Regioselective synthesis of 2,4,6-triaminopyridines

Article abstract of DOI:10.1016/j.tetlet.2006.10.159

A regioselective synthesis of 2,4,6-trisubstituted pyridine is described starting from 2,6-dibromo-4-nitropyridine. All three different regioisomers of the 2,4,6-triamino substituted pyridine have been synthesized in four to five steps. The method described is a general route to unsymmetrical 2,4,6-trisubstituted amino pyridines.

Full text of DOI:10.1016/j.tetlet.2006.10.159

Tetrahedron Letters 48 (2007) 113–117
Regioselective synthesis of 2,4,6-triaminopyridines
Rupa Shetty,a,* Duyan Nguyen,a Dietmar Flubacher,b Franziska Ruggle,b
Andreas Schumacher,b Martha Kellya and Enrique Michelottia
aDepartment of Chemistry, Locus Pharmaceuticals, Four Valley Square, 512 Townshipline Road, Blue Bell, PA 19422, USA
bSolvias AG, Klybeckstrasse 191, CH-4002 Basel, Switzerland
Received 1 December 2005; revised 27 October 2006; accepted 30 October 2006
Available online 21 November 2006
Abstract—A regioselective synthesis of 2,4,6-trisubstituted pyridine is described starting from 2,6-dibromo-4-nitropyridine. All three
different regioisomers of the 2,4,6-triamino substituted pyridine have been synthesized in four to five steps. The method described is
a general route to unsymmetrical 2,4,6-trisubstituted amino pyridines.
Ó 2006 Elsevier Ltd. All rights reserved.
The 2,4,6-triamino substituted pyridines have been of
much interest to us as a recurring motif in many struc-
tures derived from our computationally driven drug
design process.1 There are numerous examples of
triamino substituted pyridines in the literature which
are of biological relevance.2 Of particular interest to us
were all possible regioisomers of 2,4,6-trisubstituted
pyridines bearing a biphenyl amine, a pyridyl ethyl-
amine and an amino group as depicted in Figure 1.
not reactive enough for the second nucleophilic substitu-
tion. Also, a high temperature is needed for the reaction
with primary amines. The second disadvantage was
the difficulty in the removal of the chlorine atoms and
finally, only one regioisomer was accessible.
In order to access all three regioisomers, we focused our
synthetic efforts towards utilizing 2,6-dibromo-4-nitro-
pyridine-N-oxide 7 as a starting material which can be
readily synthesized in large quantities as described in
the literature.3 The 2,6-dibromo-4-nitropyridine-N-
oxide 7 was converted to 2,4,6-tribromopyridine-N-
oxide 8 by treatment with acetyl bromide in acetic acid
as described by Neumann.5 However, this procedure
gave a very low yield (<5%) of the desired 2,4,6-tri-
bromopyridine-N-oxide 8. In order to improve the yield
of this reaction other conditions were explored. We
found that when hydrogen bromide was used as the bro-
mide source, the reaction showed a remarkable improve-
ment in yield and proceeded in greater than 90% yield.
2,6-Dibromo-4-nitropyridine N-oxide 7 was reduced to
2,6-dibromo-4-nitropyridine 9 by treatment with PBr3
(Scheme 2).4
Our initial effort to synthesize these substituted pyri-
dines was based on the reports by Angiolini et al.3 The
synthesis comprises two sequential nucleophilic substitu-
tions of the fluorine atoms of commercially available
pyridine 4, followed by a hydrogenolytic removal of
chlorine atoms (Scheme 1). This methodology is limited
however by the amines that could be used, and also the
sequence in which they can be used. The first nucleophilc
substitution must be done with an arylamine since it is
Aryl
Alkyl
NH2
HN
HN
Alkyl
Aryl
Alkyl
Aryl
N
H
N
N
H
N
H
N
NH2
H2N
N
N
H
Two complementary routes starting from either 8 or 9
were developed to access the regioisomers of 2,4,6-tri-
substituted pyridines. These routes exploit the differ-
ences in the regioselectivity of nucleophilic substitution
for the intermediates. In the case of N-oxide 8, the
nucleophilic aromatic substitution occurs alternately at
the 2- and 6-positions of pyridine without affecting the
4-position, giving a 5:1 ratio of mono-substituted to
bis-substituted products. In the case of pyridine 9, the
2
3
1
Alkyl = 2-Pyridyl-2-yl-ethylamine
Aryl = 3-Biphenylamine
Figure 1.
