 15 min. To the resulting slurry was added

K CO (1.70 g, 12.3 mmol) in H O (20 mL) at 40 °C, and the

158.4; IR (ATR) 3458, 3412, 3128, 2362, 1651, 1581, 1536,

1491, 1417, 1348, 1325, 1257, 1044, 877, 837, 760, 730, 714,

2

3

2

−1

+

mixture was stirred at the same temperature for 30 min. After

cooling to room temperature, the solvent was concentrated in

vacuo. To the residue were added EtOAc (100 mL) and 10%

aqueous NaCl (50 mL), and the layers were separated. The

aqueous layer was extracted with EtOAc (2 × 100 mL), and the

combined organic layer was washed with 10% aqueous K CO (2

586, 555, 527, 447 cm ; HRMS-ESI (m/z): [M + H] calcd for

, 182.0678; found, 182.0670.

C H N O

6 8 5 2

4

.3.3. 1-(3-Chloropyridin-2-yl)guanidine (5c)

To a suspension of 2,3-dichloropyridine 4c (4.50 g, 30.4

mmol) and guanidine carbonate (16.4 g, 91.2 mmol) in 1-

methylpyrrolidin-2-one (NMP) (40 mL) was added K CO (21.0

2

3

2

3

×

50 mL) and 10% aqueous NaCl (50 mL). The organic layer

g, 152 mmol), and the mixture was heated to 140 °C and stirred

for 30 h. The mixture was filtered through a glass filter at

approximately 100 °C, and the cake was washed with EtOAc (5 ×

was concentrated in vacuo and the residue was purified by

column chromatography (NH silica gel, 1:4 EtOAc/hexane to

3

1

:97 MeOH/EtOAc) to give crude 3c (275 mg) and 7c (190 mg,

9%, pale brown solid). Crude 3c (150 mg) was triturated with

9

0 mL). The combined filtrate was washed with H O (45 mL)

2

and 10% aqueous NaCl (3 × 45 mL), and concentrated in vacuo.

The residue was suspended in EtOAc/hexane (1:2, 45 mL), and

the mixture was stirred at 50 °C for 1 h. The mixture was cooled

by ice bath and stirred for 1 h, and then filtered. The obtained

EtOAc/hexnae (1:1, 2 mL) and filtered to give 3c (148 mg, 27%)

as a pale brown solid.

4

.3. Syntheses of 1-(pyridin-2-yl)guanidine derivatives 5

solids were suspended in H O (45 mL), and the slurry was stirred

at 50 °C for 1 h. The mixture was cooled by ice bath and stirred

1

2

4

.3.1. 1-(5-Nitropyridin-2-yl)guanidine (5a)

To a suspension of 2-chloro-5-nitropyridine 4a (5.00 g, 31.5

mmol) and guanidine hydrochloride (30.1 g, 315 mmol) in t-

BuOH (250 mL) was added K CO (65.3 g, 473 mmol), and the

mixture was refluxed for 50 h. The solvent was removed by

evaporation, and H O (200 mL) was added to the residue. The

slurry was stirred at room temperature for 1 h and then filtered.

The wet cake was washed with H O (2 × 10 mL). The resulting

solids were suspended in EtOH/H O (1:6, 11 mL), and the

mixture was stirred at 60 °C for 1 h. The mixture was cooled by

ice bath and stirred for 1 h, and then filtered. The wet cake was

for 1 h, and then filtered to give 5c (2.01 g, 39%) as a white

1

solid. mp 138 °C; H NMR (500 MHz, DMSO-d ) δ 6.63 (dd, J =

6

2

3

7.7, 4.9 Hz, 1H), 6.83 (br s, 4H), 7.61 (dd, J = 7.7, 1.7 Hz, 1H),

13

7

.98 (dd, J = 4.9, 1.7 Hz, 1H); C NMR (125 MHz, DMSO-d ) δ

6

2

113.8, 123.0, 136.9, 144.1, 157.8, 159.2; IR (ATR) 3474, 3365,

148, 2357, 1609, 1555, 1512, 1421, 1311, 1230, 1154, 1121,

1036, 997, 951, 855, 764, 731, 668, 646, 558, 523, 476, 455, 431,

3

2

−1

+

2

405 cm ; HRMS-ESI (m/z): [M + H] calcd for C H ClN ,

6 8 4

1

71.0437; found, 171.0432.

.3.4. 1-(5-Chloropyridin-2-yl)guanidine (5d)

To a suspension of 5-chloro-2-fluoropyridine 4d (5.00 g, 38.0

mmol) and guanidine carbonate (20.5 g, 114 mmol) in NMP (50

mL) was added K CO (26.3 g, 190 mmol), and the mixture was

4

washed with H O (3 × 2 mL) and dried in vacuo to give the crude

2

product (3.69 g). The crude product (3.00 g) was suspended in

EtOAc/hexane (1:2, 27 mL), and the mixture was stirred at 50 °C

for 30 min. The mixture was cooled to room temperature and

stirred for 1 h, and then filtered. The obtained solids were

suspended in EtOAc/hexane (1:1, 12 mL), and the mixture was

stirred at 50 °C for 30 min. The mixture was cooled to room

temperature and stirred for 1 h, and then filtered to give 5a as an

2

3

heated to 130 °C and stirred for 8 h. To the mixture at room

temperature were added EtOAc (100 mL) and H O (200 mL),

2

and the layers were separated. The aqueous layer was extracted

with EtOAc (3 × 100 mL), and the combined organic layer was

8

Tetrahedron

washed with 10% aqueous NaCl (3 × 50 mL)

A

a

C

nd

C

co

E

nc

P

e

T

ntrat

E

D

ed MAprod

NU

uc

S

t (

C

1.

R

00IPg)

T

was suspended in EtOAc/hexane (1:2, 9 mL),

in vacuo. To the resulting residue was added EtOAc (500 mL),

and the solution was filtered through a pad of NH silica gel. The

filtrate was evaporated, and the residue was suspended in

EtOAc/hexane (1:3, 40 mL). The mixture was stirred at 40 °C for

and the mixture was stirred at 50 °C for 1 h. The mixture was

cooled to room temperature and stirred for 1 h, and then filtered

1

to give 5f (829 mg, 39%) as a white solid. mp 95–97 °C; H

NMR (500 MHz, DMSO-d ) δ 1.85–1.96 (m, 1.8H, NMP), 2.18

6

1

h. The mixture was cooled to room temperature and stirred for

h, and then filtered. The obtained solids were dissolved into

(t, J = 8.0 Hz, 1.8H, NMP), 2.70 (s, 2.7H, NMP), 3.30 (t, J = 6.9

Hz, 1.8H, NMP), 6.66 (d, J = 8.8 Hz, 1H), 7.01 (br s, 4H), 7.67

(dd, J = 8.8, 2.5 Hz, 1H), 8.35 (br s, 1H); C NMR (125 MHz,

13

H O (15 mL) at 50 °C, and the solution was gradually cooled to

2

room temperature. The slurry was stirred at room temperature for

DMSO-d ) δ 17.2 (NMP), 28.9 (NMP), 30.1 (NMP), 48.4

6

2

1

h, and then filtered to give 5d (3.03 g, 47%) as a white solid.

(NMP), 113.9 (q, J = 32.1 Hz), 118.3, 124.9 (q, J = 268.3

CF CF

3 3

1

mp 162–163 °C; H NMR (500 MHz, DMSO-d ) δ 6.60 (dd, J =

Hz), 133.1 (q, J = 2.5 Hz), 143.5 (q, J = 5.0 Hz), 158.8,

CF CF

6

8

1

2

1

4

1

.8, 0.6 Hz, 1H), 6.75 (br s, 4H), 7.48 (dd, J = 8.8, 2.8 Hz, 1H),

166.1, 173.7 (NMP); IR (ATR) 3483, 3449, 3384, 3163, 1614,

1591, 1561, 1512, 1430, 1334, 1301, 1256, 1226, 1158, 1127,

1102, 1070, 1027, 965, 859, 806, 779, 742, 695, 651, 614, 584,

13

.04 (d, J = 2.5 Hz, 1H); C NMR (125 MHz, DMSO-d ) δ

6

19.3, 120.0, 136.5, 143.7, 157.6, 162.1; IR (ATR) 3468, 3414,

362, 1627, 1573, 1543, 1518, 1463, 1370, 1314, 1278, 1229,

133, 1110, 1004, 914, 857, 834, 756, 730, 614, 572, 520 459,

−1

542, 480, 470, 448, 435, 422, 410 cm ; HRMS-ESI (m/z): [M +

+

H] calcd for C H F N , 205.0701; found, 205.0694; Anal. Calcd

7

8

3

4

−1

+

36, 405 cm ; HRMS-ESI (m/z): [M + H] calcd for C H ClN

for C₁₁_.₅H₁₅_.₁N F O : C, 47.08; H, 5.19; N, 23.39. Found: C,

6

8

4

4.9 3 0.9

71.0437; found, 171.0432.

