Highly regioselective Buchwald-Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries

Article abstract of DOI:10.1016/j.tetlet.2013.10.035

The highly regioselective Buchwald-Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides facile access to 4-chl

Full text of DOI:10.1016/j.tetlet.2013.10.035

Accepted Manuscript
Highly regioselective Buchwald-Hartwig amination at C-2 of 2,4-dichloropyr-
idine enabling a novel approach to 2,4-bisanilinopyridine (BAPyd) libraries
Rebecca J. Burton, Mandy L. Crowther, Neal M. Fazakerley, Shaun M. Fillery,
Barry M. Hayter, Jason G. Kettle, Caroline A. McMillan, Paula Perkins, Peter
Robins, Peter M. Smith, Emma J. Williams, Gail L. Wrigley
PII:
S0040-4039(13)01770-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.10.035
TETL 43673
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 July 2013
10 September 2013
8 October 2013
Please cite this article as: Burton, R.J., Crowther, M.L., Fazakerley, N.M., Fillery, S.M., Hayter, B.M., Kettle, J.G.,
McMillan, C.A., Perkins, P., Robins, P., Smith, P.M., Williams, E.J., Wrigley, G.L., Highly regioselective
Buchwald-Hartwig amination at C-2 of 2,4-dichloropyridine enabling a novel approach to 2,4-bisanilinopyridine
(BAPyd) libraries, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.10.035
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Highly regioselective Buchwald-Hartwig amination at
C-2 of 2,4-dichloropyridine enabling a novel approach
to 2,4-bisanilinopyridine (BAPyds) libraries
Leave this area blank for abstract info.
Rebecca J. Burton, Mandy L. Crowther, Neal M. Fazakerley, Shaun M. Fillery, Barry M. Hayter, Jason G. Kettle, Caroline
A. McMillan, Paula Perkins, Peter Robins, Peter M. Smith, Emma J. Williams,* Gail L. Wrigley
R1
Cl
Library production
"Pd"
Regioselective
"Pd"
Cl
4
HN
4
2
2
Ar, Het
Ar, Het
N
N
Fix C-2 Amine
Explore C-4
Chemical space
N
Cl
N
N
H
H
1
3
5