*
Corresponding author. Tel.: +1 215 358 2037; fax: +1 215 358
2030; e-mail: rshetty@locuspharma.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.159

114
R. Shetty et al. / Tetrahedron Letters 48 (2007) 113–117
NH2
NH2
NH2
Cl
Cl
Cl
Cl
Cl
Cl
F
ii
i
N
N
N
H
F
N
F
N
N
H
N
H
4
6
5
iii
NH2
N
H
N
N
H
N
3
Scheme 1. Reagents and conditions: (i) 3-biphenyl amine, 150–180 °C, microwave 60 min, 10%; (ii) 2-pyridyl-2-yl-ethylamine, 160 °C, microwave
20 min, 75%; (iii) H2, Pd/C 10%, 60 psi, MeOH, 18 h, 17%.
2,4-dimethoxybenzyl amine at a 70 °C in toluene to yield
Br
the mono-substituted product 10 in 70% yield.4 The 2,4-
i
dimethoxybenzyl amine serves as a protected amino
Br
Br
N
O
8
Br
Br
group, which can then be deprotected under acidic
conditions. The added advantage of using the 2,4-di-
methoxybenzyl amine is the control it provides in
introducing the amino group, since using ammonia as
a nucleophile does not give any selectivity towards
mono-substitution.4,5 The mono-substituted product
was then reacted with 2-pyridin-2-yl-ethylamine in 2-
methoxyethanol at 130 °C to yield the unsymmetrically
di-substituted pyridine 11. The second substitution
requires higher temperature and longer reaction times.
The reaction time however could be decreased by
subjecting the reaction to microwave conditions. The di-
amino substituted pyridine 11 was then reacted with
biphenyl amine under standard Buckwald conditions7
to yield 2,4,6-triamino substituted pyridine-N-oxide 12.
2,4-Dimethoxybenzyl group was cleaved with TFA to
give the amine and the N-oxide was reduced to yield
compound 1.4
NO2
Br
N
O
Br
NO2
ii
7
N
9
Scheme 2. Reagents and conditions: (i) HBr, AcOH, 60 °C, 2 days,
93%; (ii) PBr3, CHCl3, reflux, 19 h, 78%.
4-position is more susceptible towards nucleophilic
aromatic substitution. The two different synthetic
routes developed take advantage of these differences in
reactivities and different sequences of addition of
various nucleophiles to synthesize the three regioisomers
of the 2,4,6-trisubstituted pyridines.
The synthesis of regioisomer 1 is described in Scheme 3.
The 2,4,6-tribromo pyridine-N-oxide 8 is reacted with
Using this sequence of reactions all three of the regio-
isomers 1, 2 and 3 can be accessed. However, the nucleo-
Br
Br
Br
OMe
OMe
i
ii
Br
N
O
N
H
Br
N
O
Br
N
N
H
N
O
N
H
OMe
OMe
10
11
8
iii
NH
NH
NH
v
iv
OMe
N
N
H
N
O
NH2
N
H
N
N
H
N
NH2
N
N
H
N
O
OMe
12
13
1
Scheme 3. Reagents and conditions: (i) 2,4-dimethoxybenzylamine, 70 °C, 2 h, 70%; (ii) 2-pyridyl-2-yl-ethylamine, 2-methoxyethanol, 130 °C, 18 h,
94%; (iii) 3-biphenylamine, Pd2(dba)3, rac-BINAP, NaOtBu, toluene, 100 °C, 18 h, 37%; (iv) TFA, DCM, 18 h, 69%; (v) Fe, AcOH, 100 °C, 2 h, 26%.