46.96 H, 5.13; N, 23.17.

4

.3.5. 1-(3-(Trifluoromethyl)pyridin-2-yl)guanidine

4.3.7. 1-(4-(Trifluoromethyl)pyridin-2-yl)guanidine

(5g)

(

5e)

To a suspension of 2-chloro-3-(trifluoromethyl)pyridine 4e

10.0 g, 55.3 mmol) and guanidine carbonate (29.9 g, 166 mmol)

To a suspension of 2-chloro-4-(trifluoromethyl)pyridine 4g

(4.50 g, 24.8 mmol) and guanidine carbonate (13.4 g, 74.4 mmol)

in NMP (45 mL) was added K CO (17.1 g, 124 mmol), and the

(

in NMP (100 mL) was added K CO (38.2 g, 277 mmol), and the

2

3

2

3

mixture was heated to 120 °C and stirred for 40 h. The mixture

was filtered through a glass filter at approximately 100 °C, and

the cake was washed with EtOAc (5 × 200 mL). The combined

mixture was heated to 120 °C and stirred for 18 h. The mixture

was filtered through a glass filter at approximately 100 °C, and

the cake was washed with EtOAc (5 × 90 mL). The combined

filtrate was washed with H O (100 mL) and 10% aqueous NaCl

filtrate was washed with H O (45 mL) and 10% aqueous NaCl (3

2

(

3 × 100 mL), and concentrated in vacuo. The residue was

× 45 mL), and concentrated in vacuo. The residue was suspended

in EtOAc/hexane (1:2, 23 mL), and the mixture was stirred at 50

°C for 1 h. The mixture was cooled by ice bath and stirred for 1

purified by column chromatography (NH silica gel,

EtOAc/hexane 1:10 to 2:3) to give the crude product. To the

crude product in EtOAc (200 mL) was added activated carbon

h, and then filtered. The obtained solids were suspended in H O

2

(

500 mg), and the mixture was stirred at room temperature for 30

(13 mL) and the slurry was stirred at 50 °C for 1 h. The mixture

was gradually cooled by ice bath and stirred for 1 h, and then

min. The activated carbon was filtered off, and the filtrate was

concentrated in vacuo. The residue was dissolved into EtOAc

filtered to give 5g (2.39 g, 47%) as a white solid. mp 141–142

1

(100 mL), and 4M HCl in EtOAc (14 mL, 55.3 mmol) was added

°C; H NMR (500 MHz, DMSO-d ) δ 6.75 (s, 1H), 6.85 (dd, J =

6

13

at 5 °C. The mixture was stirred at 5 °C for 30 min, and then

filtered. To the obtained solids were added EtOAc (200 mL) and

5.4, 1.6 Hz, 1H), 6.92 (br s, 4H), 8.25 (d, J = 5.4 Hz, 1H); C

NMR (125 MHz, DMSO-d ) δ 107.5 (q, J = 2.5 Hz), 113.9 (q,

3

6

CF

3

1

2

aqueous 5% NaHCO (50 mL), and the layers were separated.

J_C_F= 3.8 Hz), 123.2 (q, J = 271.3 Hz), 137.3 (q, J = 32.5

3

CF CF

The aqueous layer was extracted with EtOAc (100 mL), and the

combined organic layer was concentrated in vacuo. To the

residue was added EtOAc/hexane (1:3, 10 mL), and the slurry

Hz), 147.7, 158.3, 164.2; IR (ATR) 3388, 3045, 1663, 1595,

1527, 1411, 1335, 1293, 1271, 1171, 1145, 1122, 1078, 980, 871,

−1

817, 793, 758, 731, 689, 667, 561, 536, 467, 444, 421, 401 cm ;

+

was stirred at 5 °C for 1 h, and then filtered to give 5e (1.31 g,

HRMS-ESI (m/z): [M + H] calcd for C H F N , 205.0701;

7

8

3

4

1

2%) as a white solid. mp 128–130 °C; H NMR (500 MHz,

found, 205.0693.

DMSO-d ) δ 6.72 (dd, J = 7.4, 4.9 Hz, 1H), 6.87 (br s, 4H), 7.78

6

13

4.3.8. 1-(6-Fluoropyridin-2-yl)guanidine (5h)

To a suspension of 2,6-difluoropyridine 4h (4.00 g, 34.8

mmol) and guanidine carbonate (12.5 g, 69.6 mmol) in N,N-

(

dd, J = 7.6, 1.9 Hz, 1H), 8.23 (dd, J = 5.0, 1.6 Hz, 1H);

C

2

NMR (125 MHz, DMSO-d ) δ 111.9, 115.8 (q, J = 28.8 Hz),

6

CF

1

3

1

4

2

24.3 (q, J = 270.0 Hz), 135.1 (q, J = 6.3 Hz), 149.7, 157.7,

CF CF

dimethylacetamide (80 mL) was added K CO₃(14.4 g, 104

2

60.5; IR (ATR) 3483, 3449, 3384, 3164, 1614, 1592, 1561,

513, 1430, 1334, 1301, 1256, 1226, 1158, 1127, 1102, 1070,

027, 965, 859, 806, 779, 742, 695, 615, 583, 543, 483, 471, 448,

mmol), and the mixture was heated to 120 °C and stirred for 6 h.

At this point, guanidine carbonate (6.27 g, 34.8 mmol) and

K CO (9.62 g, 69.6 mmol) were added, and the mixture was

−1

+

2

3

35, 422 cm ; HRMS-ESI (m/z): [M + H] calcd for C H F N ,

7

8

3

4

stirred at 120 °C for an additional 3 h. After cooling to room

05.0701; found, 205.0696.

temperature, EtOAc (160 mL) and H O (240 mL) were added,

2

4

0

.3.6. 1-(5-(Trifluoromethyl)pyridin-2-yl)guanidine

.9 1-methylpyrrolidin-2-one solvate (5f)

and the layers were separated. The aqueous layer was extracted

with EtOAc (5 × 40 mL), and the combined organic layer was

washed with saturated brine (2 × 40 mL) and 10% aqueous NaCl

(3 × 40 mL), and concentrated in vacuo. The resulting residue

was purified by column chromatography (NH silica gel,

EtOAc/hexane 1:1). The obtained solids were suspended in

EtOAc/hexane (1:2, 36 mL), and the mixture was stirred at 50 °C

for 1 h. The mixture was cooled to room temperature and stirred

for 1 h, and then filtered. The obtained solids were suspended in

To a suspension of 2-chloro-5-(trifluoromethyl)pyridine 4f

(8.00 g, 44.1 mmol) and guanidine carbonate (7.94 g, 44.1 mmol)

in NMP (80 mL) was added K CO (18.3 g, 132 mmol), and the

2

3

mixture was heated to 120 °C and stirred for 7 h. The mixture

was filtered through a glass filter at approximately 100 °C, and

the cake was washed with EtOAc (5 × 160 mL). The combined

filtrate was washed with H O (80 mL) and 10% aqueous NaCl (3

2

×

80 mL), and concentrated in vacuo. To the residue was added

H O (12 mL), and the mixture was stirred at 50 °C for 1 h. The

2

EtOAc/hexane (1:2, 40 mL), and the mixture was stirred at 50 °C

for 1 h. The mixture was cooled by ice bath and stirred for 1 h,

and then filtered to give the crude product (6.13 g). The crude

mixture was cooled to room temperature and stirred for 1 h, and

then filtered to give the crude product (2.31 g). The crude

product (1.00 g) was suspended in EtOAc/hexane (1:3, 5 mL),

9

and the slurry was stirred at 50 °C for 1 h.

gradually cooled to room temperature and stirred for 1 h, and

A

Th

C

e

C

m

E

ix

P

tu

T

re

E

w

D

as MA1H

N

),

U

7.

S

43

C

–7

R

.5

I

3 (m, 1H) 7.59 (d, J = 8.5 Hz, 1H), 7.65 (dd, J =

P

T

13

8.0, 1.1 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H),; C NMR (125 MHz,

then filtered to give 5h (866 mg, 37%) as a white solid. mp 121–

DMSO-d ) δ 121.7, 122.2, 123.4, 125.7, 127.1, 128.6, 135.9,

6

1

22 °C; H NMR (500 MHz, DMSO-d ) δ 6.27 (dd, J = 7.6, 2.2

146.4, 158.9, 162.9; IR (ATR) 3411, 2997, 1657, 1620, 1585,

1535, 1491, 1444, 1417, 1378, 1349, 1309, 1284, 1246, 1212,

1142, 1119, 1016, 1003, 974, 944, 929, 828, 788, 763, 752, 684,

6

Hz, 1H), 6.48 (dd, J = 8.0, 2.1 Hz, 1H), 6.67 (br s, 4H), 7.56 (dt,

1

3

J = 9.8, 7.9 Hz, 1H); C NMR (125 MHz, DMSO-d ) δ 96.4 (d,

6

2

4

3

−1

J = 36.3 Hz), 115.6 (d, J = 5.0 Hz), 141.5 (d, J = 6.3 Hz),

58.0, 161.2 (d, J = 233.8 Hz), 162.6 (d, J = 12.6 Hz); IR

640, 593, 550, 478, 467, 447, 416 cm ; HRMS-ESI (m/z): [M +

HF

1

3

+

1

H] calcd for C H N , 187.0984; found, 187.0976.

HF

10 11

4

(

ATR) 3485, 3310, 3137, 2255, 2179, 1709, 1635, 1608, 1564,

4

.3.11. 1-(Isoquinolin-1-yl)guanidine (5k)

To a suspension of 1-chloroisoquinoline 4k (4.50 g, 27.5

1

4

1

537, 1487, 1464, 1416, 1334, 1260, 1243, 1222, 1151, 1055,

035, 988, 957, 866, 781, 726, 696, 673, 596, 572, 555, 472, 422,

−1

+

mmol) and guanidine carbonate (14.9 g, 82.5 mmol) in NMP (45

mL) was added K CO (19.0 g, 138 mmol), and the mixture was

heated to 120 °C and stirred for 15 h. The mixture was filtered

through a glass filter at approximately 100 °C, and the cake was

washed with EtOAc (5 × 90 mL). To the combined filtrate was

04 cm ; HRMS-ESI (m/z): [M + H] calcd for C H FN ,

6

8

4

2

3

55.0733; found, 155.0725.