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Highly regioselective Buchwald-Hartwig amination at C-2 of 2,4-
dichloropyridine enabling a novel approach to 2,4-
bisanilinopyridine (BAPyd) libraries
Rebecca J. Burton, Mandy L. Crowther, Neal M. Fazakerley, Shaun M. Fillery, Barry M.
Hayter, Jason G. Kettle, Caroline A. McMillan, Paula Perkins, Peter Robins, Peter M.
Smith, Emma J. Williams,* Gail L. Wrigley
AstraZeneca Oncology iMed, Alderley Park, Cheshire SK10 4TG, U.K.
Abstract - The highly regioselective Buchwald-Hartwig amination at C-2 of the cheap and readily accessible reagent, 2,4-dichloropyridine
with a range of anilines and heterocyclic amines is described. This new methodology is robust and provides facile access to 4-chloro-N-
phenylpyridin-2-amines on 0.25 mol scale. These intermediates undergo a further Buchwald-Hartwig amination at higher temperature to
enable rapid exploration of the chemical space at C-4 and to provide a library of 2,4-bisaminopyridines. © 2013 Elsevier Science. All
rights reserved
Following on from our investigations into the structure-activity relationship (SAR) around a series of 2,4-
bisanilinopyrimidines (BAPs),1 we decided to specifically target an expansion of chemical diversity at the C-4 position of
2,4-bisanilinopyridines (BAPyds) 5. We postulated that two approaches to BAPyds 4 and 5 were possible from the cheap and
readily accessible reagent 2,4-dichloropyridine (1)2 (Scheme 1). Method A would allow specific C-4 amines of interest to be
introduced first and a subsequent expansion of chemical space at C-2. However, method B was of most interest to us as it
would allow introduction of specific C-2 amines first and therefore provide the most efficient and flexible intermediates, 4-
chloro-N-arylpyridin-2-amines 3 to explore C-4 chemical space in a library production.
Ar, Het
Ar, Het
HN
HN
Library production
Method A
4
R1
2
N
N
H
Explore C-2
Chemical space
N
Cl
Fix C-4 Amine
Cl
4
4
2
2
R1
N
Cl
Cl
1
HN
Library production
4
Method B
2
Ar, Het
Ar, Het
N
N
H
Explore C-4
Chemical space
N
N
H
Fix C-2 Amine
3
5
Scheme 1. Strategy for regioselective substitution of 2,4-dichloropyridine and subsequent synthesis of 2,4-bisanilinopyridines
Many procedures are exemplified for method A in the literature using 2,4-dichloropyridine directly to generate 2-chloro-N-
phenylpyridin-4-amines 2 using neutral,3 basic4 and acidic5 methods. A complimentary procedure utilizing Buchwald-
Hartwig6,7 methodology on more expensive mixed halogen substrates, e.g 2-fluoro-4-iodopyridine8 and 2-chloro-4-
bromopyridine9 guarantees either 2-fluoro-N-phenylpyridin-4-amines or 2-chloro-N-phenylpyridin-4-amines can also be
made, and subsequently used to expand the chemical space at C-2 and synthesise 2,4-bisanilinopyridines (BAPyds) 4.
However, a general procedure (method B) for the synthesis of a diverse set of 4-chloro-N-arylpyridin-2-amines 3 directly
from 2,4-dichloropyridine has not been reported (Scheme 1). The literature has detailed various alternative methods;
*Emma Williams. Tel.: +44 (0) 1625 233246; e-mail:emma.williams@astrazeneca.com
Keywords: Buchwald-Hartwig amination, regioselective substitution, 2-chloro-N-phenylpyridin-4-amines, 4-chloro-N-phenylpyridin-2-amines

