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LETTER18161816

letterSynthesis of 3-Substituted 2-Aminopyridines via Displacement of 3-Fluoro-2-

nitropyridineSynthesis of 3-Substituted 2-AminopyridinesJanet D. Culshaw, Jonathan M. Eden,* Susannah J. Ford, Barry Hayter, David R. Perkins,* Kurt G. Pike

Oncology iMed, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UKE-mail: [email protected]; E-mail: [email protected]

Received: 06.03.2012; Accepted after revision: 01.05.2012

Abstract: An efficient method for the substitution of 3-fluoro-2-ni-tropyridine with a range of nitrogen-containing heterocycles and al-iphatic amines is described. The reaction proceeds in aregioselective manner at moderate temperature and in reasonableyield.

Key words: nitrogen-containing heterocycles, 3-fluoro-2-nitropyr-idine, 3-substituted 2-aminopyridines, aliphatic amines

2-Aminopyridines have been used widely in the prepara-tion of secondary amines,1,2 amides,3,4 cross-couplingproducts,5 1,4-conjugate addition products,6,7 imidazopyr-idines,812 sulfonamides,13,14 thioureas,15 and ureas.1618

However, more fully functionalized 2-aminopyridinesalso have synthetic utility. For example, the ALK inhibi-tor Crizotinib launched in 2011 by Pfizer for the treatmentof non-small cell lung cancer contains a 3-alkoxy-5-pyr-azolopyridin-2-amine and Nevirapine, a reverse transcrip-tase inhibitor for the treatment of HIV, contains a 2,3-diaminopyridine motif (Figure 1).

Figure 1

As part of our studies towards the synthesis of pharmaceu-tically active compounds we were interested in utilizing awide range of 2-aminopyridines with an additional 3-ami-

no substituent, and, in particular, compounds with a nitro-gen heterocycle in the 3-position. A few examples ofsimple 2,3-diaminopyridines were commercially avail-able such asN3-methyl pyridine-2,3-diamine and 3-mor-pholinopyridin-2-amine but these were relativelyexpensive and/or only available in small quantities. Fur-thermore, the latter was the only example of a compoundwith a nitrogen-containing heterocycle in the 3-position.

In fact, there are surprisingly few examples of these syn-thetically useful compounds reported in the literature, orthe corresponding 3-amino-2-nitropyridines from which itwas envisaged the required diamines could be accessed.Yao et al. reported that treatment of 3-chloro-2-nitropyri-dine or 3-bromo-2-nitropyridine with piperidine yielded2-nitro-3-piperidylpyridine in poor yield due to nonselec-tive displacement of both the chloro and the nitro groupand nitro group migration (Scheme 1).19 Azev et al. re-ported similar results using morpholine.20

Due to the increased electronegativity of fluorine com-pared to chlorine and bromine we reasoned that reaction

with commercially available 3-fluoro-2-nitropyridinewould favour SNAr displacement of the fluorine, leadingto increased selectivity. Herein we describe a facile syn-thesis of 2,3-diaminopyridines from readily available andcheap starting materials which proceeds in high selectivi-ty to give novel 3-substituted 2-aminopyridines.

Initial trial reactions showed that reaction of 3-fluoro-2-nitropyridine with an excess of morpholine furnished therequired 4-(2-nitro-3-pyridyl)morpholine in 96% yieldeven at room temperature (2a, Table 1, entry 1). In orderto reduce the requirement for excess amine the reactionswere also trialed in acetonitrile with three equivalents of

potassium carbonate to neutralise the hydrogen fluorideformed in the reaction. At 50 C excellent conversions

Crizotinib Nevirapine

NH2N

O

Cl

Cl

F

N

N

NH

N

HN

N

O

N

Scheme 1

N NO2

X

N

X

N N

NO2

N

N NO2

N

+ +

1a X = Cl1b X = Br

HN

+

2a (58%)2b (19%)

3a (18%)3b (14%)

4a (24%)4b (17%)

SYNLETT2012, 23, 18161820Advanced online publication: 21.06.2012093 6- 5 214 143 7- 20 96DOI: 10.1055/s-0031-1290397; Art ID: ST-2012-D0203-L

Georg Thieme Verlag Stuttgart New York

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LETTER Synthesis of 3-Substituted 2-Aminopyridines 1817

Georg Thieme Verlag Stuttgart New York Synlett2012, 23, 18161820

were observed with only 1.05 equivalents of butylamineand pyrrolidine (2b,c, Table 1, entries 2 and 3). None ofthe product formed by displacement of the nitro group

was isolated. The required 2,3-diaminopyridines were ob-tained in good yield by reduction of the nitro group usingstandard hydrogenation conditions (Table 1).