4

.3.9. 1-(3-Chloro-5-(trifluoromethyl)pyridin-2-

yl)guanidine (5i)

To a suspension of 2,3-dichloro-5-(trifluoromethyl)pyridine 4i

added H O (45 mL) and the layers were separated. The organic

2

(

10.0 g, 46.3 mmol) and guanidine carbonate (8.34 g, 46.3 mmol)

layer was washed with 10% aqueous NaCl (3 × 45 mL) and

concentrated in vacuo. The residue was purified by column

chromatography (NH silica gel, EtOAc/hexane 1:1). The

in NMP (100 mL) was added K CO (19.2 g, 139 mmol), and the

2

3

mixture was heated to 100 °C and stirred for 5 h. The mixture

was filtered through a glass filter at approximately 100 °C, and

the cake was washed with EtOAc (200 mL). To the combined

filtrate was added 10% aqueous NaCl (100 mL), and the layers

were separated. The aqueous layer was extracted with EtOAc (3

obtained solids were suspended in H O (45 mL) and the slurry

2

was stirred at 50 °C for 1 h. The mixture was cooled to room

temperature and stirred for 1 h, and then filtered to give the crude

product (3.30 g). The crude product (700 mg) was suspended in

EtOAc/hexane (1:2, 11 mL), and the mixture was stirred at 50 °C

for 1 h. The mixture was cooled to room temperature and stirred

×

100 mL). The combined organic layer was washed with 10%

aqueous NaCl (3 × 100 mL) and concentrated in vacuo. To the

residue was added EtOAc (100 mL), and the solution was cooled

by ice bath. To the solution was added 4M HCl in EtOAc (23

mL, 92.6 mmol), and the mixture was stirred for 2 h, and then

filtered. To the obtained solids were added EtOAc (200 mL),

for 1 h, and then filtered to give 5k (0.627 g, 58%) as a white

1

solid. mp 193–194 °C; H NMR (500 MHz, DMSO-d ) δ 6.98 (d,

6

J = 6.0 Hz, 1H), 7.11 (br s, 4H), 7.43 (ddd, J = 8.2, 6.9, 1.3 Hz,

1H), 7.58 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H), 7.61–7.67 (m, 1H), 7.90

13

H O (50 mL) and 8M NaOH (12 mL, 92.6 mL), and the layers

(d, J = 5.7 Hz, 1H), 8.62 (d, J = 8.5 Hz, 1H); C NMR (125

2

were separated. The aqueous layer was extracted with EtOAc (3

MHz, DMSO-d ) δ 111.3, 125.5, 125.6, 126.0, 126.8, 130.0,

6

×

100 mL). The combined organic layer was concentrated in

137.3, 140.4, 158.9, 162.0; IR (ATR) 3382, 3046, 2179, 1586,

1519, 1489, 1443, 1390, 1363, 1315, 1277, 1211, 1139, 1089,

1020, 964, 950, 877, 810, 797, 757, 728, 682, 658, 584, 520, 463,

vacuo. The residue was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:3 to 1:1) to give the crude product. To

the crude product was added H O (10 mL), and the mixture was

−1

+

2

425, 404 cm ; HRMS-ESI (m/z): [M + H] calcd for C H N ,

10 11 4

stirred at 60 °C for 1 h. The mixture was cooled to room

187.0984; found, 187.0976.

4.3.12. 1-(Benzo[d]oxazol-2-yl)guanidine (5m)

temperature and stirred for 1 h, and then filtered to give 5i (4.02

1

g, 36%) as a white solid. mp 146–149 °C; H NMR (500 MHz,

To a suspension of 2-chlorobenzo[d]oxazole 4m (4.50 g, 29.3

mmol) and guanidine carbonate (5.28 g, 29.3 mmol) in NMP (90

mL) was added K CO (12.1 g, 87.9 mmol), and the mixture was

DMSO-d ) δ 7.14 (br s, 4H), 7.91 (d, J = 2.2 Hz, 1H), 8.30 (dd, J

6

13

=

2.4, 1.1 Hz, 1H); C NMR (125 MHz, DMSO-d ) δ 113.9 (q,

6

1 3

2

J_C_F= 32.5 Hz), 122.8, 124.0 (q, J = 268.8 Hz), 132.9 (q, J

=

2

3

CF

3

heated to 100 °C and stirred for 1 h. After cooling to room

2.5 Hz), 141.7 (q, J = 5.0 Hz), 159.2, 161.5; IR (ATR) 3511,

CF

temperature, EtOAc (135 mL) and H O (225 mL) were added,

3

1

8

457, 3405, 3324, 1624, 1600, 1542, 1519, 1461, 1405, 1382,

331, 1307, 1257, 1153, 1112, 1088, 1054, 999, 937, 910, 878,

2

and the layers were separated. The aqueous layer was extracted

with EtOAc (3 × 90 mL). The combined organic layer was

washed with 10% aqueous NaCl (3 × 23 mL) and concentrated in

vacuo. The residue was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:3 to 1:1). The obtained solids were

−

1

09, 773, 721, 670, 641, 598, 543, 481, 465, 421, 405 cm ;

+

HRMS-ESI (m/z): [M + H] calcd for C H ClF N , 239.0311;

7

3

4

found, 239.0309.

.3.10. 1-(Quinolin-2-yl)guanidine (5j)

To a suspension of 2-chloroquinoline 4j (4.50 g, 27.5 mmol)

4

suspended in H O (23 mL) and the mixture was stirred at 40 °C

2

for 1 h. The mixture was cooled by ice bath and stirred for 1 h,

and then filtered to give the crude product (3.83 g). The crude

product (700 mg) was suspended in EtOAc/hexane (1:2, 11 mL),

and the mixture was stirred at 50 °C for 1 h. The mixture was

cooled to room temperature and stirred for 1 h, and then filtered

to give 5m as a white solid (535 mg, 57%). mp 185–186 °C

and guanidine carbonate (14.9 g, 82.5 mmol) in NMP (45 mL)

was added K CO (19.0 g, 138 mmol), and the mixture was

2

3

heated to 120 °C and stirred for 17 h. After cooling to room

temperature, EtOAc (90 mL) was added, and the mixture was

filtered through a glass filter. The cake was washed with EtOAc

26

1

(

4 × 90 mL). To the combined filtrate was added H O (45 mL),

(lit. 186 °C); H NMR (500 MHz, DMSO-d ) δ 7.03 (dd, J =

2

6

and the layers were separated. The organic layer was washed

with 10% aqueous NaCl (2 × 45 mL) and concentrated in vacuo.

The residue was suspended in EtOAc/hexane (1:2, 45 mL), and

the mixture was stirred at 50 °C for 1 h. The mixture was cooled

to room temperature and stirred for 1 h, and then filtered. The

7.7, 1.1 Hz, 1H), 7.07–7.20 (m, 1H), 7.18 (br s, 4H), 7.20–7.30

13

(m, 1H), 7.30–7.40 (m, 1H); C NMR (125 MHz, DMSO-d ) δ

6

108.5, 115.3, 120.8, 123.0, 142.5, 146.6, 159.8, 166.4; IR (ATR)

3448, 3340, 3196, 3056, 1609, 1547, 1455, 1344, 1316, 1251,

1177, 1101, 1029, 1007, 962, 919, 755, 728, 504, 434, 416, 409

−1

+

obtained solids were suspended in H O (14 mL), and the mixture

cm ; HRMS-ESI (m/z): [M + H] calcd for C H N O, 177.0776;

2

8 9 4

was stirred at 50 °C for 1 h. The mixture was cooled by ice bath

found, 177.0768.

4.4. 2-Chloro-1-(5-nitropyridin-2-yl)guanidine (6a)

and stirred for 1 h, and then filtered to give 5j (2.54 g, 50%) as a

1

white solid. mp 218–219 °C; H NMR (500 MHz, DMSO-d ) δ

6

.80 (d, J = 8.8 Hz, 1H), 7.18 (br s, 4H), 7.22 (td, J = 7.4, 1.3 Hz,

1

0

Tetrahedron

To a suspension of 5a (544 mg, 3.00 mm

A

o

C

l)

C

in

E

M

P

eC

T

N

E

(27 MA10

D

NU

62

, 1

S

0

C

29

R

, 962, 907, 794, 779, 772, 749, 675, 635, 579, 561,

I

P

T

−

1

+

mL) was added N-chlorosuccinimide (NCS, 441 mg, 3.30 mmol)

at 40 °C, and the mixture was stirred at this temperature for 15

min. The mixture was cooled by ice bath and stirred for 30 min,

and then filtered to give 6a (584 mg, 90%) as a pale yellow solid.

mp 154–155 °C; H NMR (500 MHz, DMSO-d ) δ 7.35 (d, J =

537, 408 cm ; HRMS (ESI): [M+H ] calcd for C H ClN ,

6

4

169.0281; found, 169.0273.

4

.5.4. 8-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-

1

amine (7c)

6

16

1

mp 270-271 °C (decompose) (lit. 275–276 °C); H NMR

(600 MHz, DMSO-d ) δ 6.56 (s, 2H), 6.75 (dd, J = 7.0, 7.0 Hz,

9

.5 Hz, 1H), 7.58 (br s, 2H), 8.44 (dd, J = 9.5, 2.8 Hz, 1H), 9.05

13

6

(d, J = 2.5 Hz, 1H), 10.3 (s, 1H); C NMR (125 MHz, DMSO-

1

3

1

H), 7.28 (d, J = 7.1 Hz, 1H), 8.06 (dd, J = 6.8, 0.8 Hz, 1H);

C

d₆) δ 111.2, 133.7, 137.8, 144.5, 157.5, 157.9; IR (ATR) 3461,

NMR (150 MHz, DMSO-d ) δ 111.2, 120.0, 121.6, 124.0, 143.2,

6

3

1

6

228, 3056, 1659, 1599, 1562, 1523, 1478, 1413, 1322, 1287,

243, 1159, 1111, 1014, 978, 954, 889, 850, 833, 756, 723, 697,

09, 528, 499, 416 cm ; HRMS (ESI): [M+H ] calcd for

1

49.8; IR (ATR) 3265, 3106, 1658, 1629, 1575, 1517, 1500,

−1

+

1439, 1414, 1378, 1331, 1154, 1128, 1043, 1036, 943, 935, 882,

−1

8

68, 781, 758, 727, 687, 651, 568, 557, 539, 510, 409, 404 cm ;

C H N O Cl, 216.0288; found, 216.0287.

6

7

5

2

+

HRMS (ESI): [M+H ] calcd for C H ClN , 169.0281; found,

169.0273.