2
Tetrahedron Letters
additional substitution on the pyridine ring, e.g., trimethylsilyl groups to block C-4 substitution,10 electron-withdrawing
groups para to C-2 and aniline protecting group strategies, e.g., N-arylacetamides11 to enhance the C-2 regioselectivity and
more expensive, mixed halogenated pyridines.12 However, the disadvantage of these is the requirement for extra synthetic
steps or the use of more expensive, less accessible starting materials compared to 2,4-dichloropyridine. More recently,
Schnüch et al. highlighted that direct amination of 2,4-dichloropyridine with p-anisidine using palladium was possible but
gave an equimolar ratio of regioisomers in less than 10% yield when subjected to a relatively high temperature of 180 °C in a
microwave reactor.8 Miyata et al. also provide one example of the direct amination of 2,4-dichloropyridine with aniline in
19% yield, but with no evidence provided of regioselectivity.13 Focused studies on the coupling of substituted 2-amino-1,3-
oxazoles with chloroheterocycles by Noonan et al. showed that 2,4-dichloropyridine could be displaced regioselectively at C-
2 using palladium, and that the results could be optimised through the use of electron-rich and electron-poor substituents on
the oxazole.14 However, to date, there is no general procedure described for C-2 substitution of 2,4-dichloropyridine with
commonly used aryl and heterocyclic amines. Based on these observations, and recognising the gap, we felt compelled to
disclose our own work in this area. We have successfully utilised Buchwald-Hartwig methodology directly on cheap and
readily accessible 2,4-dichloropyridine utilising simple, unprotected anilines and heterocyclic amines to provide a highly
regioselective synthesis of 4-chloro-N-phenylpyridin-2-amines 3. Herein, we report our findings in synthesising key
intermediates 3 and the utilization of these to expand the chemical space at C-4 directly and deliver a library of 2,4-
bisaminopyridines 5.
The synthesis of 2-chloro-N-phenylpyridin-4-amines 2 (Scheme 2) was attained using conditions A. Subsequent isolation and
1
structural analysis confirmed regioisomers, with H NMR (nOe) being employed to determine that indeed the 4-regioisomer
was the major product. Investigations into the syntheses of 4-chloro-N-phenylpyridin-2-amines, 3 were first carried out using
conditions B. Gratifyingly, the crude reaction profile on LCMS showed the C-2 regioisomers were formed almost
exclusively, in >95:5 ratio, as initially confirmed by comparing with the crude reaction LCMS profiles for the C-4
regioisomers. Typically, the C-4 regioisomer eluted around 0.5 minutes later than its C-2 counterpart. Subsequent isolation
allowed structural confirmation of the C-2 regioisomers by 1H NMR (nOe). The preferential substitution at C-2 is assumed to
be as a result of the neighbouring pyridine nitrogen stabilising the developing radical during oxidative addition of
palladium.15 It is noteworthy that product ratios were not affected by the nature of the substituent on the anilines, i.e., by
electron-withdrawing or -donating groups. There was no obvious trend identified at this stage to explain some of the observed
modest yields other than these were initial unoptimised results (Table 1).
R1
Cl
Cl
HN
(Het)Ar-NH2
Conditions B
(Het)Ar-NH2
Conditions A
R1
N
N
H
N
Cl
N
Cl
3a-g
1
2a-g
Scheme 2. Regioselective synthesis of either 2-chloro-N-phenylpyridin-4-amines 2 or 4-chloro-N-phenylpyridin-2-amines 3. Conditions A: NaH (60%
dispersion in mineral oil), 1:1 ratio of heterocyclic amine or aniline:2,4-dichloropyridine, DMA, 22 °C, 24 h; Conditions B: Pd(OAc)2, Cs2CO3, Xantphos,
1:1 ratio of heterocyclic amine or aniline:2,4-dichloropyridine, 1,4-dioxane, 30 min, 100 °C, microwave.
Table 1. Summary of 2- / 4- regioselectivity in reactions of anilines with 2,4-dichloropyridine under either Buchwald-Hartwig or NaH/DMA conditions
Conditions A
Conditions B
Entry
1
(Het)Ar-NH2
Product
Ratioa 2:3
Yieldb (%)
36
Product
Ratioa 2:3
Yieldb (%)
23
NH2
85:15
90:10
90:10
85:15
5:95
2:98
5:95
5:95
2a
3a
MeO
NH2
NH2
NH2
2
3
4
39
45
43
64
37
64
2b
2c
2d
3b
3c
3d
Me
Cl

Tetrahedron Letters
3
NH2
5
6
7
85:15
85:15
85:15
65
83
51
3:97
2:98
2:98
44
37
47
2e
2f
3e
3f
OMe
NH2
MeO
N
NH2
2g
3g
a Product ratios taken from LCMS of crude reaction mixtures prior to work-up
b Isolated yield after reverse phase HPLC on Phenomenex Gemini 5  silica, C18 30 mm diameter, 100 mm length using decreasingly polar mixtures of H2O
(containing 0.5% NH3) and MeCN as eluents.
Recognising the potential of this early success, we subsequently discovered the methodology could be transferred to more
diverse anilines and some six-membered aminoheterocycles. However, the reaction was less successful with electron-
deficient five-membered aminoheterocycles, e.g., 1,3-thiazol-2-amine and 1,3-oxazol-2-amine. Lower reaction temperatures
tended to give cleaner results by crude LCMS, and higher yields for those anilines that contained electron-donating groups
(Scheme 3, Table 2). The chemistry was subsequently scaled up to 0.25 mol to provide many of the intermediates listed
(Table 2) on 20-30 gram scale. This demonstrates how effective and robust this chemistry is to execute.
Cl
Cl
"Pd"
Ar(Het)
Ar(Het)
N
N
N
Cl
H2N
H
3h-t
1
Scheme 3. Further expansion of the regioselective synthesis of 4-chloro-N-phenylpyridin-2-amines 3 with anilines and amino heterocycles
Table 2. Expansion of the Buchwald-Hartwig methodology to reactions of more diverse substrates with 2,4-dichloropyridine
Entry
1
Product
Temp (°C)
80
Time (h)
16
(Het)Ar-NH2
Yield (%)a,b
68a
MeO
NH2
3h
MeO
OMe
NH2
2
3
4
50
100
50
4
83a
48a
59b
3i
3j
OMe
OMe
NH2
O2N
1.5
21
N
NH2
3k

