Palladium-Catalyzed C,N-Cross coupling reactions of 3-Halo-2-aminopyridines

Article abstract of DOI:10.1021/ol200371n

A simple approach toward N³-substituted-2,3-diaminopyridines is presented, based on Pd-catalyzed C,N-cross coupling. The use of RuPhos- and BrettPhos-precatalysts in combination with LiHMDS allows for C,N-cross coupling reactions of unprotected

Full text of DOI:10.1021/ol200371n

ORGANIC
LETTERS
2011
Vol. 13, No. 8
1984–1987
Palladium-Catalyzed C,N-Cross Coupling
Reactions of 3-Halo-2-aminopyridines
Felix Perez and Ana Minatti*
Department of Medicinal Chemistry, Amgen Inc.,
One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States
aminatti@amgen.com
Received February 8, 2011
ABSTRACT
A simple approach toward N3-substituted-2,3-diaminopyridines is presented, based on Pd-catalyzed C,N-cross coupling. The use of RuPhos- and
BrettPhos-precatalysts in combination with LiHMDS allows for C,N-cross coupling reactions of unprotected 3-halo-2-aminopyridines with primary
and secondary amines.
In the past decade, N3-subsituted 2,3-diaminopyridines
have been disclosed as potential therapeutics1À3 for multi-
ple indications. They also serve as versatile intermediates
in the synthesis of further elaborated, biologically active
heterocycles.4À8
on 3-halo-2-nitropyridines followed by nitro reduction,5,9
reductive alkylation4,8,10 of 2,3-diaminopyridines, or
amide coupling6,8 of the aforementioned diamine fol-
lowed by reduction.11 Additionally, two modestlyefficient
copper-catalyzed aminations have been described, which
are limited to 2-amino-3-iodopyridines7 or the corre-
sponding boronic ester.2 Most importantly, all methods
described to date are limited to the synthesis of N3-
alkylated 2,3-diaminopyridines while N3-arylated products
remain inaccessible.
Given the potential utility of N3-subsituted 2,3-diami-
nopyridines, we felt that there was a need for a general and
convenient synthetic method for their construction. We
envisioned that a Pd-catalyzed C,N-cross coupling reac-
tion of 3-bromo-2-aminopyridine might be amenable to
the problem, given the maturity of the field and several
recent advances.12
Despite the emerging utility of N3-substituted 2,3-
diaminopyridines, the known synthetic routes remain
mostly limited to two-step procedures: SNAr reactions
(1) Kanai, K.; Hashimoto, K.; Goto, K. JP Patent 62223173, 1987.
(2) Steinig, A. G.; Mulvihill, M. J.; Wang, J.; Werner, D. S.; Weng,
Q.; Kan, J.; Coate, H.; Chen, X. U.S. Patent 2009197862, 2009.
(3) (a) Illig, C. R.; Ballentine, S. K.; Chen, J.; Meegalia, S,; Rudolph,
J.; Wall, M. J.; Wilson, K. J.; Desjarlais, R.; Manthey, C. L.; Flores,
C. M.; Molloy, C. J. WO Patent 2006047504, 2006. (b) Illig, C. R.; Chen,
J.; Wall, M. J.; Wilson, K. J.; Ballentine, S. K.; Rudolph, M. J.; DesJarlais,
R. L.; Chen, Y.; Schubert, C.; Petrounia, I.; Crysler, C. S.; Molloy, C. J.;
Chaikin, M. A.; Manthey, C. L.; Player, M. R.; Tomczuk, B. E.; Meegalla,
S. K. Bioorg. Med. Chem. Lett. 2008, 18, 1642.
(4) Goehring, R. R.; Matsumura, A. A,; Shao, B.; Taoda, Y.; Tsuno,
N.; Whitehead, J. W. F.; Yao, J. WO Patent 2009027820, 2009.
(5) Jones, E. D.; Coates, J. A. V.; Rhodes, D. I.; Deadman, J. J.; Van-
Degraff, N. A.; Winfiled, L. J.; Thienthong, N.; Issa, W.; Choi, N.;
Macfarlane, K. WO Patent 2008077188, 2008.
The potential challenges of3-bromo-2-aminopyridine as
the substrate in a Pd-catalyzed C,N-cross coupling reac-
tion are 3-fold: (1) prevention or retardation of oxidative
(6) Grewal, G,; Hennessy, E,; Kamhi, V.; Li, D.; Lyne, P.; Oza, V.;
Saeh, J. C.; Su, Q.; Yang, B. WO Patent 2008056150, 2008.
(7) Shipps, G. W. Jr.; Cheng, C. C.; Huang, X.; Fischmann, T. O.;
Duca, J. S.; Richards, M.; Zeng, H.; Sun, B.; Reddy, P. A.; Wong, T. T.;
Tadikonda, P. K.; Siddiqui, M. A.; Labroli, M. M.; Poker, C.; Guzi, T. J.
WO Patent 2008054702, 2008.
(8) Ohtsuka, M.; Haginoya, N.; Ichikawa, M.; Matsunaga, H.; Saito,
H.; Shibata, Y.; Tsunemi, T.; Ishibashi, K. WO Patent 2010016490,
2010.
(10) Khanna, I. K.; Weier, R. M.; Lentz, K. T.; Swenton, L.; Lankin,
D. C. J. Org. Chem. 1995, 60, 960.
(11) Additionally, the synthesis of 3-butylamino-2-amino-pyridine
via nucleophilic substitution has been reported: Liu, Y.; Zhang, W.;
Sayre, L. M J. Heterocycl. Chem. 2010, 47, 683.
(12) (a) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv.
Synth. Catal. 2006, 348, 23. (b) Tasler, S.; Mies, J.; Langa, M. Adv.
Synth. Catal. 2007, 349, 2286. (c) Torborg, C.; Beller, M. Adv. Synth.
Catal. 2009, 351, 3027. (d) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010,
2, 27.
(9) Exception: For an SNAr on 3-bromo-2-amino-5-phenylpyridine
under harsh reaction conditions, seeChrisman, W.; Knize, M. G.;
Tanga, M. J. J. Heterocyclic Chem. 2008, 45, 1641.
r
10.1021/ol200371n
Published on Web 03/25/2011
2011 American Chemical Society