6

4

.5. Syntheses of [1,2,4]triazolo[1,5-a]pyridin-2-amines 3 and

[

1,2,4]triazolo[4,3-a]pyridin-3-amines 7

4

.5.5. 6-Chloro-[1,2,4]triazolo[4,3-a]pyridin-3-

4

.5.1. 6-Nitro-[1,2,4] triazolo[1,5-a]pyridin-2-

amine (7d)

amine (3a)

Compound 5d (512 mg, 3.00 mmol) in MeOH (51 mL) was

4

.5.1.1. Synthesis from 6a

treated with NCS (441 mg, 3.30 mmol) and K CO (871 mg, 6.3

2

3

mmol) in H O (10 mL), and work-up was conducted according to

2

To a suspension of 6a (431 mg, 2.00 mmol) in MeCN (22 mL)

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:1 to EtOAc) to give crude 7d (262

mg). Crude 7d (150 mg) was triturated with EtOAc/hexane (2:1,

was added K CO (581 mg, 4.20 mmol) in H O (9 mL) at 40 °C,

2

3

2

and the mixture was stirred at this temperature for 30 min. After

cooling to room temperature, H O (35 mL) was added, and the

2

mixture was cooled by ice bath and stirred for 30 min, and then

2

mL) and filtered to give 7d (145 mg, 50%) as a pale yellow

filtered to give 3a (332 mg, 93%) as a yellow solid. mp 311–312

1

solid. mp 256 °C (decompose); H NMR (600 MHz, DMSO-d ) δ

15

1

6

°

2

(

1

3

1

7

C (lit. mp 310 °C); H NMR (600 MHz, DMSO-d ) δ 6.68 (s,

6

.48 (s, 2H), 7.08 (dd, J = 9.8, 1.9 Hz, 1H), 7.50 (dd, J = 9.8, 0.8

H), 7.47 (d, J = 9.5 Hz, 1H), 8.16 (dd, J = 9.4, 2.3 Hz, 1H), 9.64

13

Hz, 1H), 8.34 (dd, J = 1.7, 0.9 Hz, 1H); C NMR (150 MHz,

13

d, J = 1.9 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 110.9,

6

DMSO-d ) δ 116.5, 118.3, 120.1, 125.8, 144.1, 148.5; IR (ATR)

6

23.8, 126.9, 135.1, 152.6, 168.7; IR (ATR) 3449, 3320, 3237,

110, 3070, 3033, 1633, 1561, 1522, 1488, 1448, 1422, 1328,

290, 1256, 1205, 1139, 1081, 1038, 946, 888, 831, 760, 744,

3

1

4

248, 3094, 1664, 1630, 1578, 1509, 1447, 1391, 1359, 1337,

165, 1137, 1034, 928, 851, 824, 817, 790, 734, 676, 572, 540,

−1

+

16 cm ; HRMS (ESI): [M+H ] calcd for C H ClN , 169.0281;

−1

+

6 6 4

25, 697, 610, 582, 550, 489, 424 cm ; HRMS (ESI): [M+H ]

found, 169.0279.

calcd for C H N O , 180.0521; found, 180.0514.

6

5

2

4

.5.6. 8-(Trifluoromethyl)[1,2,4]triazolo[1,5-

4

.5.1.2. One-pot synthesis from 5a

a]pyridin-2-amine (3e)

Compound 5e (817 mg, 4.00 mmol) in MeOH (82 mL) was

To a suspension of 5a (362 mg, 2.00 mmol) in MeOH (36

treated with NCS (588 mg, 4.40 mmol) and K CO (1.16 g, 8.40

mL) was added NCS (294 mg, 2.20 mmol) at 40 °C, and the

mixture was stirred at this temperature for 15 min. To the

resulting slurry was added K CO (581 mg, 4.20 mmol) in H O

2

3

mmol) in H O (16 mL), and work-up was conducted according to

2

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:4 to EtOAc) to give crude 3e (473

mg) and crude 7e (189 mg). Crude 3e (200 mg) was purified by

column chromatography (NH silica gel, EtOAc/hexane 1:4 to

2

3

2

(

7 mL) at 40 °C, and the mixture was stirred at this temperature

for 30 min. After cooling to room temperature, H O (29 mL) was

2

added, and the mixture was stirred for 30 min, and then filtered to

give 3a (312 mg, 87%) as a yellow solid.

1

(

:1), and the obtained solids were triturated with EtOAc/hexane

4

(

.5.2. 8-Nitro[1,2,4]triazolo[1,5-a]pyridin-2-amine

3b)

Compound 3b was synthesized from 5b (544 mg, 3.00 mmol)

according to the procedure described for the one-pot synthesis of

a. Yellow solid, 461 mg, 86% yield. mp 350 °C (decompose);

1:1, 1 mL) and filtered to give 3e (151 mg, 44%) as a white

1

solid. mp 221 °C; H NMR (600 MHz, DMSO-d ) δ 6.44 (s, 2H),

6

7.00 (t, J = 7.2 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 8.84 (d, J = 6.8

1

3

2

Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 109.9, 112.6 (q, J

6

CF

1

3

= 33.0 Hz), 122.9 (q, J = 270.0 Hz), 127.2 (q, J = 4.5 Hz),

CF CF

1

H NMR (600 MHz, DMSO-d ) δ 6.71 (s, 2H), 7.04 (dd, J = 7.5,

131.2, 146.8, 166.8; IR (ATR) 3342, 3209, 1640, 1582, 1524,

1509, 1460, 1421, 1352, 1330, 1303, 1226, 1199, 1166, 1112,

1068, 1028, 959, 929, 906, 807, 794, 762, 717, 667, 593, 526,

6

7

.5 Hz, 1H), 8.41 (dd, J = 8.3, 1.1 Hz, 1H), 8.99 (dd, J = 6.4, 1.1

13

Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 109.2, 127.2, 132.7,

6

−1

+

1

4

33.4, 145.2, 167.7; IR (ATR) 3361, 3309, 3220, 3173, 3101,

631, 1561, 1519, 1442, 1413, 1340, 1272, 1194, 1149, 1077,

038, 984, 898, 841, 835, 795, 752, 738, 686, 596, 563, 543, 474,

507 cm ; HRMS (ESI): [M+H ] calcd for C H F N , 203.0545;

7 6 3 4

found, 203.0540.

−1

+

4.5.7. 8-(Trifluoromethyl)[1,2,4]triazolo[4,3-

a]pyridin-3-amine (7e)

52 cm ; HRMS (ESI): [M+H ] calcd for C H N O , 180.0521;

6 6 5 2

found, 180.0513.

Crude 7e (100 mg) was triturated with EtOAc/hexane (1:1, 1

4

.5.3. 8-Chloro-[1,2,4]triazolo[1,5-a]pyridin-2-

mL) and filtered to give 7e (87 mg, 20%) as a yellow solid. mp

1

amine (3c)

2

58 °C (decompose); H NMR (600 MHz, DMSO-d ) δ 6.64 (s,

6

1

mp 225 °C; H NMR (600 MHz, DMSO-d ) δ 6.25 (s, 2H),

2H), 6.88 (t, J = 7.0 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 8.30 (d, J

6

13

6

8

1

.86 (dd, J = 7.7, 6.6 Hz, 1H), 7.60 (dd, J = 7.7, 0.9 Hz, 1H),

= 7.2 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 109.9, 115.9

6

2 1 3

13

.55 (dd, J = 6.8, 1.1 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ

(q, J = 33.0 Hz), 122.5 (q, J = 270.0 Hz), 125.0 (q, J

=

6

CF

10.9, 116.9, 126.7, 128.1, 148.4, 166.1; IR (ATR) 3323, 3164,

641, 1627, 1544, 1506, 1407, 1308, 1221, 1203, 1136, 1121,

6.0 Hz), 126.6, 140.6, 149.2; IR (ATR) 3304, 3153, 1661, 1637,

1585, 1558, 1508, 1450, 1424, 1390, 1338, 1313, 1240, 1163,

1

2

C

1

5

2

139, 1114, 1046, 1031, 946, 872, 773, 742, 7

64, 520, 504 cm ; HRMS (ESI): [M+H ] calcd for C H F N ,

03.0545; found, 203.0540.

A

33

C

, 6

C

90

E

, 6

P

4

T

2,

E

61

D

1, MA12

N

4.

U

8 (

S

q,

J

RI

= 33.0 Hz), 143.9, 149.4; IR (ATR) 3272, 3081,

P

T

CF

−1

+

1651, 1572, 1509, 1481, 1428, 1371, 1336, 1293, 1263, 1145,

1050, 1035, 937, 887, 826, 793, 779, 741, 731, 688, 674, 639,

06, 576, 526, 459, 433, 407 cm ; HRMS (ESI): [M+H ] calcd

7

6

3

4

−1

+

6

4

.5.8. 6-(Trifluoromethyl)[1,2,4]triazolo[1,5-

for C H F N , 203.0545; found, 203.0540.