4
Tetrahedron Letters
O
57b
63b
73b
24c
30e
40d
58e
62d
56d
N
NH2
5
6
50
50
21
3l
3m
3n
3o
3p
3q
3r
3s
Me
N
N
NH2
21
N
N
NH2
7
100
100
80
2
NH2
8
6
N
N
NH2
9
18
48
18
18
18
N
O
NH2
10
11
12
13
100
80
F
OMe
NH2
Me
S
O
O
O
80
NH2
N
O
Me2N
80
3t
NH2
a Isolated yield after reverse phase HPLC on Phenomenex Gemini 5  silica, C18 30 mm diameter, 100 mm length using decreasingly polar mixtures of H2O
(containing 0.5% NH3) and MeCN as eluents.
b
Isolated yield after flash silica chromatography, eluting gradient 0-50% EtOAc/iHex
Crude reaction yield from LCMS of reaction mixtures prior to work-up
c
d Purified by trituration of the crude material using IPA
e Purified by trituration of the crude material using CH2Cl2:Et2O (1:1)
Previous diversification of the pyridine core, in our hands, had been limited to variations at C-2 once the C-4 aniline had been
set through the SNAr reaction. We recognized there was a real opportunity for us to exploit the new methodology by
introducing a C-2 substituent first through the described Buchwald-Hartwig protocol and then diversify the C-4 position

