DOI 10.1515/hc-2012-0139   Heterocycl. Commun. 2012; 18(5-6): 227–232

Ewa Woli ń ska*

Sequential amination of heteroaromatic halides with aminopyridine 1 - oxides and their N- protected derivatives based on novel aza-Smiles rearrangement Abstract: The S

N Ar and Pd-catalyzed amination of chloro

derivatives of azines, diazines, and triazines with 2-ami-

nopyridine 1-oxides and their N -protected derivatives was

described.

Keywords: 2-aminopyridine 1-oxide; 1-pyridyloxypyri-

dinium salts; Buchwald amination; formamidine; Smiles

rearrangement; S N Ar substitution.

*Corresponding author: Ewa Woli ń ska, Department of Chemistry,

Siedlce University, 08-110 Siedlce, Poland, e-mail: ewol@uph.edu.pl

Introduction N -Arylation of heteroaromatic amines with aryl and

(hetero)aryl halides via aromatic nucleophilic substi-

tution or mediated by transition metals have acquired

importance due to the versatility of products that are prev-

alent in compounds of biological, pharmaceutical, and

materials interest (Hartwig et al., 2007). In the course of

our research efforts, we required an access to a number of

N -arylated and N -(hetero)arylated 3-amino-1,2,4-triazines

for their application in asymmetric bifunctional catalysis

(Ma and Cahard, 2004; Denmark and Beutner, 2008). The

former compounds bearing chiral oxazoline ring ( Figure

1 ) were prepared via a two-step synthesis, with the key

step being a palladium-catalyzed aryl amination between

2-(2 ′ -aminophenyl)oxazolines and corresponding 3-halo-

geno-1,2,4-triazines in the presence of chelating bisphos-

phine ligand (Karczmarzyk et al., 2011).

Although clearly effective, such approach is not

always well suited for the N -(hetero)arylation of electron-

poor heteroaromatic amines. In particular, such amines

require their own optimized catalyst or ligand system,

and minor structural variations within the substrate

may dramatically change the outcome of the catalytic

process (Garnier et al., 2004). An alternative approach to

the synthesis of the aforementioned systems may involve

the nucleophilic aromatic substitution of the 1,2,4-tria-

zine substrate by appropriately modified heteroaromatic

amines. Unlike aminopyridines, their N -oxides have lower

basicity (Andreev, 2009) and as bifunctional nucleo-

philes can react with electrophiles at either oxygen or

amino nitrogen atoms (Rykowski and Pucko, 1998). The

use of 2-aminopyridine 1-oxides in the amination reac-

tion of electrophilic chloronitropyridines has recently

been shown to be an effective and operationally simple

route for the synthesis of nitro-substituted 2,2 ′ -dipyri-

dylamine 1-oxides (Woli ń ska and Pucko, 2012). More-

over, their formamidine-protected derivatives were also

reacted with chloronitropyridines, giving rise to interme-

diary 1-pyridyloxypyridinium salts that easily underwent

base-catalyzed rearrangement into nitro derivatives of

2,2 ′ -dipyridylamine N -oxides in good yield (Woli ń ska

and Pucko, 2012). On the basis of the latter studies, we

became interested in determining whether this protocol

would be applicable to the less electrophilic heteroaro-

matic halides without an electron withdrawing group. In

view of the importance of pyridine N- oxides in coordina-

tion and medicinal chemistry (Balzarini et al., 2006) as

well as their facile deoxygenation and transformation

into a wide range of other functional groups (Leclerc and

Fagnou, 2006), such cross-coupling reactions involving

various aminopyridine 1-oxides have been a challenging

target. Here we report the results of our initial investiga-

tions on S N Ar vs. Pd-catalyzed aminations of chloro deri-

vatives of azines, diazines, and triazines using as nucleo-

philes 2-aminopyridine 1-oxides and/or their N -protected

derivatives.

Results and discussion Initial experiments were performed with a readily avail-

able 3-chloro-5,6-diphenyl-1,2,4-triazine ( 1 ) as the model

substrate. The reaction of 2-aminopyridine 1-oxide ( 2a )

with 1 in DMF at 100 ° C for 5 h led to the exclusive formation

Brought to you by | Brown University Rockefeller LibraryAuthenticated | 128.148.252.35

Download Date | 2/21/13 4:43 PM

228      E. Wolińska: Novel aza-Smiles rearrangement

of an expected S N Ar product 3 (75%) ( Scheme 1 , Table 1 ).