7

6

3

4

a]pyridin-2-amine (3f)

Compound 5f (1.17 g, 4.00 mmol) in MeOH (117 mL) was

4.5.12. 8-Chloro-6-

trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-

amine (3i)

(

treated with NCS (588 mg, 4.40 mmol) and K CO (1.16 g, 8.40

2

3

mmol) in H O (23 mL), and work-up was conducted according to

2

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:1 to 4:1) to give 3f (184 mg, 23%) as

Compound 5i (716 mg, 3.00 mmol) in MeOH (72 mL) was

treated with NCS (441 mg, 3.30 mmol) and K

CO (871 mg, 6.30

2

3

mmol) in H O (14 mL), and work-up was conducted according to

2

1

a white solid and crude 7f (454 mg). mp 182 °C; H NMR (600

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:5 to 5:1) to give crude 3i (420 mg)

and crude 7i (129 mg). Crude 3i (200 mg) was triturated with

EtOAc/hexane (1:1, 2 mL) and filtered to give 3i (193 mg, 57%)

MHz, DMSO-d ) δ 6.37 (s, 2H), 7.52 (d, J = 9.4 Hz, 1H), 7.68

6

1

3

(

dd, J = 9.1, 1.9 Hz, 1H), 9.18 (s, 1H); C NMR (150 MHz,

DMSO-d ) δ 112.8, 113.4 (q, J = 33.5 Hz), 123.7 (q, J =

69.0 Hz), 124.9 (q, J = 3.0 Hz), 126.6 (q, J = 4.5 Hz),

CF CF

51.4, 167.5; IR (ATR) 3343, 3172, 2360, 2341, 1648, 1564,

543, 1522, 1428, 1358, 1331, 1307, 1181, 1120, 1058, 1034,

2

1

6

CF

3

2

1

9

1

as a white solid. mp 238–239 °C; H NMR (600 MHz, DMSO-

1

3

d

) δ 6.62 (s, 2H), 7.99 (d, J = 1.5 Hz, 1H), 9.22 (s, 1H);

C

6

−

1

2

38, 864, 809, 761, 740, 674, 639, 562, 537, 438, 415 cm ;

HRMS (ESI): [M+H ] calcd for C H F N , 203.0545; found,

NMR (150 MHz, DMSO-d ) δ 113.3 (q, JCF = 34.5 Hz), 117.5,

6

1 3 3

+

123.1 (q, JCF = 268.5 Hz), 124.2 (q, JCF = 1.5 Hz), 125.9 (q, JCF

7

6

3

4

2

03.0538.

= 4.5 Hz), 149.5, 167.3; IR (ATR) 3379, 3299, 3165, 3111, 1627,

1

9

4

2

542, 1401, 1351, 1321, 1306, 1219, 1170, 1116, 1074, 1031,

75, 920, 883, 869, 841, 758, 691, 652, 628, 551, 532, 502, 449,

4

.5.9. 6-(Trifluoromethyl)[1,2,4]triazolo[4,3-

a]pyridin-3-amine (7f)

−1

+

10 cm ; HRMS (ESI): [M+H ] calcd for C H ClF N ,

7

5

3

4

Crude 7f (200 mg) was dissolved in EtOAc and washed with

37.0155; found, 237.0148.

5

% aqueous K CO . After evaporation of the solvent, the

2 3

4

.5.13. 8-Chloro-6-

obtained solids were triturated with EtOAc/hexane (1:1, 2 mL)

and filtered to give 7f (184 mg, 52%) as a yellow solid. mp 249

(

trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridin-3-

1

amine (7i)

°

C (decompose); H NMR (600 MHz, DMSO-d ) δ 6.72 (s, 2H),

6

7

=

3

.23 (dd, J = 9.8, 1.5 Hz, 1H), 7.63 (d, J = 9.8 Hz, 1H), 8.77 (d, J

Crude 7i (129 mg) was triturated with EtOAc/hexane (1:1, 1

1

3

2

1.5 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 114.0 (q, J

=

mL) and filtered to give 7i (72 mg, 9%) as a white solid. mp 266

°C (decompose); H NMR (600 MHz, DMSO-d

7.58 (d, J = 1.1 Hz, 1H), 8.79 (s, 1H); C NMR (150 MHz,

6

CF

3

1

3.5 Hz), 117.0, 119.8 (q, J = 3.0 Hz), 123.2 (q, J = 6.0

6

) δ 6.89 (s, 2H),

CF

1

13

Hz), 123.6 (q, J = 269.0 Hz), 144.7, 149.5; IR (ATR) 3257,

CF

2

3

1

5

105, 1666, 1650, 1588, 1531, 1450, 1405, 1376, 1322, 1170,

119, 1031, 930, 889, 833, 801, 777, 743, 651, 633, 584, 566,

DMSO-d ) δ 113.9 (q, JCF = 34.0 Hz), 119.0 (q, JCF = 2.7 Hz),

6

3 1

121.7, 122.6 (q, JCF = 6.0 Hz), 123.0 (q, JCF = 269.5 Hz), 142.5,

150.9; IR (ATR) 3472, 3297, 3228, 3104, 2998, 1647, 1572,

1542, 1518, 1441, 1377, 1345, 1312, 1234, 1163, 1115, 1069,

−1

+

42, 522, 425, 410 cm ; HRMS (ESI): [M+H ] calcd for

C H F N , 203.0545; found, 203.0539.

7

6

3

4

1

4

2

037, 948, 905, 884, 873, 865, 831, 754, 732, 685, 651, 630, 550,

4

.5.10. 7-(Trifluoromethyl)[1,2,4]triazolo[1,5-

−

1

+

46, 424 cm ; HRMS (ESI): [M+H ] calcd for C H ClF N ,

7

5

3

4

a]pyridin-2-amine (3g)

37.0155; found, 237.0151.

Compound 5g (817 mg, 4.00 mmol) in MeOH (82 mL) was

4

.5.14. [1,2,4] Triazolo[1,5-a]quinolin-2-amine (3j)

Compound 5j (745 mg, 4.00 mmol) in MeOH (75 mL) was

treated with NCS (588 mg, 4.40 mmol) and K CO (1.16 g, 8.40

mmol) in H O (16 mL), and work-up was conducted according to

2

3

2

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:4 to 10:1) to give 3g (131 mg, 16%)

treated with NCS (588 mg, 4.40 mmol) and K

2 3

CO (1.16 g, 8.40

mmol) in H O (15 mL), and work-up was conducted according to

2

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:5 to EtOAc/MeOH 99:5) to give

crude 3j (168 mg) and crude 7j (370 mg). Crude 3j (130 mg) was

purified by column chromatography (NH silica gel,

EtOAc/hexane 1:2), and the obtained solids were triturated with

as a pale yellow solid and crude 7g (496 mg). mp 167–168 °C;

1

H NMR (600 MHz, DMSO-d ) δ 6.35 (s, 2H), 7.15 (dd, J = 7.0,

6

13

2

.1 Hz, 1H), 7.82 (s, 1H), 8.78 (d, J = 7.2, 1H); C NMR (150

3

MHz, DMSO-d ) δ 106.7 (q, J = 3.0 Hz), 109.7 (q, J = 3.8

Hz), 123.3 (q, J = 270.8 Hz), 128.7 (q, J = 33.0 Hz), 128.7,

6

CF

1

2

CF

1

7

49.5, 167.4; IR (ATR) 3327, 3166, 1650, 1556, 1523, 1509,

483, 1326, 1272, 1256, 1211, 1180, 1119, 1057, 1035, 951, 860,

EtOAc/hexane (1:3, 3 mL) and filtered to give 3j (115 mg, 20%)

1

as a pale pink solid. mp 196 °C; H NMR (600 MHz, DMSO-d

)

6

−1

89, 758, 740, 673, 582, 568, 544, 443, 413 cm ; HRMS (ESI):

δ 6.09 (s, 2H), 7.45–7.54 (m, 2H), 7.78 (t, J = 7.9 Hz, 1H), 7.94

(d, J = 9.4 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.3 Hz,

+

[

M+H ] calcd for C H F N , 203.0545; found, 203.0539.

7 6 3 4

1

3

1

3

1

5

H); C NMR (150 MHz, DMSO-d ) δ 113.2, 114.5, 121.9,

6

4

.5.11. 7-(Trifluoromethyl)[1,2,4]triazolo[4,3-

24.0, 129.0, 129.7, 130.2, 132.5, 148.5, 165.6; IR (ATR) 3328,

178, 1651, 1611, 1561, 1530, 1449, 1418, 1392, 1355, 1330,

215, 1092, 1054, 810, 767, 756, 745, 691, 643, 615, 554, 522,

a]pyridin-3-amine (7g)

Crude 7g (200 mg) was dissolved in EtOAc and washed with

1

0% aqueous NH Cl and H O. After evaporation of the solvent,

−1

+

4

2

08, 477, 424, 409 cm ; HRMS (ESI): [M+H ] calcd for

the obtained solids were triturated with EtOAc/hexane (1:1, 4

mL) and filtered to give 7g (162 mg, 50%) as a white solid. mp

2

Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 106.6 (q, J = 3.0

Hz), 114.6 (q, J = 5.5 Hz), 123.3 (q, J = 270.5 Hz), 124.1,

C H N , 185.0827; found, 185.0820.

10

9

4

1

4

.5.15. [1,2,4] Triazolo[4,3-a]quinolin-1-amine (7j)

Crude 7j (300 mg) was purified by column chromatography

75 °C (decompose); H NMR (600 MHz, DMSO-d ) δ 6.71 (s,

6

H), 6.99 (dd, J = 7.6, 1.5 Hz, 1H), 7.99 (s, 1H), 8.25 (d, J = 7.6

13

3

(NH silica gel, EtOAc), and the obtained solids were triturated

with EtOAc/hexane (1:1, 3 mL) and filtered to give 7j (231 mg,

6

CF

3

1

CF

1

2

Tetrahedron

28

27

+

3

9%) as a pink solid. mp 255–256 (lit. mp

A

17

C

5–

C

17

E

7

P

°C

T

,

E

lit

D

.

MA

H

N

RM

U

S

(

C

ES

R

I):IP[M

T

+H ] calcd for C H N O S, 271.0501; found,

9 11 4 4

1

mp 250–253 °C); H NMR (600 MHz, DMSO-d ) δ 6.31 (br s,

271.0497.

6

2

H), 7.40 (d, J = 9.4 Hz, 1H), 7.45–7.55 (m, 2H), 7.65 (t, J = 7.6

13

To

a

stirred solution of ethyl [(5-nitropyridin-2-

Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 8.52 (d, J = 8.3 Hz, 1H);

NMR (150 MHz, DMSO-d ) δ 115.1, 115.9, 124.0, 125.3, 127.4,

1

8

C

yl)carbamothioyl]carbamate (1.00 g, 3.70 mmol) in EtOH (10

mL) were added N,N-diisopropylethylamine (1.43 g, 11.1 mmol)

and hydroxylamine hydrochloride (1.29 g, 18.5 mmol), and the

mixture was stirred at 50 °C for 1.5 h. After cooling to room

6

28.5, 128.6, 131.9, 146.1, 151.5; IR (ATR) 3292, 3126, 1654,

612, 1567, 1546, 1539, 1471, 1449, 1440, 1390, 1341, 1329,

278, 1214, 1171, 1150, 1126, 1065, 1039, 1008, 968, 930, 879,

−1

temperature, H O (10 mL) was slowly added to the mixture. The

2

54, 803, 754, 739, 691, 680, 609, 565, 536, 509, 440, 418 cm ;

+

slurry was stirred at room temperature for 1 h and then filtered.