R. Shetty et al. / Tetrahedron Letters 48 (2007) 113–117
Table 1. Investigated amines and overall yields
115
philic aromatic substitution proceeds in much lower
yield when an aryl amine is used. The yield of the reduc-
tion of N-oxide was also poor. Therefore we explored
alternate synthetic routes which did not involve N-oxide
as the starting material.
Entry
Amine (R1R2NH)
Yield of 16 (%)
OMe
1
40
H2N
OMe
This alternate synthetic route utilizes 2,6-dibromo-4-
nitropyridine 9 as the starting material. There is a prece-
dence in the literature for nucleophilic displacement of
the nitro group by either thiolate or alkoxide salts.6
The displacement of the nitro group by either primary
or secondary amines was reported under thermal dis-
placement conditions using the amine as the solvent.6
Also reported is the displacement of the nitro group
with the Na salt of an arylamine and by aliphatic pri-
mary amines using organic bases.8 In the case of the
2,6-dibromo-4-nitropyridine 9 thermal displacement
with secondary amine 14 resulted in the displacement
of 2-bromide to give 15 as shown in Scheme 4. This is
in contrast to what is observed in the case of 2,6-di-
chloro-4-nitropyridine where thermal nucleophilic dis-
placement conditions result in the displacement of the
nitro group.8
H2N
N
2
3
40
32
N
H
N
H
4
5
30
57
O
H2N
6
7
51
48
F
NH2
We then explored conditions that would selectively
displace the nitro group of pyridine 9 using a variety
of amines. We found that using the lithium salt of
amines to displace the nitro group is more versatile with
respect to the types of amines that could be introduced.
As shown in Scheme 5, the substitution of the nitro
group of 9 with the lithium salt of amine at À78 °C
yielded 4–amino substituted 2,6-dibromopyridine 16
exclusively in a 30–60% yield. The reaction worked with
a variety of amines such as anilines, primary amines and
secondary amines with yields in the range of 30–60%.
This method provides a more convenient route to access
various 4-amino-2,6-dibromopyridines. The investigated
amines (R1R2NH) and overall yield of products 16 are
reported in Table 1.
H2N
N
O
All products were isolated and characterized by NMR and MS spec-
troscopy; unoptimized yields.
2,4,6-triamino substituted pyridine can be synthesized
as shown in Scheme 6.
The general synthetic route first involves the displace-
ment of the nitro group at 4-position of the pyridine 9
by the lithium salt of the desired amine. The second
amine is then introduced at the 2-position by the reac-
tion of 4-amino-2,6-dibromopyridine with the desired
amine in 2-methoxyethanol at 130 °C. Finally the third
amine is introduced at the 6-position via a Buckwald
reaction.
Taking advantage of the reaction conditions developed
to introduce the amino group at the 4-position by dis-
placement of the nitro group, all three regioisomers of
To illustrate the feasibility of this general synthetic
route, the synthesis of regioisomer 2 is shown in Scheme
7. 4-Nitro-2,6-dibromopyridine 9 is reacted with the lith-
ium salt of 2-pyridyl-2-yl-ethylamine at À78 °C to give
NO2
NO2
N
H
i
O
Br
N
Br
Br
N
N
O
15
14
9
NHR1
NHR1
Scheme 4. Reagents and conditions: (i) 2-methoxyethanol, 100 °C, 2 h,
90%.
R3
R2
Buckwald
Coupling
N
H
N
R2
N
H
Br
N
N
H
Thermal
SNAr
NO2
NR1R2
NO2
i
NHR1
S
NAr
Br
N
Br
Br
N
Br
Br
N
9
Br
16
Li Salt of Amine
Br
N
Br
9
Scheme 5. Reagents and conditions: (i) NHR1R2 2 equiv, n-BuLi 2
equiv, À78 °C, 1 h.
Scheme 6. Retrosynthetic analysis for 2,4,6-triaminopyridines.