When increasing the temperature to 150 ° C, a complete

conversion of 1 was observed within 2 h; however, the

reaction was not selective and provided a mixture of the

desired compound 3 (68%) and deoxygenated product 5

(13%). To circumvent the formation of 5 , we proceeded to

optimize the reaction with respect to the temperature and

solvent. As can be seen from Table 1 , the reaction of 2a

with 3-chloro-5,6-diphenyl-1,2,4-triazine ( 1 ) in dioxane at

80 ° C in the presence of dry potassium carbonate was com-

pleted within 5 h, providing direct access to compound 3

in 88% yield. For a comparison, we tried to couple 1 with

2-aminopyridine ( 4 ) under the conditions mentioned

above. However, even traces of the amination product 5

could not be detected in the reaction mixture. This last

result reflects an important role of the N- oxide functional-

ity in 2-aminopyridine 1 - oxides during N- (hetero)arylation

reaction.

To investigate further the scope of this new coupling

protocol, we examined the reaction of 2-aminopyridine

1-oxides 2a,b with 2,4-dichloropyrimidine ( 6 ) ( Scheme

2 ). The coupling of 6 with 2a,b in DMF at room temper-

ature led to monoaminated products 11a,b as colorless

precipitates in moderate yield. Less reactive 2-chloropy-

rimidine ( 7 ) did not react under these conditions. The

insolubility of substrates 6 and 2a , b in dioxane at room

temperature excluded the use of this solvent as reaction

medium. Attempts to improve the yield of compounds

11a , b by increasing the reaction temperature to 80 ° C or

100 ° C failed because the reaction was not selective; a

N

NNPh

Ph Cl

N

N

NH2

NH2

O

N

NNPh

Ph NH

N

N

NNPh

Ph NH

N

O

1

2a

3

4 5

Scheme 1

Substrate Solvent Temperature ( ° C) Time (h) Yield (%) 3 5

2a DMF 100 5 75 0

2a DMF 150 2 68 13

2a Dioxane 80 5 88 0

4 DMF or dioxane 100 5 – 0

Table 1  Reactions of 3-chloro-5,6-diphenyl-1,2,4-triazine ( 1 ) with

2a and 4 .

N

NNPh

Ph NH

N O

R

Figure 1  Chiral oxazoline ligands for asymmetric catalysis.

complicated mixture of products was obtained under such

conditions. The yield of products 11a,b was improved by

a parallel synthesis. We found that the reaction of 6 with

an equimolar amount of formamidine protected 2-amino-

pyridine 1-oxide 8a in DMF at room temperature afforded

intermediary 1-(2-chloropyrimidin-4-yloxy)pyridinium salt

9a in 80% yield. Likewise, the reaction of formamidine

protected 2-amino-5-methylpyridine 1-oxide 8b with 6

in DMF at 0 ° C gave the expected pyridinium salt 9b .

These results clearly demonstrate the high nucleophilic-

ity of oxygen in formamidine-protected 2-aminopyridine

1 - oxides. The salts thus obtained are sufficiently stable to

be isolated in the pure state and characterized by spectro-

scopic methods and elemental analysis (see Experimental

section). The deprotection of the amino groups in 9a and

9b upon treatment with aqueous ammonia results in the

formation of the rearrangement products 11a,b within a

few minutes. The fast rate of this reaction suggests that it

N

N

ClCl

N NH2

O 2a,b

N

N

ClNH

N

O

R

R

a: R = H; b: R = Me

6

11a,b

N

N

O

8a,b

R

N(Me)2

NO N

N

Cl

N

N(Me)2

9a,b

NO N

N

Cl

N

10a,b

25% NH4OH

ClR R

H

DMFrt

EtOH

Scheme 2

Brought to you by | Brown University Rockefeller LibraryAuthenticated | 128.148.252.35

Download Date | 2/21/13 4:43 PM

E. Wolińska: Novel aza-Smiles rearrangement      229

is intramolecular in nature. It seems reasonable to assume

that the base-induced hydrolysis of the carbon-nitrogen

double bonds in 9a,b leads to unprotected intermediates

10a,b , which, through the intramolecular nucleophilic

attack of the imino group on C-4 carbon of pyrimidine

ring, yield the corresponding N -arylated products 11a,b

( Scheme 2 ).