The wet solids were suspended in EtOAc/n-heptane (1:1, 10 mL),

and the mixture was stirred at 50 °C for 30 min. The mixture was

cooled to room temperature and stirred for 1 h, and then filtered

to give 3a (587 mg, 89%) as a yellow solid.

HRMS (ESI): [M+H ] calcd for C H N , 185.0827; found,

1

10

9

4

85.0820.

4

.5.16. [1,2,4] Triazolo[5,1-a] isoquinolin-2-amine

(

3k)

Compound 5k (745 mg, 4.00 mmol) in MeOH (75 mL) was

treated with NCS (588 mg, 4.40 mmol) and K CO (1.16 g, 8.40

4

.7. Synthesis of 3c from 3-chloropyridin-2-amine 1c

2

3

mmol) in H O (15 mL), and work-up was conducted according to

4.7.1. Ethyl [(3-Chloropyridin-2-

2

the general procedure. The residue obtained after evaporation of

the organic layer was purified by column chromatography (NH

silica gel, EtOAc/hexane 1:2 to EtOAc/MeOH 98:2) to give

crude 3k (361 mg) and crude 7k (141 mg). Crude 3k (300 mg)

was purified by column chromatography (NH silica gel,

EtOAc/hexane 1:2), and the obtained solids were triturated with

EtOAc/hexane (2:1, 9 mL) and filtered to give 3k (212 mg, 35%)

yl)carbamothioyl]carbamate (2c)

To a stirred solution of 3-chloropyridin-2-amine 1c (800 mg,

6

.22 mmol) in acetone (8 mL) was added ethoxycarbonyl

isothiocyanate (1.22 g, 9.33 mmol), and the mixture was stirred

at 50 °C for 1 h. After cooling to room temperature, H O (16 mL)

was slowly added, and the mixture was stirred at 40 °C for 30

min. The mixture was cooled to room temperature and stirred for

2

1

as an orange solid. mp 193–195 °C; H NMR (600 MHz, DMSO-

^d6⁾^δ⁶^.⁰³⁽^s^,²^H⁾^,⁷^.²⁷⁽^d^,^J⁼⁷^.²^H^z^,¹^H⁾^,⁷^.⁷⁰⁽^t^d^,^J⁼⁷^.⁵^,¹^.³

1

h, and then filtered to give 2c (1.39 g, 86%) as a white solid.

1

mp 126–128 °C; H NMR (600 MHz, DMSO-d ) δ 1.27 (t, J =

6

Hz, 2H), 7.95 (d, J = 7.5 Hz, 1H), 8.29 (d, J = 7.7 Hz, 1H), 8.37

7

.2 Hz, 3H), 4.23 (q, J = 7.2 Hz, 2H), 7.42 (dd, J = 8.1, 4.7 Hz,

13

(

d, J = 7.2 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ 110.7,

6

1H), 8.04 (dd, J = 7.9, 1.5 Hz, 1H), 8.45 (dd, J = 4.5, 1.5 Hz,

1

3

1

20.1, 123.1, 124.6, 127.3, 127.7, 129.2, 131.0, 148.1, 165.3; IR

1

6

3

1

H), 11.4–11.5 (m, 2H); C NMR (150 MHz, DMSO-d ) δ 14.1,

6

(ATR) 3320, 3175, 1638, 1556, 1537, 1523, 1486, 1434, 1400,

2.1, 124.4, 128.5, 138.7, 147.1, 148.5, 153.4, 180.0; IR (ATR)

152, 2989, 1723, 1578, 1510, 1474, 1447, 1423, 1370, 1321,

266, 1235, 1171, 1137, 1068, 1041, 1031, 870, 795, 769, 753,

1

7

370, 1330, 1298, 1258, 1137, 1095, 1058, 904, 823, 778, 747,

−1

04, 682, 659, 613, 570, 548, 509, 416 cm ; HRMS (ESI):

+

−1

[

M+H ] calcd for C H N , 185.0827; found, 185.0820.

10 9 4

736, 708, 680, 647, 598, 551, 534, 418 cm ; HRMS (ESI):

+

[

M+H ] calcd for C H ClN O S, 260.0261; found, 260.0258.

9 11 3 2

4

.5.17. [1,2,4] Triazolo[3,4-a] isoquinolin-3-amine

(

7k)

Crude 7k (141 mg) was purified by column chromatography

NH silica gel, EtOAc/hexane 1:1 to EtOAc), and the obtained

4

.7.2. Synthesis of 3c from 2c

To a stirred solution of 2c (1.00 g, 3.85 mmol) in EtOH (10

(

mL) were added N,N-diisopropylethylamine (1.49 g, 11.6 mmol)

and hydroxylamine hydrochloride (1.34 g, 19.3 mmol), and the

mixture was stirred at 50 °C for 2 h. After cooling to room

solids were triturated with EtOAc/hexane (1:1, 2 mL) and filtered

to give 7k (98 mg, 13%) as an orange solid. mp 263 °C

1

(decompose); H NMR (600 MHz, DMSO-d ) δ 6.47 (s, 2H),

6

temperature, H O (10 mL) was slowly added to the mixture. The

2

7

.07 (d, J = 7.2 Hz, 1H), 7.63 (dt, J = 7.7 Hz , 2H), 7.79 (d, J =

.0 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 8.31 (d, J = 7.1 Hz, 1H);

slurry was stirred at room temperature for 1 h and then filtered.

The wet solids were suspended in EtOAc/n-heptane (1:1, 10 mL),

and the mixture was stirred at 50 °C for 30 min. The mixture was

cooled to room temperature and stirred for 1 h, and then filtered

to give 3c (443 mg, 68%) as a white solid.

13

C NMR (150 MHz, DMSO-d ) δ 112.1, 119.8, 121.6, 122.0,

6

1

6

27.3, 128.5, 129.0 (2C), 143.7, 149.9; IR (ATR) 3311, 3139,

644, 1567, 1557, 1525, 1480, 1459, 1437, 1370, 1325, 1303,

132, 1044, 982, 926, 896, 783, 769, 750, 741, 708, 700, 679,

−1

4

.8. Synthesis of 7c from 2,3-dichloropyridine 4c

36, 560, 507, 484, 471, 462, 443, 432, 421, 405 cm ; HRMS

+

(ESI): [M+H ] calcd for C H N , 185.0827; found, 185.0821.

2 9

10

9

4

.8.1. 3-Chloro-2-hydrazinylpyridine (8)

4

.6. Synthesis of 3a from 5-nitropyridin-2-amine

To a stirred solution of 4c (5.00 g, 33.8 mmol) in EtOH (25

mL) was added hydrazine monohydrate (6.77 g, 135 mmol), and

the mixture was heated to reflux for 20 h. At this point, additional

hydrazine monohydrate (1.69 g, 33.8 mmol) was added, and the

mixture was heated to reflux for 20 h. The mixture was cooled by

ice bath and stirred for 1 h, and then filtered to give 8 (4.40 g,

To a stirred solution of 5-nitropyridin-2-amine (1.00 g, 7.19

mmol) in acetone (10 mL) was added ethoxycarbonyl

isothiocyanate (1.41 g, 10.8 mmol), and the mixture was stirred

at 50 °C for 22 h. After cooling to room temperature, H O (10

2

mL) was slowly added to the mixture. The slurry was stirred at

room temperature for 1 h and then filtered to give ethyl [(5-

25

1

9

1%) as a white solid. mp 164–166 °C (lit. mp 163–164 °C); H

NMR (600 MHz, DMSO-d ) δ 4.22 (br s, 2H), 6.61 (dd, J = 7.6,

6

nitropyridin-2-yl)carbamothioyl]carbamate (1.46 g, 75%) as a

4

.9 Hz, 1H), 7.52– 7.64 (m, 2H), 8.05 (dd, J = 4.7, 1.3 Hz, 1H);

1

brown solid. mp 178–179 °C; H NMR (600 MHz, DMSO-d ) δ

13

6

C NMR (150 MHz, DMSO-d ) δ 113.2, 113.6, 136.2, 145.7,

6

1

9

1

.28 (t, J = 7.2 Hz, 3H), 4.25 (q, J = 7.2 Hz, 2H), 8.69 (dd, J =

.2, 3.0 Hz, 1H), 8.90 (d, J = 9.4 Hz, 1H), 9.22 (d, J = 2.6 Hz,

1

6

55.7; IR (ATR) 3284, 3195, 1592, 1494, 1455, 1412, 1343,

264, 1122, 1033, 991, 968, 957, 930, 787, 761, 750, 726, 634,

10, 543, 497, 438, 423, 416 cm ; HRMS (ESI): [M+H ] calcd

13

H), 12.0 (br s, 1H), 12.5 (br s, 1H); C NMR (150 MHz,

−1

+

DMSO-d ) δ 14.0, 62.5, 113.9, 134.2, 140.8, 144.6, 153.3, 155.2,

6

for C H ClN , 144.0328; found, 144.0323.