116
R. Shetty et al. / Tetrahedron Letters 48 (2007) 113–117
N
N
NO2
NH
NH
OMe
i
ii
Br
N
Br
Br
N
Br
N
H
N
Br
MeO
17
16
9
iii
N
N
iv
NH
NH
OMe
H2N
N
N
H
N
H
N
N
H
MeO
2
18
Scheme 7. Reagents and conditions: (i) 2-pyridyl-2-yl-ethylamine, n-BuLi, À78 °C, 2 h, 40%; (ii) 2,4-dimethoxybenzyl amine, 2-methoxyethanol,
130 °C, 18 h, 49%; (iii) 3-biphenylamine, Pd2(dba)3, rac-BINAP, NaOtBu, toluene, 100 °C, 18 h, 46%; (iv) TFA, DCM, 6 h, 42%.
4-aminoethyl-2-pyridine 16.10 Dibromopyridine 16 is
then treated with excess of 2,4-dimethoxybenzyl amine
in 2-methoxyethanol at 130 °C to yield the 2,4-diamino
substituted pyridine 17.11 The 3-biphenylamine was
installed via a standard Buckwald coupling to give the
triamino substituted intermediate 18,12 which was then
treated with TFA to provide the final compound 2.
HN
NO2
HN
N
F
F
i
Br
N
Br
Br
N
Br
O
Br
9
20
19
This synthetic route provides access to all three regio-
isomers 1, 2 and 3. The 4-nitro group of compound 9
can be displaced by the lithium salt of aliphatic primary
amines, secondary amines and arylamines, providing a
handle to have varied amines at the 4-position. The ther-
mal displacement of 2-bromide is suitable for primary
and secondary alkylamines; however, arylamines are
poor nucleophilic displacement partners in this reaction.
Lastly the Buckwald reaction works well with both alkyl
and arylamines.7
iii
HN
N
F
O
N
O
21
Scheme 8. Reagents and conditions: (i) 3-fluoro-2-biphenylamine, n-
BuLi À78 °C, 2 h, 51%; (ii) 2 M MeONa, dioxane, 100 °C, 18 h, 78%;
(iii) 3-biphenylamine, Pd2(dba)3, rac-BINAP, NaOtBu, toluene,
100 °C, 18 h, 91%.
This synthetic sequence was expanded to make other
2,4,6-trisubstituted pyridines. Since the 4-nitro group
of compound 9 can be displaced by thiolates and alkox-
ides,6 it is possible to introduce alkoxy or thioalkoxy
groups at the 4-position. Once the nitro group is dis-
placed, 2-bromo can also be substituted by other nucleo-
philes such as alkoxides. Finally 6-bromide, which
provide, a handle for the last substitution via a coupling
reaction, can be used for other coupling reactions such
as a Suzuki coupling.9 The synthesis of compounds 21
in Scheme 8 is shown to illustrate the diversity of this
synthetic approach. The nitro group is initially displaced
with a biphenyl amine to give intermediate 19, which
when reacted with NaOMe in dioxane at 100 °C gives
2-methoxy compound 20. The 6-bromo-2-methoxy
pyridine can then undergo a Buckwald reaction to give 21.
mediates. The second synthetic route has one fewer
step and provides a method to synthesize diverse 2,4,6-
trisubstituted pyridines.
References and notes
1. (a) Moore, W. R., Jr. Curr. Opin. Drug Disc. Dev. 2005, 8,
355; (b) Clark, M. J. Inf. Model 2005, 45, 30.