To confirm that the intramolecular attack of amine

nitrogen in 10a,b plays primary role in the amina-

tion reaction, we carried out a crossover experiment in

which 1 equivalent of 9b and 1 equivalent of 9c , readily

obtained from 8a and 2-chloro-5-nitropyridine (Woli ń ska

and Pucko, 2012), were dissolved in ethanol and treated

with aqueous ammonia (Eq. 1). In the reaction products

obtained, we could identify only compounds 11b and

12 , and no traces of other products were detected in the

mixture. This result clearly shows that only intramolecu-

lar amination takes place during the reaction of com-

pounds 9b and 9c with aqueous ammonia and strongly

suggests that the nucleophilic substitution of halogen

in electrophilic heteroaromatic halides by unprotected

2-aminopyridine 1-oxides may also proceed via an intra-

molecular rearrangement.

The transformation of the intermediates 10a , b to 11a , b is mechanistically similar to the well-known Smiles

rearrangement (Plesniak et al., 2007). However, the major

difference between these processes is in the structure of

the substrates. Because the imino group in 10a , b respon-

sible for nucleophilic attack is connected to a moiety

containing a nitrogen atom instead of an alkyl-chain

linker, the observed conversion can be called aza-Smiles

rearrangement.

With the first coupling in hand, the next question was

what conditions would be required for the second cou-

pling, particularly in the one-pot fashion. It was expected

that somewhat more forcing conditions would be required

because the C-2 position in the pyrimidine ring is signifi-

cantly less reactive than the C-4 position toward nucleo-

philic displacement. However, after a more thorough liter-

ature investigation, we found an acid-mediated approach

to synthesize substituted 2-anilinopyrimidines (Hattinger

et al., 2002). Fortunately, these conditions were effective

for the one-pot double-coupling reaction of 2,4-dichloro-

pyrimidine ( 6 ) with 2-aminopyridine 1-oxide ( 2a ). Treat-

ment of 6 with 2.2 equivalent of 2-aminopyridine 1-oxide

( 2a ) in DMF at 100 ° C in the presence of 1 equivalent of

TsOH afforded disubstituted product 13 in 50% yield.

The same reaction conditions proved to be effective for

2-chloropyrimidine ( 7 ), 2-(1-oxidopyridin-2-yl)aminopy-

rimidine ( 14 ) being obtained in 64% yield ( Scheme 3 ).

NO

N

N

N(Me)2

9c

Cl 11bN N

HN

NO2

25% NH4OH

NO212O

9b, EtOH(1)

N

N

Cl2a

N

N

NH

N

O7 14

(i)

6 2a(i)

N NH

N

N

NH

N

O O

N NH

N

N

NH

N

(iii)

13 13'

N Cl2a

N NH

N

O16

(i) or (ii)

N NH

N

16'

(iii)

15

N

N

NH

N

14'

(iii)

(i): TsOH, DMF, 100°C; (ii): Pd2dba3, Xantphos, Cs2CO3, dioxane, 100°C; (iii): 10% Pd/C, HCO2NH4

11aN N

HN

N

11a'

(iii)

Scheme 3

Brought to you by | Brown University Rockefeller LibraryAuthenticated | 128.148.252.35

Download Date | 2/21/13 4:43 PM

230      E. Wolińska: Novel aza-Smiles rearrangement

When 2-aminopyridine 1-oxide ( 2a ) was subjected to the

reaction with an equimolar amount of 6 in DMF at 100 ° C

in the presence of TsOH, monosubstituted ( 11a ) and dis-

ubstituted ( 13 ) products were formed in low yields.

In contrast to the results obtained with 6 or 7 , the reac-

tion of 2-chloropyridine ( 15 ) with 2a in DMF under acid-

mediated conditions proceeds in very low yield. Further

investigations revealed that the poor outcomes associ-

ated with the low reactivity of 15 may be overcome using

the Buchwald-Hartwig amination (Hartwig et al., 2007).

The reaction of 15 (1 equivalent) with 2a (1 equivalent)

using our previously reported procedure (Karczmarzyk

et al., 2011) (Pd 2 dba

3 , Xantphos, Cs

2 CO

3 , dioxane, 105 ° C)

afforded 2-(pyridin-2-yl)aminopyridine 1-oxide ( 16 ) in 65%

yield ( Scheme 3 ). This approach may give an easy access

to a variety of biheteroaromatic amine 1-oxides and is cur-

rently under investigation in our laboratory.

If desired, the amination products 11a , 13 , 14 , and 16

can be easily deoxygenated. The treatment of these com-

pounds with ammonium formate and palladium/carbon

in methanol under reflux conditions (Kaczmarek et al.,

1990) gave the corresponding free bases 11a ′ , 13 ′ , 14 ′ , and 16 ′ in a quantitative yield ( Scheme 3 ).