5

7

3

1

7

77.9; IR (ATR) 3162, 2994, 1720, 1579, 1529, 1508, 1455,

355, 1311, 1243, 1192, 1143, 1110, 1038, 1004, 949, 870, 840,

4.8.2. 2-(3-Chloropyridin-2-yl)-N-(2,4,4-

trimethylpentan-2-yl)hydrazinecarbothioamide (9)

−

1

99, 757, 734, 714, 700, 628, 596, 525, 501, 436, 412 cm ;

1

3

To a stirred solution of 8 (3.00 g, 20.9 mm

mL) was added 2-isothiocyanato-2,4,4-trimethylpentane (4.30 g,

5.1 mmol), and the mixture was stirred at room temperature for

4 h. The mixture was concentrated in vacuo, and the residue

A

o

C

l)

C

in

E

T

P

H

T

F

E

(1

D

50 MAN

W

U

e

S

th

C

an

RI

PTr. Kenichi Oka and Ms. Yoko Fujioka for

k

M

LC/MS analysis, Ms. Itsuko Nakase for elemental analysis, and

Dr. David Cork for his advice on the manuscript.

2

1

was purified by column chromatography (EtOAc/hexane 1:5) to

give the crude product. The crude product was suspended in

hexane (35 mL), and the mixture was stirred at 50 °C for 30 min.

The mixture was cooled to room temperature and stirred for 1 h,

Supplementary data

1

13

Copies of H NMR and C NMR data for all products in this

article, HMBC spectrum of 6a, HMBC and NOESY spectra of

3a, 3b, 3c, 7c, 7d, 3e, 7e, 3f, 7f, 3g, 7g, 3i, 7i, 3j, 7j, 3k and 7k.

Supplementary data associated with this article can be found in

the online version, at

and then filtered to give 9 (5.84 g, 89%) as a white solid. mp

1

6

2

05–106 °C; H NMR (600 MHz,CDCl ) δ 0.93 (s, 9H), 1.60 (s,

3

H), 1.91 (s, 2H), 6.86 (m, 2H), 7.11 (br s, 1H), 7.52–7.63 (m,

H), 8.18 (d, J = 4.5 Hz, 1H); C NMR (150 MHz,CDCl ) δ 28.9

13

3

(2C), 31.4 (3C), 31.5, 52.3, 57.6, 116.3, 118.1, 137.3, 146.5,

1

5

52.5, 181.9; IR (ATR) 3360, 3332, 3208, 2954, 1586, 1567,

533, 1503, 1472, 1454, 1402, 1387, 1365, 1323, 1266, 1225,

156, 1127, 1101, 1065, 1034, 1005, 979, 791, 754, 735, 668,

References and notes

−1

+

1. Bergamini, G.; Bell, K.; Shimamura, S.; Werner, T.; Cansfield,

A.; Müller, K.; Perrin, J.; Rau, C.; Ellard, K.; Hopf, C.; Doce, C.;

Leggate, D.; Mangano, R.; Mathieson, T.; O'Mahony, A.; Plavec,

I.; Rharbaoui, F.; Reinhard, F.; Savitski, M. M.; Ramsden, N.;

Hirsch, E.; Drewes, G.; Rausch, O.; Bantscheff, M.; Neubauer, G.

Nat. Chem. Biol. 2012, 8, 576–582.

96, 553, 441, 412, 401 cm ; HRMS (ESI): [M+H ] calcd for

C H ClN S, 315.1410; found, 315.1405.

14

24

4

[

.8.3. 8-Chloro-N-(2,4,4-trimethylpentan-2-yl)-

1,2,4] triazolo[4,3-a]pyridin-3-amine (10)

To a stirred solution of 9 (3.80 g, 12.1 mmol) in THF (114

mL) were added triethylamine (4.01 g, 29.0 mmol) and 2-chloro-

-methylpyridinium iodide (4.01 g, 15.7 mmol), and the mixture

2. Dugan, B. J.; Gingrich, D. E.; Mesaros, E. F.; Milkiewicz, K. L.;

Curry, M. A.; Zulli, A. L.; Dobrzanski, P.; Serdikoff, C.; Jan, M.;

Angeles, T. S.; Albom, M. S.; Mason, J. L.; Aimone, L. D.;

Meyer, S. L.; Huang, Z.; Wells-Knecht, K. J.; Ator, M. A.;

Ruggeri, B. A.; Dorsey, B. D. J. Med. Chem. 2012, 55, 5243–

5254.

1

was stirred at room temperature for 5 h. To the mixture were

added EtOAc (228 mL) and H O (38 mL), and the layers were

2

separated. The organic layer was washed with 5% aqueous

NaHCO (2 × 38 mL) and H O (2 × 38 mL). To the organic layer

3. Cleghorn, L. A. T.; Woodland, A.; Collie, I. T.; Torrie, L. S.;

Norcross, N.; Luksch, T.; Mpamhanga, C.; Walker, R. G.;

Mottram, J. C.; Brenk, R.; Frearson, J. A.; Gilbert, I. H.; Wyatt, P.

G. ChemMedChem 2011, 6, 2214–2224.

3

2

was added activated carbon (380 mg), and the mixture was

stirred at room temperature for 30 min. The mixture was filtered

and the filtrate was concentrated in vacuo. The residue was

purified by column chromatography twice (EtOAc/hexane 1:10

to 1:1, then EtOAc/hexane 1:3) to give the crude product. The

crude product was suspended in EtOAc/n-hexane (1:5, 114 mL),

and the mixture was stirred at 50 °C for 30 min. The mixture was

cooled to room temperature and stirred for 1 h, and then filtered

4

.

East, S. P.; White, C. B.; Barker, O.; Barker, S.; Bennett, J.;

Brown, D.; Boyd, E. A.; Brennan, C.; Chowdhury, C.; Collins, I.;

Convers-Reignier, E.; Dymock, B. W.; Fletcher, R.; Haydon, D.

J.; Gardiner, M.; Hatcher, S.; Ingram, P.; Lancett, P.; Mortenson,

P.; Papadopoulos, K.; Smee, C.; Thomaides-Brears, H. B.; Tye,

H.; Workman, J.; Czaplewski, L. G. Bioorg. Med. Chem. Lett.

2

009, 19, 894–899.

5

.

Flohr, A.; Gobbi, L.; Groebke, Z. K.; Koerner, M.; Peters, J-U.

PCT Int. Appl. WO 2012076430, 2012

to give 10 (1.72 g, 51%) as a pale brown solid. mp 182–183 °C;

1

6

7

.

Ellard, K.; Ramsden, N. PCT Int. Appl. WO 2012000970, 2012

Middlemiss, D.; Leriche, C. PCT Int. Appl. WO 2011161159,

2011

H NMR (600 MHz, DMSO-d ) δ 0.92 (s, 9H), 1.51 (s, 6H), 1.93

6

(

s, 2H), 6.22 (s, 1H), 6.73 (t, J = 7.0 Hz, 1H), 7.29 (d, J = 6.8 Hz,

13

1

2

1

5

H), 8.26 (d, J = 7.2 Hz, 1H); C NMR (150 MHz, DMSO-d ) δ

6

8

.

For recent examples, see: (a) Oehlrich, D.; Rombouts, F. J. R.;

Berthelot, D.; Bischoff, F. P.; De Cleyn, M. A. J.; Jaroskova, L.;

Macdonald, G.; Mercken, M.; Surkyn, M.; Trabanco, A. A.;

Tresadern, G.; Van Brandt, S.; Velter, A. I.; Wu, T.; Gijsen, H. J.

M. Bioorg. Med. Chem. Lett. 2013, 23, 4794–4800. (b) Siu, M.;

Pastor, R.; Liu, W.; Barrett, K.; Berry, M.; Blair, W. S.; Chang,

C.; Chen, J. Z.; Eigenbrot, C.; Ghilardi, N.; Gibbons, P.; He, H.;

Hurley, C. A.; Kenny, J. R.;Khojasteh, S. C.; Le, H.; Lee, L.;

Lyssikatos, J. P.; Magnuson, S.; Pulk, R.; Tsui, V.; Ultsch, M.;

Xiao, Y.; Zhu, B-Y.; Sampath, D. Bioorg. Med. Chem. Lett. 2013,

23, 5014–5021. (c) Oguro, Y.; Cary, D. R.; Miyamoto, N.;

Tawada, M.; Iwata, H.; Miki, H.; Hori, A.; Imamura, S. Bioorg.

Med. Chem. 2013, 21, 4714–4729.

9.4 (3C), 31.1 (2C), 31.4, 49.9, 55.3, 110.9, 120.0, 121.8, 124.3,

42.9, 148.3; IR (ATR) 3360, 3332, 3209, 2953, 1586, 1567,

533, 1503, 1471, 1454, 1402, 1387, 1365, 1323, 1266, 1225,

156, 1127, 1101, 1065, 1033, 1005, 979, 791, 754, 735, 667,

−1

+

93, 553, 442, 413 cm ; HRMS (ESI): [M+H ] calcd for

C H ClN , 281.1533; found, 281.1530.

14

22

4

.8.4. Synthesis of 7c from 10

To a stirred solution of 10 (500 mg, 1.78 mmol) in MeOH (2.5

mL) was added 6M HCl (2.5 mL), and the mixture was stirred at

0 °C for 5 h. At this point, MeOH (2.5 mL) and 6M HCl (2.5

5

9

.

(a) Verĉek, B.; Ogorevc, B.; Stanovnik, B.; Tiŝler, M. Monatsh.

Chem. 1983, 114, 789–798. (b) Nettekoven, M.; Püllmann, B.;

Schmitt, S. Synthesis 2003, 1649–1652.

mL) were added, and the mixture was stirred at 50 °C for 2 h.

Then additional MeOH (2.5 mL) and 6M HCl (2.5 mL) were

added, and the mixture was stirred at 50 °C for 1.5 h. The

mixture was concentrated in vacuo. To the residue were added

10. Ishimoto, K.; Fukuda, N.; Nagata, T.; Sawai, Y.; Ikemoto, T. Org.

Process Res. Dev. 2014, 18, 122–134.

1

1. Grenda, V. J.; Jones, R. E.; Gal, G.; Sletzinger, M. J. Org. Chem.

965, 30, 259–261.