2. (a) Ono, M.; Sun, L.; Wada, Y.; Przewloka, T.; Li, H.; Ng,
Howard P.; Demko, Z. PCT Int. Appl. WO 2005046603,
2005; (b) Zhou, Y.; Vourloumis, D.; Gregor, V. E.;
Winters, G.; Hermann, T.; Ayida, B.; Sun, Z.; Murphy,
D.; Simonsen, K. PCT Int. Appl. WO 2005028467, 2005;
(c) Angiolini, M.; Menichincheri, M.; Fusar Bassini, D.;
In conclusion two different general regioselective routes
were developed for the synthesis of 2,4,6- triaminopyri-
dine in 4–5 synthetic steps from easily accessible inter-

R. Shetty et al. / Tetrahedron Letters 48 (2007) 113–117
117
Gude, M. PCT Int. Appl. WO 2004024711, 2004; (d)
Russell, M. G. N.; Baker, R. J.; Barden, L.; Beer, M. S.;
Bristow, L.; Broughton, H. B.; Knowles, M.; McAllister,
G.; Patel, S.; Castro, J. L. J. Med. Chem. 2001, 44, 3881;
(e) Gong, Y.; Becker, M.; Choi-Sledski, Y. M.; Davis, R.;
Salvino, J. M.; Chu, V.; Brown, K. D.; Pauls, H. W.
Bioorg. Med. Chem. Lett. 2000, 10, 1033–1036.
benzyl amine (1.19 g, 7.1 mmol) and the reaction mixture
was sealed and heated at 130 °C for 18 h. The reaction
mixture was cooled to room temperature, concentrated,
diluted with EtOAc. The organic layer was washed with
bicarbonate, followed by brine, dried over anhydrous
Na2SO4, filtered and concentrated. The crude product was
chromatographed on Silica gel using 10:1 DCM/MeOH to
give 140 mg (49% yield) of 17. MS (APCI): m/z = 443.6
3. Menichincheri, M.; Bassini, D. F.; Gude, M.; Angiolini,
M. Tetrahedron Lett. 2003, 44, 519–522.
1
[M+H+]. H NMR (400 MHz, CDCl3): d (ppm) 8.53 (d,
4. Nettekoven, M.; Jenny, C. Org. Process Res. Dev. 2003, 7,
38.
J = 4.7 Hz, 1H), 7.59 (dt, J = 7.6, 1.6 Hz, 1H), 7.17 (d,
J = 8.0 Hz, 1H), 7.15–7.09 (m, 2H), 6.43 (d, J = 2.1 Hz,
1H), 6.40 (dd, J = 8.1, 2.3 Hz, 1H), 6.02 (d, J = 1.6 Hz,
1H), 5.42 (d, J = 1.6 Hz, 1H), 4.85 (t, J = 5.9 Hz, 1H),
4.74, (t, J = 5.3 Hz, 1H), 4.25 (d, J = 6.1 Hz, 2H), 3.79 (s,
3H), 3.77 (s, 3H), 3.46 (q, J = 6.2 Hz, 2H), 3.00 (t,
J = 6.5 Hz, 2H). 13C NMR (400 MHz, CDCl3): d (ppm)
160.5, 159.8, 158.6, 156.5, 149.6, 141.1, 136.8, 129.7, 123.6,
121.9, 119.3, 104.1, 102.1, 98.7, 86.0, 55.6, 55.5, 42.4, 41.7,
37.0.
5. Neumann, U.; Vo¨gle, F. Chem. Ber. 1989, 122, 589.
6. (a) Riemer, C.; Borroni, E.; Levet-Trafit, B.; Martin, J. R.;
Poli, S.; Porter, R. H. P.; Bo¨s, M. J. Med. Chem. 2003, 46,
1273; (b) Talik, T.; Talik, Z. Prace Naukowe Akademii
Ekononicznej imienia Oskara Langego we Wroclawiu 1989,
476, 189.
7. Harris, M. C.; Geis, O.; Buckwald, S. L. J. Org. Chem.
1999, 64, 6019.
8. (a) Kim, B. Y.; Ahn, J. B.; Lee, H. W.; Kang, S. K.; Lee, J.
H.; Shin, J. S.; Ahn, S. K.; Hong, C. I.; Yoon, S. S. Euro.
J. Med. Chem. 2004, 39, 433; (b) Wanner, M. J.; Von
Frijtag Drabbe Kunzel, J. K.; IJzerman, A. P.; Koomen,
G.-J. Bioorg. Med. Chem. Lett. 2000, 10, 2141.