This method21 was subsequently applied to a wide rangeof pyrazole, imidazole, and benzimidazole nucleophilesfurnishing the 3-amino-2-nitropyridines in yields rangingfrom 4584% (Table 2). For those heterocycles contain-ing a halogen substituent, iron/ammonium chloride was

chosen as the preferred reducing agent to furnish the di-aminopyridines (Table 2, entry 1).

Table 1 Synthesis of Compounds 2ac and 3ac

Entry Substrate Methoda NO2 pyridine product Yield (%) NH2 pyridine product Yield (%)

1 A 96 100

2 B 99 93

3 B 97 100

a Method A: 3-fluoro-2-nitropyridine (1.0 equiv), morpholine (2.5 equiv), r.t.; Method B: 3-fluoro-2-nitropyridine (1.0 equiv), amine (1.05equiv), K2CO3 (3.0 equiv), MeCN, 50 C, 18 h.

+

1ac 2ac 3ac

methodA or B

N NO2

F

R1

NR2

N NH2

H2, Pd/C, EtOAc

NR2R1

H

R1

NR2

N NO2

O

HN

N NO2

N

O

N

N

O

NH2

NH2

N NO2

N

N NH2

N

HN

N NO2

N

N

N

NH2

Table 2 Synthesis of Compounds 2dj and 3dj

Entry Substrate NO2 pyridine product Yield (%) Methoda NH2 pyridine product Yield (%)

1 57 B 60

2 54 A 82

3 76 A 91

+

1dj 2dj 3dj

N

HETK2CO3

MeCN

reduction

methodA or BN NO2

F N

N NO2

HET

N

N NH2

HET

50 C

N

HNCl

N

N

N NO2

ClN

N

N NH2

Cl

N

HN

N

N

N NO2

N

N

N NH2

N

HN

N

N

N NH2

N

N

N NH2



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1818 J. D. Culshaw et al. LETTER

Synlett2012, 23, 18161820 Georg Thieme Verlag Stuttgart New York

Given the success of these reactions we expanded the

scope of nucleophiles to include more functionalised het-erocycles where regioisomeric products could be formed,for example 3-methyl-1H-pyrazole (Table 3, entry 1). Theexact regioisomer was determined by NOE experiments.In this example an NOE was observed between the pyri-dine hydrogen and the pyrazole hydrogen (and not themethyl group) indicating that the product formed was iso-mer1 (Figure 2).

Other functionalised triazoles and imidazoles gave simi-larly good yields of the 3-substituted-2-nitropyridines andthe corresponding amines (Table 3). The exact structureswere confirmed by 1H NMR studies and/or NOE experi-

ments, further details of which can be found in the Sup-porting Information. In all but one example only oneregioisomer was isolated from the reaction. However, asmight be expected, reaction with 1,2,3-triazole affordedthe two isomers 2p and 2q in an approximately 4:1 ratio.

Figure 2

In conclusion, we have developed a robust synthesis ofnovel 3-substituted-2-aminopyridines from commerciallyavailable 3-fluoro-2-nitropyridine. Our initial success

with morpholine encouraged us to try other aliphaticamines and subsequently a range of simple heterocyclicnitrogen nucleophiles. The resulting nitropyridine inter-mediates were reduced to the desired 2,3-diamino pyri-dines either by standard hydrogenation conditions oriron/ammonium chloride reduction. Following the suc-cess with these nucleophiles we expanded the scope to in-clude more functionalised heterocycles. In all cases thereactions furnished the substituted nitropyridines in mod-erate to good yields and no evidence was seen of the prod-ucts formed by displacement of the nitro group as reportedby Yao19 for similar reactions with 3-chloro- or 3-bromo-2-nitropyridine.

4 65 A 100

5 77 A 85

6 45 A 77

7 84 A 50

a Method A: 10% Pd/C, H2, EtOH, r.t.; Method B: Fe, NH4Cl, EtOH, H2O, 80 C.

Table 2 Synthesis of Compounds 2dj and 3dj (continued)


+

1dj 2dj 3dj

N

HETK2CO3

MeCN

reduction

methodA or BN NO2

F N

N NO2

HET

N

N NH2

HET

50 C

N

HN

N

N

N NO2

N

N

N NH2

N

HN

N NO2

N

N

N

N

N NH2

N

HN N

N

N NO2

NN

N NH2

NHN

NN

N NO2

NN

N NH2

NN

N NO2

HH

NN

N NO2

H

3kisomer 1 3kisomer 2



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LETTER Synthesis of 3-Substituted 2-Aminopyridines 1819

Georg Thieme Verlag Stuttgart New York Synlett2012, 23, 18161820

Acknowledgement

The authors would like to thank Sarah Kate Cantlie and HowardBeeley for NMR Spectroscopy, Madeleine Vickers and Paul Daveyfor mass spectrometry and Professor Joe Sweeney, Tom McGuire,and Chris De Savi for their contribution to the writing of this paper.