EtOAc (100 mL) and 5% aqueous NaHCO (50 mL), and the

3

1

layers were separated. The aqueous phase was extracted with

EtOAc (2 × 100 mL). The combined organic layer was washed

1

2. (a) Allen, D. A; McGee, D. P. C.; Spencer, J. R. WO01/44172

A1, 2001 (b) Spencer, J. R.; McGee, D.; Allen, D.; Katz, B. A.;

Luong, C.; Sendzik, M.; Squires, N.; Mackman, R. L. Bioorg.

Med. Chem. Lett. 2002, 12, 2023–2026.

with 5% aqueous NaHCO (2 × 20 mL) and 10% aqueous NaCl

3

(20 mL) and concentrated in vacuo. The resulting residue was

1

3. There is only one report that describes chlorination of gaunidines

bearing a free amino group. Ying, C.; Xing-Zhu, G.; Xiu-Min, S.;

Jian, W. Chin. J. Chem. 2005, 23, 448–453.

suspended in EtOAc/n-hexane (1:1, 10 mL), and the mixture was

stirred at 50 °C for 30 min. The mixture was cooled to room

temperature and stirred for 1 h, and then filtered to give 7c (97.0

mg, 32%) as a white solid.

4. During the measurement of HMBC in DMSO-d

30 min), degradation of 6a (about 10%) was observed. Due to the

low solubility of 6a, other deuterated solvents (CDCl , Methanol-

) could not be used.

6

(approximately

3

d

4

Acknowledgements

14

Tetrahedron

ACCEPTED MANUSCRIPT

1

5. Although an alternative synthesis of 3a has been reported,

NMR data is not shown. Potts, K. T.; Surapaneni, C. R. J.

Heterocycl. Chem. 1970, 7, 1019–1027.

1

6. Although an alternative synthesis of 7c has been reported, NMR

data is not shown. Potts, K. T.; Husain, S. J. Org. Chem. 1970, 35,

8

08–811.

7. Comas, H.; Bernardinelli, G.; Swinnen, D. J. Org. Chem. 2009,

4, 5553–5558.

7

1

2

8. We appreciate the reviewer's very insightful comment.

9. Graham, W. H. J. Am. Chem. Soc. 1965, 87, 4396–4397.

0. Moss, R. A.; Wlostowska, J.; Guo, W.; Fedorynski, M.; Springer,

J. P.; Hirshfield, J. M. J. Org. Chem. 1981, 46, 5048–5050.

1. Moss, R. A.; Terpinski, J.; Cox, D. P.; Denny, D. Z.; Krogh-

Jespersen, K. J. Am. Chem. Soc. 1985, 107, 2743–2748.

2. We appreciate the reviewer's helpful suggestion regarding the

alternative reaction mechanism.

2

3. Bégué, D.; Qiao, G. G.; Wentrup, C. J. Am. Chem. Soc. 2012, 134,

5

339–5350.

4. There is also a possibility that the carbodiimide might be

generated via Tiemann-type rearrangement. (a) Tiemann, F. Ber.

Dtsch. Chem. Ges. 1891, 24, 4162–4147. (b) Yamamoto, Y.;

Mizuno, H.; Tsuritani, T.; Mase, T. Tetrahedron Lett. 2009, 50,

5

813–5815.

2

5. Carbon, J. A.; Tabata, S. H. J. Org. Chem. 1962, 27, 2504–2509.

6. Dolzhenko, A. V.; Chui, W-K.; Dolzhenko, A. V. Synthesis 2006,

5

97–602.

2

7. Ramalingam, T.; Murty, M. S. R.; Nageswar, Y. V. D.; Sattur, P.

B. J. Heterocyclic Chem. 1990, 27, 981–982.

8. Dreikorn, B. A.; Kramer, K. E. U.S. Patent 3,953,457, 27 Apr,

1

976

9. Zhao, Y.; Wang, G.; Dong, W.; Shi, Y.; Li, B.; Wang, S.; Li, Z.

ARKIVOC, 2010, 2, 16–30.

ACCEPTED MANUSCRIPT

Supporting Information

Oxidative Cyclization of 1-(Pyridin-2-yl)guanidine Derivatives: A Synthesis of

[

1,2,4]Triazolo[1,5-a]pyridin-2-amines and An Unexpected Synthesis of

1,2,4]Triazolo[4,3-a]pyridin-3-amines

Kazuhisa Ishimoto*, Toshiaki Nagata, Mika Murabayashi and Tomomi Ikemoto

Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17-85,

Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan

e-mail: kazuhisa.ishimoto@takeda.com

Table of Contents

1

13

1

2

3

. H NMR and C NMR spectra of 5a–5m

S2–S13

1

13

. H NMR, C NMR and HMBC spectra of 6a

S14–S15

1

13

. H NMR, C NMR, HMBC and NOESY spectra of 3a, 3b, 3c, 7c, 7d, 3e, 7e, 3f, 7f, 3g, 7g, 3i,

7

i, 3j, 7j, 3k and 7k

S16–S66

1

13

4

. H NMR and C NMR spectra of Ethyl [(5-nitropyridin-2-yl)carbamothioyl]carbamate, 2c, 8, 9

and 10

S67–S71

S1

ACCEPTED MANUSCRIPT

1-(5-nitropyridin-2-yl)guanidine (5a)

¹H NMR spectrum

5a proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M08(m)

M04(d)

M07(d)

M05(br. s.)

M06(dd)

M02(dt)

M01(s)

M03(br. s.)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5a carbon.esp

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S2

ACCEPTED MANUSCRIPT

1-(3-nitropyridin-2-yl)guanidine (5b)

¹H NMR spectrum

5b proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M08(m)

M05(br. s.)

M07(m(ortho))

M04(dd)

M02(dt)

M03(s)

M01(s)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5b carbon.esp

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S3

ACCEPTED MANUSCRIPT

1-(3-chloropyridin-2-yl)guanidine (5c)

¹H NMR spectrum

5c proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M05(br. s.)

M04(dd)

M07(dd)

M02(m)

M01(s)

M03(s)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5c carbon.esp

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S4

ACCEPTED MANUSCRIPT

1-(5-chloropyridin-2-yl)guanidine (5d)

¹H NMR spectrum

5d proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M04(br. s.)

M03(dd)

M06(d)

M05(dd)

M02(m)

M01(s)

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5d carbon.esp

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S5

ACCEPTED MANUSCRIPT

1-(3-(trifluoromethyl)pyridin-2-yl)guanidine (5e)

¹H NMR spectrum

5e proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M02(dt)

M06(dd)

M07(dd)

M05(br. s.)

M04(dd*)

M03(s)

M01(s)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5e carbon.esp

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S6

ACCEPTED MANUSCRIPT

1-(5-(trifluoromethyl)pyridin-2-yl)guanidine 0.9 1-methylpyrrolidin-2-one solvate (5f)

¹H NMR spectrum

5f proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M04(br. s.)

M05(s)

M02(m)

M03(t)

M06(t)

M08(br. s.)

M07(d)

M10(br. s.)

M09(dd)

M01(s)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5f carbon.esp

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S7

ACCEPTED MANUSCRIPT

1-(4-(trifluoromethyl)pyridin-2-yl)guanidine (5g)

¹H NMR spectrum

5g proton.esp

1.5

1.0

0.5

M05(br. s.)

M03(s)

M04(dd*)

M06(d)

M02(dt)

M01(s)

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5g carbon.esp

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S8

ACCEPTED MANUSCRIPT

1-(6-fluoropyridin-2-yl)guanidine (5h)

¹H NMR spectrum

5h proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M02(dt)

M06(br. s.)

M07(dt)

M05(dd)

M04(dd)

M01(s)

M03(br. s.)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5h carbon.esp

0.13

0.12

0.11

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S9

ACCEPTED MANUSCRIPT

1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)guanidine (5i)

¹H NMR spectrum

5i proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M06(dd*) M04(br. s.)

M05(d)

M03(s)

M02(dt)

M01(s)

0

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5i carbon.esp

0.13

0.12

0.11

0.10

0.09

0.08

0.07

0.06

0.05

0.04

0.03

0.02

0.01

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S10

ACCEPTED MANUSCRIPT

1-(quinolin-2-yl)guanidine (5j)

¹H NMR spectrum

5j proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M03(td*)

M02(d)

M04(m)

M06(dd)

M07(d)

M05(d)

M01(m)

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5j carbon.esp

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S11

ACCEPTED MANUSCRIPT

1-(isoquinolin-1-yl)guanidine (5k)

¹H NMR spectrum

5k proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M06(t)

M07(m)

M08(d)

M04(br. s.)

M03(d*)

M02(m)

M09(d)

M01(s)

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5k carbon.esp

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S12

ACCEPTED MANUSCRIPT

1-(benzo[d]oxazol-2-yl)guanidine (5m)

¹H NMR spectrum

5m proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M02(s)

M03(dd*)

M04(m)

M05(m)

M06(m)

M01(m)

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

5m carbon.esp

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S13

ACCEPTED MANUSCRIPT

2-chloro-1-(5-nitropyridin-2-yl)guanidine (6a)

¹H NMR spectrum

6a proton.esp

1.4

1.3

1.2

1.1

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

M05(br. s.)

M04(d)

M07(d)

M08(s)

M06(dd)

M02(dt)

M01(s)

M03(s)

11

10

9

8

7

6

5

4

3

2

Chemical Shift (ppm)

¹³C NMR spectrum

6a carbon.esp

0.30

0.25

0.20

0.15

0.10

0.05

0

200

180

160

140

120

100

80

60

40

Chemical Shift (ppm)

S14

Article Doi

Oxidative cyclization of 1-(pyridin-2-yl)guanidine derivatives: A synthesis of [1,2,4]triazolo[1,5-a]pyridin-2-amines and an unexpected synthesis of [1,2,4]triazolo[4,3-a]pyridin-3-amines

DOI: 10.1016/j.tet.2014.12.015

Source and publish data:

Authors:

Article abstract of DOI:10.1016/j.tet.2014.12.015

Full text of DOI:10.1016/j.tet.2014.12.015

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