Conclusions 2-Aminopyridine 1 - oxides and their N- protected derivatives

are reactive species that smoothly undergo N -(hetero)aryla-

tion with activated heteroaromatic halides in the absence

of a catalyst. Products may be easily deoxygenated with

ammonium formate and palladium/carbon in excellent

yield. It was also demonstrated that the use of aminoazine

N -oxides in Buchwald-Hartwig amination extends the scope

of the method to unactivated heteroaromatic halides as well.

Experimental

General Melting points are uncorrected. 1 H and 13 C NMR spectra were recorded

with a Varian Gemini spectrometer. Chemical shift s ( δ ) are given in

parts per million from tetramethylsilane, with the solvent resonance

as the internal standard. Mass spectra were obtained using AMD 604

(AMD Intectra GmbH, Harpstedt, Germany) spectrometer. Infrared

spectra were determined in KBr with a Magna FT-IR-760 (Nicolet)

apparatus. Elemental analyses were recorded with a Perkin-Elmer

2400-CHN analyzer. Thin-layer chromatography was carried out

on aluminum sheets coated with silica gel 60 F 254

(Merck). Column

chromatography separations were performed with Merck Kieselgel

60 (0.040 – 0.060 mm). Solvents were dried and distilled according

to standard procedures. All reagents were purchased from Aldrich.

Preparation of 5,6-diphenyl-3-(1-oxi-dopyridin-2-ylamino)-1,2,4-triazine (3) and 5,6-diphenyl-3-(pyridin-2-ylamino)-1,2,4-triazine (5) Methods A and B  A mixture of 2-aminopyridine 1-oxide ( 2a , 0.12

g, 1.1 mmol), 3-chloro-5,6-diphenyl-1,2,4-triazine ( 1 , 0.27 g, 1 mmol),

and a catalytic amount of potassium iodide in dry DMF (5 ml) was

heated at 100 ° C for 5 h (Method A) or at 150 ° C for 2 h (Method B).

The precipitate was fi ltered off . According to Method A, product 3 was

the only product obtained. Products 3 and 5 (obtained in Method B)

were separated by column chromatography using dichloromethane/

methanol (10:1) as eluent.

Method C  A mixture of 2-aminopyridine 1-oxide ( 2a , 0.12 g, 1.1

mmol), 3-chloro-5,6-diphenyl-1,2,4-triazine ( 1 , 0.27 g, 1 mmol) and

potassium carbonate (0.14 g, 1 mmol) in dry dioxane (10 ml) was

heated at 80 ° C for 5 h. The mixture was fi ltered off , and the fi ltrate

was evaporated in vacuo . Compound 3 was purifi ed by column chro-

matography (dichloromethane/methanol 10:1).

5,6-Diphenyl-3-(1-oxidopyridin-2-ylamino)-1,2,4-triazine (3)  Yield 75% (Method A), 68% (Method B) and 88% (Method C);

mp 106 – 108 ° C; IR: 3250, 1200 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 10.37

(br s, 1H), 8.85 (d, 1H, J = 8.0 Hz), 8.36 (d, 1H, J = 6.0 Hz), 7.57 – 7.30 (m,

11H), 6.99 – 6.96 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 156.74, 156.71,

152.5, 143.6, 137.1, 135.5, 135.1, 130.8, 129.6, 129.2, 129.0, 128.4, 127.8,

117.9. Anal. Calcd for C 20

H 15

N 5 O: C, 70.37; H, 4.43; N, 20.52. Found: C,

70.24; H, 4.70; N, 20.22.

5,6-Diphenyl-3-(pyridin-2-ylamino)-1,2,4-triazine (5)  Yield 13%

(Method B); mp 241 – 243 ° C; 1 H NMR (400 MHz, CDCl 3 ): δ 9.04 (br s,

1H), 8.61 (d, 1H, J = 8.4 Hz), 8.42 (d, 1H, J = 4.0 Hz), 7.79 (dt, 1H, J = 1.6 Hz, 8.4 Hz), 7.59 – 7.57 (m, 2H), 7.51 – 7.49 (m, 2H), 7.47 – 7.43 (m, 1H),

7.40 – 7.34 (m, 5H), 7.05 – 7.02 (m, 1H). HRMS: Calcd for C 20

H 16

N 5 : m/z

326.1400. Found: m/z 326.1402.

Synthesis of 2-chloro-4-(1-oxidopyridin-2-ylamino)pyrimidine (11a) and 2-chloro-4-(5-methyl-1-oxidopyridin-2-ylamino)pyrimidine (11b) A mixture of 1-oxide 2a or 2b (2 mmol), 2,4-dichloropyrimidine ( 6 ,

0.15 g, 1 mmol) in dry DMF (5 ml) was stirred at room temperature for

22 h. The precipitate was fi ltered off . Products 11a , b were purifi ed by

crystallization from toluene.