12. A typical procedure for Buckwald coupling to introduce the
third amine: In a tube (designed for microwave reactions)
was added bromopyridine 17 (0.100 g, 0.23 mmol), 3-
aminobiphenyl (0.19 g, 1.13 mmol), NaOtBu (0.110 g,
1.1 mmol), rac-BINAP (3 mg, 0.004 mmol), Pd2(dba)3
(4 mg, 0.004 mmol), 1 mL of toluene and bubbled with
argon. The tube was sealed and the reaction was heated at
100 °C for 18 h. The reaction was cooled to room
temperature and water (2.0 mL) was added, followed by
3.0 mL of 1 N HCl. The resulting aqueous solution was
extracted with (3 x 30 mL) CH2Cl2. The combined organic
layer was washed with water, brine, dried (MgSO4) and
concentrated. The crude mixture was chromatographed on
Silica gel using 10:1 DCM/MeOH to give 55 mg (46%
9. Miyura, N.; Suzuki, A. Chem. Rev. 1999, 95, 2457.
10. A typical procedure for nucleophilic displacement of 4-nitro
with Li salt of amines: To the 2-pyridyl-2-yl-ethylamine
amine (0.3 mL, 2.2 mmol) in 5 mL of anhydrous THF at
À78 °C was added n-BuLi (0.9 mL, 2.2 mmol) dropwise
and stirred for 30 min. The salt formed was added via a
canula to a solution of the nitro compound 9 in 5.0 mL of
anhydrous THF at À78 °C dropwise. After complete
addition, the reaction was stirred for 2 h and then
quenched at À78 °C with EtOAc, washed with water
followed by brine. The EtOAc layer was dried over
anhydrous Na2SO4, filtered and concentrated. The crude
product was chromatographed on Silica gel using 10:1
DCM/MeOH to give 255 mg (40% yield) of 16. MS
(APCI): m/z = 358.4 [M+H+]. 1H NMR (400 MHz,
CDCl3): d (ppm) 8.47 (d, J = 4.7 Hz, 1H), 7.56 (m, 1H),
7.10 (d, J = 7.8 Hz, 2H), 6.50 (s, 2H), 5.59 (s, 1H), 3.44 (q,
J = 5.9 Hz, 2H), 2.99 (t, J = 6.2 Hz, 2H). 13C NMR
(400 MHz, CDCl3): d (ppm) 158.9, 156.3, 149.5, 140.9,
137.1, 123.7, 122.2, 110.1, 42.3, 36.3.
1
yield) of 18. MS (APCI): m/z = 532.9 [M+H+]. H NMR
(400 MHz, CDCl3): d (ppm) 8.51 (d, J = 4.1 Hz, 1H),
7.58–7.53 (m, 3H), 7.48 (t, J = 1.9 Hz, 1H), 7.42–7.37 (m,
2H), 7.35–7.29 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 7.17 (td,
J = 7.5, 1.3 Hz, 1H), 7.13–7.07 (m, 2H), 6.46–6.39 (m,
2H), 6.18 (s, 1H), 5.60 (d, J = 1.4 Hz, 1H), 5.21 (d,
J = 1.4 Hz, 1H), 4.58 (t, J = 6.0 Hz, 1H), 4.39 (t,
J = 5.5 Hz, 1H), 4.33 (d, J = 5.9 Hz, 2H), 3.81 (s, 3H),
3.78 (s, 3H), 3.48 (q, J = 6.3 Hz, 2H), 3.01 (t, J = 6.5 Hz,
2H). 13C NMR (400 MHz, CDCl3): d (ppm) 160.3, 159.6,
159.5, 158.6, 156.9, 155.6, 149.6, 142.4, 142.1, 141.5, 136.8,
129.8, 129.6, 128.9, 127.5, 127.4, 123.6, 121.7, 120.8, 120.3,
119.2, 119.0, 104.1, 98.7, 82.7, 81.8, 55.6, 55.5, 42.8, 41.7,
37.6.
11. A typical procedure for thermal nucleophilic displacement of
2-bromides with amines: To amine 16 (0.255 g, 0.71 mmol)
in 1 mL of 2-methoxyethanol was added 2,4-dimethoxy-