Tetrahedron Letters
5
using a further higher temperature coupling protocol to generate new libraries from the less activated 4-chloro-N-
phenylpyridin-2-amine intermediates 3 (Scheme 4). This second coupling reaction was optimized (150 °C for 1 h) to provide
a practically simple, robust, high throughput reaction process. Key to the successful outcome was the use of polymer-
supported MP-TMT (2,4,6-trimercaptotriazine) resin16 to scavenge palladium from the reaction mixture. This resin is a highly
cross-linked macroporous polystyrene and was effective in our DMA:water reaction solvent at removing residual palladium,
which was thought to be causing rapid deterioration and blockages within the reverse phase columns used for our trial
reactions. Consequently, we believe we saved in the region of £64000 on column expenditure through direct application of
this resin technology. Altogether >4000 reactions were purified by reverse phase preparative HPLC resulting in ~3000
isolated compounds (Figure 1).
R2
Cl
HN
~ 400 x H2NR2
Conditions C
R1
R1
N
N
N
N
H
H
3
5
~17 intermediates
~3000 compounds
Scheme 4. Use of Buchwald-Hartwig methodology to deliver 2,4-bisaminopyridines. Conditions C: Pd(OAc)2, Xantphos, Cs2CO3, H2NR2, DMA:H2O, 150
°C, 1 h, then MP-TMT resin, DMA:H2O, 22 °C, 18 h
600
2500
2000
400
200
Count
Count
1500
1000
500
50
60
70
80
90
100
0
10 20 30 40 50 60 70 80
Isolated Wt (mg)
Purity (%)
Figure 1 Graphical representations summarising the purity and weight of the compounds isolated: The purity was high with 72% of samples showing 100%
purity by LC with a UV-Vis detector. The isolated weight of samples registered into the AstraZeneca compound database showed 50% >20 mg, 80% >10
mg.
In conclusion, we have described a highly selective approach to the regioselective substitution of cheap and readily
accessible 2,4-dichloropyridine with anilines and heterocyclic amines using Buchwald-Hartwig methodology to provide
almost exclusively 2-amino-4-chloropyridines. We believe the preferential substitution at C-2 is as a result of the
neighbouring pyridine nitrogen stabilising the developing radical during oxidative addition of palladium. Subsequently, we
have demonstrated that these intermediates can be diversified rapidly at C-4 by introduction of other anilines and heterocyclic
amines using a robust practical procedure at a higher temperature to afford libraries of 2,4-bisaminopyridines.
Acknowledgements
We would like to acknowledge Mr. Howard Beeley, Mr. Paul Davey, Mr. Scott Boyd and Mr. David Whittaker for their
analytical support.
Supplementary Data
1
Full experimental procedures and supporting LCMS, H, 13C, nOe and HRMS characterisation data are available via the on
line version. Included are representative examples from the library production run.
References and notes
1. (a) Bardelle, C.; Coleman, T.; Cross, D.; Davenport, S.; Kettle, J. G.; Ko, E. J.; Leach, A. G.; Mortlock, A.; Read, J.; Roberts, N. J.; Robins, P.;
Williams, E. J. Bioorg. Med. Chem. Lett. 2008, 18, 2776-2780. (b) Bardelle, C.; Coleman, T.; Cross, D.; Davenport, S.; Kettle, J. G.; Ko, E. J.;
Leach, A. G.; Mortlock, A.; Read, J.; Roberts, N. J.; Robins, P.; Williams, E. J.; Bioorg. Med. Chem. Lett. 2008, 18, 5717-5721.
2. 2,4-Dichloropyridine (£2.32/g), 2-fluoro-4-iodopyridine (£102/g), 2-chloro-4-iodopyridine (£8.80/g), 4-bromo-2-fluoropyridine (£42/g), 4-
bromo-2-chloropyridine (£4.80/g), 4-chloro-2-iodopyridine ($2000/g), 2-bromo-4-chloropyridine (price on request), 2-bromo-4-fluoropyridine
($119/g), 2-chloro-4-fluoropyridine (£3.40/g). Prices sourced April 2013 from available ACD suppliers.