2-Chloro-4-(1-oxidopyridin-2-ylamino)pyrimidine (11a)  Yield

30%; mp 275 – 276 ° C (dec); IR: 3120, 1205 cm 1 ; 1 H NMR (400 MHz, DM-

SO- d 6 ): δ 10.22 (d, 1H, J = 8.2 Hz), 9.94 (d, 1H, J = 6.4 Hz), 9.77 (d, 1H,

J = 7.2 Hz), 9.44 (t, 1H, J = 8.2 Hz), 9.00 (d, 1H, J = 7.2 Hz), 8.87 (t, 1H,

J = 6.4 Hz); 13 C NMR (100 MHz, DMSO- d 6 ): δ 160.3, 158.7, 158.4, 143.6,

Brought to you by | Brown University Rockefeller LibraryAuthenticated | 128.148.252.35

Download Date | 2/21/13 4:43 PM

E. Wolińska: Novel aza-Smiles rearrangement      231

137.5, 126.9, 118.6, 114.9, 108.8. Anal. Calcd for C 9 H

7 N

4 ClO: C, 48.55; H,

3.17; N, 25.17. Found: C, 48.42; H, 2.96; N, 25.14.

2-Chloro-4-(5-methyl-1-oxidopyridin-2-ylamino)pyrimidine (11b)  Yield 37%; mp 272 – 273 ° C (dec); 1 H NMR (400 MHz, DMSO- d

6 ):

δ 9.28 (br s, 1H), 8.90 (d, 1H, J = 5.8 Hz), 8.38 (s, 1H), 7.90 (d, 1H, J = 9.0 Hz), 7.63 (d, 1H, J = 5.8 Hz), 7.38 (d, 1H, J = 9.0 Hz), 2.19 (s, 3H);

13 C NMR (100 MHz, DMSO- d 6 ): δ 168.0, 162.5, 158.1, 150.1, 145.2, 133.8,

122.5, 115.6, 107.4, 16.3. Anal. Calcd for C 11

H 9 N

4 ClO: C, 50.75; H, 3.83; N,

23.67. Found: C, 50.81; H, 3.98; N, 23.58.

Synthesis of 2-{[( N,N- dimethylamino)methylene]amino } -5-methylpyridine 1-oxide (8b)  A mixture of 2-amino-5-methyl-

pyridine 1 - oxide ( 2b , 2.18 mmol, 0.27 g) and N,N-dimethylformamide

dimethyl acetal (1.9 ml) was stirred at room temperature for 24 h. The

precipitate was fi ltered off , washed with ethyl ether, and dried in a

vacuum desiccator over phosphorus oxide. Compound 8b was ob-

tained in 92% yield; mp 110 – 112 ° C; IR: 1264, 2922 cm -1 ; 1 H NMR (400

MHz, CDCl 3 ): δ 9.07 (s, 1H), 7.96 (s, 1H), 6.95 (d, 1H, J = 8.2 Hz), 6.82

(d, 1H, J = 8.2 Hz), 3.07 (s, 3H), 3.06 (s, 3H), 2.20 (s, 3H); 13 C NMR (100

MHz, CDCl 3 ): δ 156.5, 150.7, 139.5, 128.9, 127.3, 120.0, 43.6, 33.9, 17.5.

HRMS: Calcd for C 9 H

14 N

3 : m/z 180.1131. Found: m/z 180.1132.

General procedure for the preparation of pyridinium salts 9a,b To formamidine protected 2-aminopyridine 1 - oxide 8a (Woli ń ska and

Pucko, 2012) or 8b (1 mmol) and 2,4-dichloropyrimidine ( 6 , 0.15 g,

1 mmol) was added dry DMF (2 ml). The mixture of compounds 8a

and 6 was stirred at room temperature and the mixture of 8b and 6

at 0 ° C for 24 h. Aft er that time, the products were fi ltered off , washed

with diethyl ether, and dried in vacuo .