Supporting Information for this article is available online athttp://www.thieme-connect.com/ejournals/toc/synlett. SupportingInformationSupportingInformation

References and Notes

(1) Singh, O. M.; Singh, S. J.; Kim, S. N.; Lee, S. Bull. KoreanChem. Soc.2007, 28, 115.

(2) Inglis, S. R.; Jones, R. K.; Booker, G. W.; Pyke, S. M.Bioorg. Med. Chem. Lett.2006, 16, 387.

(3) Mathes, B. M.; Hudziak, K. J.; Schaus, J. M.; Xu, Y.;Nelson, D. L.; Wainscott, D. B.; Nutter, S. E.; Gough, W. H.;Branchek, T. A.; Zgombick, J. M.; Filla, S. A. Bioorg. Med.Chem. Lett.2004, 14, 167.

(4) Richards, M. L.; Lio, S. C.; Sinha, A.; Banie, H.; Thomas,R. J.; Major, M.; Tanji, M.; Sircar, J. C. Eur. J. Med. Chem.2006, 41, 950.

Table 3 Synthesis of Compounds 2fq and 3kq


1 82 A 81

2 53 B 59

3 62 A 88

4 89 A 99

5 52 A 94

6 36 A 100

7 11 A 100

a Method A: 10% Pd/C, H2, EtOH, r.t.; Method B: Fe, NH4Cl, EtOH, H2O, 80 C.

+

1kq 2kq 3kq

HN

HET

K2CO3

MeCN

reduction

methodA or BN NO2

F N

N NO2

HET N

N NH2

HET

50 C

NHN

N

N

N NO2

N

N

N NH2

N

N

HN

Cl

NN

N

N NO2

Cl

N

N

N

N NH2

Cl

N

HN

CF3

NN

N NO2

CF3

NN

N NH2

CF3

N

N

HN

NN

N

N NO2

NN

N

N NH2

NN

HN

NN

N

N NO2

NN

N

N NH2

N

N

HNN

N

N

N NO2

N

N

N

N NH2

N

N

HN

N N

N

N NO2

NN N

N NH2



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1820 J. D. Culshaw et al. LETTER

Synlett2012, 23, 18161820 Georg Thieme Verlag Stuttgart New York

(5) Huang, K. S.; Haddadin, M. J.; Kurth, M. J. J. Org. Chem.2002, 67, 2382.

(6) Ravina, I.; Zicane, D.; Petrova, M.; Gudriniece, E.; Kalejs,U. Chem. Heterocycl. Compd.2002, 38, 836.

(7) Cocco, M. T.; Congiu, C.; Onnis, V. Chem. Pharm. Bull.2001, 49, 703.

(8) Gueiffier, A.; Viols, H.; Blache, Y.; Chapat, J. P.;Chavignon, O.; Teulade, J. C.; Fauvelle, F.; Grassy, G.;Dauphin, G. J. Heterocycl. Chem.1997, 34, 765.

(9) Yamamoto, H.; Matsuura, M.; Ikeda, H.; Kubota, M.;Kawamura, M. EP 158516A1, 2005.

(10) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.;Mouaddib, A.; Guillaumet, G. J. Org. Chem.2007, 72, 7650.

(11) Almario-Garcia, A.; Lardeenois, P.; Olivier, A. US2009/0253735A1, 2009.

(12) Wu, Z.; Fraley, M. E.; Bilodeau, M. T.; Kaufman, M. L.;Tasber, E. S.; Balitza, A. E.; Hartman, G. D.; Coll, K. E.;Rickert, K.; Shipman, J.; Shi, B.; Sepp-Lorenzino, L.;Thomas, K. A. Bioorg. Med. Chem. Lett.2004, 14, 909.

(13) Dubey, P. K.; Kumar, R. V. Indian J. Chem., Sect. B: Org.Chem. Incl. Med. Chem.2000, 39, 746.