6
Tetrahedron Letters
3. (a) Barlaam, B. C.; Ducray, R.; PCT Int. Appl. 2009, WO2009010794; Chem. Abstr. 2009, 150, 168380. (b) Rodgers, J. D.; Wang, H.; PCT Int.
Appl. 2004, WO2004002410; Chem. Abstr. 2004, 140, 77032.
4. Pfister, K. B.; Wagman, A. S.; Ng, S.; Sendzik, M.; Sutton, J.; Wiesmann, M. PCT Int. Appl. 2008, WO2008144062; Chem. Abstr. 2008, 150,
5723.
5. Wanker, E.; Wiglenda, T.; Babila, J. T.; Bödrich, A.; Schmidt, M.; Neuendorf, S.; Schiele, F. PCT Int. Appl. 2011, WO2011020883; Chem.
Abstr. 2011, 154, 283979.
6. Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 1995, 34, 1348.
7. Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
8. Koley, M.; Schnüch, M.; Mihovilovic, M.D. Tetrahedron 2011, 67, 4169-4178
9. (a) Jianguo, J.; Tao, L.; Bunnelle,W. H. Org. Lett. 2003, 5, 4611-4614 (b) Vidal, J. B.; Fernandez, C. J. Eur. Pat Appl. 2012, EP2489663; Chem.
Abstr. 2012, 157, 410308. (c) Qin, L.; Cui, H.; Zou, D.; Li, J.; Wu, Y.; Zhu, Z.; Wu, J. Tetrahedron Lett. 2010, 51, 4445-4448
10. Schlosser, M.; Bobbio, C.; Rausis, T. J. Org. Chem. 2005, 70, 2494-2502
11. (a) Delvare, C.; Koza, P.; Morgentin, R. Synthesis 2011, 2431-2436. (b) Barlaam, B.; Foote, K.; Hassall, L.; Hawkins, J.; Jones, C. D.; Le
Griffon, A.; Morgentin, R.; Peru, A.; Plé, P. Synth. Commun. 2012, 42, 8-24
12. Koley, M.; Schnüch, M.;, Mihovilovic, M.D. Synlett 2010, 1505-1510
13. Suzuki, T.; Igari, S.; Hirasawa, A.; Hata, M.; Ishiguro, M.; Fujieda, H.; Itoh, Y.; Hirano, T.; Nakagawa, H.; Ogura, M.; Makishima, M.;
Tsujimoto, G.; Miyata, N. J. Med. Chem. 2008, 51, 7640-7644
14. Noonan, G.; Dishington, A.P.; Pink, J.; Campbell, A.D. Tetrahedron Lett. 2012, 53, 3038-3043.
15. Garcia, Y.; Schoenebeck, F.; Legault, C. Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2009, 131, 6632-6639
16. (a) Welsh, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.; Da Silva, J.; Henderson, D. W.; Laing, B.; Mathre, D. J.; Spencer, S.; Bu, X.;
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Table 1. Summary of 2- / 4- regioselectivity in reactions of anilines with 2,4-dichloropyridine under either Buchwald-Hartwig or NaH/DMA conditions
Conditions A
Conditions B
Entry
1
(Het)Ar-NH2
Product
Ratioa 2:3
Yieldb (%)
36
Product
Ratioa 2:3
Yieldb (%)
23
NH2
85:15
90:10
90:10
85:15
85:15
85:15
85:15
5:95
2:98
5:95
5:95
3:97
2:98
2:98
2a
3a
MeO
NH2
NH2
NH2
2
3
4
5
6
7
39
45
43
65
83
51
64
37
64
44
37
47
2b
2c
2d
2e
2f
3b
3c
3d
3e
3f
Me
Cl
NH2
OMe
NH2
MeO
N
NH2
2g
3g
a Product ratios taken from LCMS of crude reaction mixtures prior to work-up
b Isolated yield after reverse phase HPLC on Phenomenex Gemini 5  silica, C18 30 mm diameter, 100 mm length using decreasingly polar mixtures of H2O (containing
0.5% NH3) and MeCN as eluents.
Table 2. Expansion of Buchwald-Hartwig methodology to reactions of more diverse substrates with 2,4-dichloropyridine
Entry
8
Product
Temp (°C)
80
Time (h)
16
(Het)Ar-NH2
Yield (%)a,b
68a
MeO
NH2
3h
MeO
OMe
NH2
9
50
100
50
4
83a
48a
59b
57b
3i
3j
3k
3l
OMe
OMe
NH2
O2N
10
11
12
1.5
21
21
N
NH2
O
N
NH2
50

Me
N
63b
73b
24c
30e
40d
58e
62d
56d
N
NH2
13
14
15
16
17
18
19
20
50
100
100
80
21
2
3m
3n
3o
3p
3q
3r
3s
N
NH2
N
NH2
6
N
N
NH2
18
48
18
18
18
N
O
NH2
100
80
F
OMe
NH2
Me
S
O
O
O
80
NH2
N
O
Me2N
80
3t
NH2
a Isolated yield after reverse phase HPLC on Phenomenex Gemini 5  silica, C18 30 mm diameter, 100 mm length using decreasingly polar mixtures of H2O (containing
0.5% NH3) and MeCN as eluents.
b
Isolated yield after flash silica chromatography, eluting gradient 0-50% EtOAc/iHex
Crude reaction yield from LCMS of reaction mixtures prior to work-up
c
d Purified by trituration of the crude material using IPA
e Purified by trituration of the crude material using CH2Cl2:Et2O (1:1)