1-(2-Chloropyrimidin-4-yloxy)-2-{[( N , N- dimethylamino)meth-ylene]amino } pyridin-1-ium chloride (9a)  Yield 80%; mp 139 ° C

(dec); IR: 3609 cm -1 ; 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.91 (d, 1H, J = 5.6

Hz), 8.88 – 8.86 (m, 2H), 8.30 – 8.26 (m, 1H), 8.10 (dd, 1H, J = 1.6 Hz, 8.8

Hz), 7.70 (d, 1H, J = 5.6 Hz), 7.39 (dt, 1H, J = 1.6 Hz, 7.2 Hz), 3.24 (s, 3H),

2.82 (s, 3H); 13 C NMR (100 MHz, DMSO- d 6 ): δ 168.9, 163.1, 159.5, 158.5,

155.0, 144.2, 139.0, 117.8, 116.2, 105.5, 41.5, 35.0. Anal. Calcd for C 12

H 13

N 5 OCl

2 : C, 45.88; H, 4.17; N, 22.29. Found: C, 45.68; H, 4.26; N, 22.11.

1-(2-Chloropyrimidin-4-yloxy)-2-{[( N,N- dimethylamino)methyl-ene]amino } -5-methylpyridin-1-ium chloride (9b)  Yield 47%; mp

147 ° C (dec); 1 H NMR (400 MHz, DMSO- d 6 ): δ 8.91 (d, 1H, J = 5.6 Hz),

8.84 – 8.78 (m, 2H); 8.19 (dd, 1H, J = 2.0 Hz, 9.2 Hz), 7.97 – 7.95 (m, 1H),

7.69 (d, 1H, J = 5.6 Hz), 3.22 (s, 3H), 2.80 (s, 3H), 2.34 (s, 3H); 13 C NMR

(100 MHz, DMSO- d 6 ): δ 168.8, 163.2, 159.3, 158.5, 153.2, 146.1, 136.6,

126.7, 116.9, 105.4, 41.3, 34.8, 16.6. HRMS: Calcd m/z for C 13

H 15

N 5 OCl:

292.0959. Found: m/z 292.0964.

General procedure for the rearrangement of pyridinium salts 9a,b into N -(hetero) arylated products 11a,b To the solution of pyridinium salt 9a or 9b (1 mmol) in anhydrous

ethanol (6 ml), 25% ammonia (0.3 ml) was added. The mixture was

stirred at room temperature for 5 min. The precipitate was fi ltered

off and crystallized from toluene. The yield of 11a was 48%, and the

yield of 11b was 67%.

Crossover experiment between 9b and 9c To the solution of pyridinium salts 9b (0.1 mmol) and 9c (0.1 mmol)

in ethanol (2 ml), 25% ammonia (0.1 ml) was added. The mixture

was stirred at room temperature for 5 min. Aft er the evaporation

of solvent, the mixture of products was analyzed by 1 H NMR in

CDCl 3 using nitromethane as internal reference; 11b , yield: 37%;

12 , yield: 63%.

General procedure for the preparation of N -(hetero)arylated 2-aminopyridine 1-oxides 13, 14, and 16 Method A  The mixture of 2-aminopyridine 1-oxide ( 2a , 0.24 g, 2.2

mmol), appropriate chloro compound ( 6 , 7 , or 15 , 1.0 mmol), and p -

toluenesulfonic acid (0.17 g, 1.0 mmol) in DMF (20 ml) was stirred at

80 ° C for 24 h and then poured into ice water (100 ml). Aft er neutrali-

zation with sodium bicarbonate, the precipitate was fi ltered and pu-

rifi ed by column chromatography using dichloromethane/methanol

(10:1) as an eluent.

Method B  The solution of Pd 2 dba

3 (0.06 g, 0.06 mmol) and Xant-

phos (0.084 g, 0.14 mmol) in dry dioxane was stirred for 10 min

under argon. The mixture was added to a fl ask containing 2-chloro-

pyridine ( 15 , 0.15 g, 1.3 mmol), 2-aminopyridine 1-oxide ( 2a , 0.17 g,

1.6 mmol), Cs 2 CO

3 (1.7 g, 5.3 mmol), and dioxane (4 ml). The mixture

was stirred for 42 h at 110 ° C. The solid material was fi ltered off , and

the fi ltrate concentrated. The residue of 13, 14, or 16 was purifi ed by

column chromatography using dichloromethane/methanol (50:1)

as an eluent.