(14) Sharma, A. K.; Das, S. K. Synth. Commun.2004, 34, 3807.(15) Sarkis, G. Y.; Faisal, E. D. J. Heterocycl. Chem.1985, 22,

137.(16) Andrews, K.; Booker, S.; Cee, V. J.; DAngelo, N.;

Herberich, B. J.; Hong, F.; Jackson, C. L. M.; Lanman, B.;Liao, H.; Liu, L.; Nishimura, N.; Norman, M. H.; Pettus, L.H.; Reed, A. B.; Smith, A. L.; Tadesse, S.; Tamayo, N. A.;Wu, B.; Wurz, R. WO 2010/126895A1, 2010.

(17) Blankley, C. J.; Doherty, A. M.; Hamby, J. M.; Panek, R. L.;Schroeder, M. C.; Showalter, H. D. H.; Connolly, C.US 5733913A1, 1998.

(18) Balicki, R.; Kaczmarek, L.; Sobotka, W. J. Prakt. Chem.1989, 331, 995.

(19) Yao, J.; Blake, P. R.; Yang, J. Heterocycles2005, 65, 2071.(20) Azev, Y. A.; Mokrushina, G. A.; Postovskii, I. Y. Chem.

Heterocycl. Compd.1974, 10, 687.(21) Typical Procedure for the Preparation of Nitropyridines

Illustrated for Table 2, entry 1: K2CO3 (5.15 g, 37.23 mmol)was added in one portion to 3-fluoro-2-nitropyridine (2.65 g,18.62 mmol) and 4-chloro-1H-pyrazole (2.00 g, 19.55mmol) in MeCN (50 mL), and the resulting mixture wasstirred at 50 C for 5 h. The cooled reaction mixture wasdiluted with H2O (100 mL) and extracted with EtOAc

(2 50 mL). The combined extracts were washed with brine(100 mL), dried (MgSO4), filtered, and evaporated. Thecrude product was purified by flash silica chromatography,elution gradient 30% to 60% CH2Cl2 in heptane. Purefractions were evaporated to dryness to afford 3-(4-chloro-1H-pyrazol-1-yl)-2-nitropyridine (2.40 g, 57%) as a solid;mp 113114 C. 1H NMR (400 MHz, CDCl3): = 8.54 (1 H,dd,J= 4.6, 1.5 Hz), 8.07 (1 H, dd,J= 8.1, 1.5 Hz), 7.75 (1H, s), 7.697.73 (2 H, m). 13C NMR (101 MHz, CDCl3): =

114.28, 127.41, 128.00, 128.21, 134.85, 141.77, 147.32,189.75. HRMS (ES): m/zcalcd for (C8H5N4O2Cl)

+:224.0101; found: 224.0103.Typical Procedure for the Reduction of Nitropyridines

Using Method A

A suspension of the nitropyridine (2.06 mmol) and 10%Pd/C (0.03 mmol) in EtOH (20 mL)EtOAc (3 mL) wasstirred under an atmosphere of hydrogen at ambienttemperature for 16 h. The reaction mixture was filteredthrough Celite, evaporated and the crude gum triturated withEt2Oheptane to give a solid, which was collected byfiltration and dried under vacuum to give the aminopyridine.Typical Procedure for the Reduction of Nitropyridines

Using Method B

Illustrated for Table 2, entry 1: NH4

Cl (2.70 g, 50.53 mmol)was added to 3-(4-chloro-1H-pyrazol-1-yl)-2-nitropyridine(2.27 g, 10.11 mmol) and iron (3.61 g, 64.64 mmol) in EtOH(30 mL) and H2O (5 mL), and the resulting mixture wasstirred at 80 C for 3 h. The solvent was evaporated, and thecrude product was slurried with MeOH and filtered througha Whatman No. 3 filter paper before purification by ion-exchange chromatography, using an SCX 2 column. Thedesired product was eluted from the column using 2 M NH3MeOH, and pure fractions were evaporated to dryness toafford crude product. The product was dissolved in CH 2Cl2and washed with H2O (2). The organic layer was dried overMg2SO4, filtered, and evaporated to afford 3-(4-chloro-1H-pyrazol-1-yl)pyridin-2-amine (1.17 g, 59%) as a solid; mp134135.6 C. 1H NMR (400 MHz, DMSO): = 8.44 (1 H,

s), 8.03 (1 H, dd,J= 4.8, 1.6 Hz), 7.89 (1 H, s), 7.62 (1 H,dd,J= 7.7, 1.6 Hz), 6.70 (1 H, dd,J= 7.7, 4.8 Hz), 6.32 (2H, s). 13C NMR (101 MHz, DMSO, 30 C): = 110.07,112.24, 120.09, 128.98, 131.43, 138.69, 147.44, 152.81.HRMS (ES): m/zcalcd for [C8H8N4Cl]

+: 195.0432; found:195.0431.



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