2,4-Bis(1-oxidopyridin-2-ylamino)pyrimidine (13)  Yield 50%

(Method A); mp 237 – 238 ° C; IR: 3136, 3304, 1203 cm -1 ; 1 H NMR (400

MHz, DMSO- d 6 ): δ 10.46 (br s, 1H), 9.79 (br s, 1H), 8.66 (dd, 1H, J =

1.6 Hz, 8.4 Hz), 8.55 (dd, 1H, J = 1.6 Hz, 8.4 Hz), 8.39 – 8.35 (m, 3H),

7.50 – 7.41 (m, 2H), 7.15 (d, 1H, J = 6.0 Hz), 7.11 – 7.02 (m, 2H); 13 C NMR

(100 MHz, DMSO- d 6 ): δ 159.6, 157.2, 156.8, 144.3, 144.0, 137.4, 137.0,

127.2, 126.9, 118.0, 117.0, 115.2, 113.2, 103.8. Anal. Calcd for C 14

H 12

N 6 O

2 · 0.5H

2 O: C, 55.08; H, 4.29; N, 27.53. Found: C, 54.79; H, 4.34;

N, 27.69.

2-(1-Oxidopyridin-2-ylamino)pyrimidine (14)  Yield 67% (Meth-

od A); mp 152 – 153 ° C; IR: 3245 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ

10.08 (br s, 1H), 8.72 (dd, 1H, J = 2.0 Hz, 8.8 Hz), 8.56 (d, 2H, J = 4.8

Hz), 8.28 (d, 1H, J = 4.0 Hz), 7.33 (dt, 1H, J = 1.2 Hz, 8.8 Hz), 6.92 (t,

1H, J = 5.2 Hz), 6.88 (dt, 1H, J = 1.6 Hz, 7.6 Hz); 13 C NMR (100 MHz,

CDCl 3 ): δ 158.3, 158.1, 144.7, 137.1, 127.7, 116.2, 114.7, 113.4. Anal. Calcd

for C 9 H

8 N

4 O: C, 57.44; H, 4.28; N, 29.77. Found: C, 57.35; H, 4.32; N,

29.79.

2-(Pyridin-2-ylamino)pyridine 1-oxide (16)  Yield 19% (Method A)

and 66% (Method B); mp 165 – 166 ° C (lit. mp 165 – 166 ° C; Rykowski and

Pucko, 1998).

Brought to you by | Brown University Rockefeller LibraryAuthenticated | 128.148.252.35

Download Date | 2/21/13 4:43 PM

232      E. Wolińska: Novel aza-Smiles rearrangement

General procedure for the deoxygenation of 1-oxides 11a, 13, 14, and 16 The suspension of the appropriate 1 - oxide (1 mmol), ammonium

formate (8 mmol), 10% Pd/C (0.2 g) in methanol (45 ml) was heated

under refl ux for 2 h. The reaction mixture was fi ltered off and concen-

trated in vacuo . The product was purifi ed by column chromatography

using dichloromethane/methanol (20:1) as an eluent and crystallized

from ethanol-water.

4-(Pyridin-2-ylamino)pyrimidine (11a ′ )  Yield 97%; mp 181 ° C. IR:

3250 cm -1 ; 1 H NMR (200 MHz, CDCl 3 ) δ : 8.80 (br s, 1H), 8.46 – 8.32 (m,

2H), 7.97 (s, 1H), 7.74 – 7.51 (m, 3H), δ 6.98 (ddd, 1H, J = 7.1 Hz, 4.9 Hz,

0.9 Hz); 13 C NMR (100 MHZ, DMSO- d 6 ): δ 159.0, 157.9, 156.2, 153.8, 147.6,

138.0, 117.6, 113.3, 108.1. HRMS: Calcd for C 9 H

8 N

4 : m/z

172.0749. Found:

m/z 172.0747.

2,4-Bis(pyridin-2-ylamino)pyrimidine (13 ′ )  Yield 99%; mp 80 –

81 ° C; IR: 3427, 3252 cm -1 ; 1 H NMR (400 MHz, CDCl 3 ): δ 9.00 (br s, 2H),

8.33 – 8.28 (m, 3H), 8.24 (d, 1H, J = 5.6 Hz), 7.72 – 7.65 (m, 3H), 6.05 – 7.93

(m, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 159.6, 158.5, 157.9, 153.0, 152.8,

147.4, 118.0, 117.4, 113.9, 113.5, 101.0. HRMS: Calcd for C 14

H 13

N 6 : m/z

265.1196. Found: m/z 265.1198.

2-(Pyridin-2-ylamino)pyrimidine (14 ′ )  Yield 95%; mp 152 ° C (lit.

mp 152 ° C; Bock et al., 1997); IR: 3237 cm -1 ; 1 H NMR (200 MHz, CDCl 3 ):

δ 8.53 (d, 2H, J = 4.8 Hz), 8.41 (dt, 1H, J = 1.0 Hz, 8.5 Hz), 8.35 (ddd, 1H,

J = 0.9 Hz, 1.9 Hz, 4.9 Hz), 7.75 – 7.65 (m, 1H), 6.95 (ddd, 1H, J = 1.0 Hz,

5.0, Hz, 7.3 Hz), 6.81 (t, 1H, J = 4.8 Hz). Anal. Calcd for C 9 H

8 N

4 : C, 62.78;

H, 4.68; N, 32.54. Found: C, 62.65; H, 4.59; N, 32.74.

Bis(pyridin-2-yl)amine (16 ′ )  Yield 90%; mp 94 – 95 ° C (lit. mp 94 –

95 ° C; Rykowski and Pucko, 1998).

Acknowledgments: We are grateful to Ms. Emilia Ł ukasik

and Mr. Szymon Nasi ł owski for technical assistance and

to Prof. Andrzej Rykowski for helpful discussions.

Received September 12, 2012; accepted October 18, 2012; previously

published online November 23, 2012

References Andreev, V. P. Relative nucleophilic reactivity of pyridines and

pyridine n -oxides (supernucleophilicity of pyridine N -oxides). Russ. J. Org. Chem. 2009 , 45, 1061 – 1069.

Balzarini, J.; Keyaerts, E.; Vijgen, L.; Vandermeer, F.; Stevens,

M.; Clercq, E. D.; Egberink, H.; Ranst, M. V. Pyridine N -oxide

derivatives are inhibitory to the human SARS and feline

infectious peritonitis coronavirus in cell culture. J. Antimicrob. Chemother . 2006 , 57 , 472 – 481.

Bock, H.; Schodel, H.; Nather, C.; Butenschon, F. Wechselwirkungen

in Kristallen. 110. Mitteilung. Die Dimorphic von (2-Pyridyl)

(2-pyrimidyl)amin. Helv. Chim. Acta 1997 , 80 , 593 – 605.

Denmark, S. E.; Beutner, G. L. Lewis base catalysis in organic

synthesis. Angew. Chem. Int. Ed . 2008 , 47 , 1560 – 1638.

Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.; Poullain,

D.; Lebret, B.; Guillaumet, G. Easy access to 3- or

5-heteroarylamino-1,2,4-triazines by SNAr, SNH, and

palladium-catalyzed N-heteroarylations. J. Org. Chem . 2004 ,

69 , 7809 – 7815.

Hartwig, J. F.; Shekhar, S.; Shen, Q.; Barrios-Landeros, F. Synthesis

of Anilines. In The Chemistry of Anilines ; Rapoport, Z., Ed.

Wiley-Interscience: New York, 2007; pp 455 – 536.

Hattinger, G.; Stanetty, P.; Eberle, M. Preparation of N-phenyl-4-(4-

pyridinyl)pyrimidin-2-amines. GB Patent 2002, 2369359.

Kaczmarek, L.; Balicki, R.; Malinowski, M. Reduction of

4-nitropyridine N-oxide with low valent titanium reagent.

J. Prakt. Chem . 1990 , 332 , 423 – 424.

Karczmarzyk, Z.; Woli ń ska, E.; Fruzi ń ski, A.

N-[2-[(4S)-4-tert-Butyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl } -5,6-

diphenyl-1,2,4-triazin-3-amine. Acta Crystallogr . 2011 , E67 , 0651.

Leclerc, J.-P.; Fagnou, K. Palladium-catalyzed cross-coupling

reactions of diazine n -oxides with aryl chlorides, bromides,

and iodides. Angew. Chem. Int. Ed. 2006 , 45, 7781 – 7786.

Ma, J.-A.; Cahard, D. Towards perfect catalytic asymmetric

synthesis: dual activation of the electrophile and the

nucleophile. Angew. Chem. Int. Ed . 2004 , 43 , 4566 – 4583.

Plesniak, K.; Zarecki, A.; Wicha, J. The Smiles rearrangement and

the Julia-Kocienski olefination reaction. Top. Curr. Chem . 2007 ,

275 , 163 – 250.

Rykowski, A.; Pucko, W. Cine substitution in reaction of unactivated

2-halopyridines with 2-aminopyridine 1-oxide formation of

3-(2-pyridylamino)-2(1 H )-pyridone. Polish J. Chem. 1998 , 72, 2378 – 2383.

Woli ń ska, E.; Pucko, W. Diversity of reactions of isomeric

aminopyridine N- oxides with chloronitropyridines: an

experimental and theoretical study. J. Heterocycl. Chem. 2012

(in press).

Brought to you by | Brown University Rockefeller LibraryAuthenticated | 128.148.252.35

Download Date | 2/21/13 4:43 PM