addition due to potential coordination/chelation of palla-
dium by the amidine-like structure, (2) hindrance of trans-
metalation due to coordination of the proximal amino
group to the Pd(II) center after oxidative addition, and (3)
formation of homocoupling product due to competition
of 2-amino-halopyridine as the nucleophilic component.
While there are few reports of each of these scenarios
(Scheme 1, equations I13 and II14), there is no precedent for
a Pd-catalyzed C,N-cross coupling with a substrate that
combines all three challenges (Scheme 1, equation III).
proven to be competent catalysts in the N-arylation of
2-aminopyridine itself and in the amination of 2-bro-
moaniline (Scheme 1, equation I), three representative
ligands L9ÀL11 of this class were also included in the
catalyst screen.16
Scheme 1. Proposed Pd-Catalyzed Amination Reaction of
3-Bromo-2-aminopyridine and Potential Challenges
a See ref 13.
b See ref 14.
We decided to react 3-bromo-2-aminopyridine with
morpholine under the same conditions as described pre-
viously for 5-chloro-2-aminopyridine14 [Pd2dba3 (2 mol
%)/XPhos (L1, 8 mol %) and LiHMDS (2.5 equiv) in
THF at 65 °C for 16 h]. We were pleased to obtain 40% of
the desired product along with unreacted starting material
and 2-aminopyridine. Encouraged by this result, we ex-
amined structurally related biarylmonophosphine ligands
L1ÀL8 and palladacycles Pre-L1, -L3, -L4, -L815 leaving
all the other reaction parameters unchanged (Figure 1). As
palladium complexes of bidentate phosphine ligands have
Figure 1. Ligand screen for C,N-cross coupling of morpholine to
3-bromo-2-aminopyridine. Yields are an average of two runs
and were determined by GC analysis using dodecane as an
internal standard.
The screening study revealed that the ligands RuPhos
(L3), SPhos (L4), and BINAP (L9) performed similarly,
affording the desired product in high yield (71, 76, and
71%, respectively) after 16 h (Figure 1). The yields ob-
tained with the precatalysts were slightly lower in compar-
ison to the corresponding Pd2dba3/ligand catalyst system,
except for the RuPhosÀprecatalyst (Pre-L3), which ex-
hibited a ∼10% increase resulting in the highest yield
(83%). Notably, at no point did we observe formation of
“homocoupling product” due to 2-amino-halopyridine
competing as the nucleophilic component nor the forma-
tion of 2,3-diaminopyridine as a consequence of LiHMDS
functioning as an ammonia surrogate.
The superior performance of the RuPhos-precatalyst
(Pre-L3, Table 1, entry 2) compared to the catalyst system
Pd2dba3/BINAP (L9, Table 1, entry 3) was further demon-
strated by its ability to effectively catalyze the reaction at
room temperature (Table 1, entries 4 and 5) and to even
couple 3-chloro-2-aminopyridine (Table 1, entries 6 and 7)
(13) Buckley, R. B.; Christie, S. D. R.; Elsegood, M. R. J.; Gillings,
C. M.; Page, P. C. B.; Pardoe, W. J. M. Synlett 2010, 6, 939.
(14) Anderson, K. W.; Tundel, R. E.; Ikawa, T; Altman, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
(15) Palladacycles based upon biarylmonophosphines are operation-
ally simple to handle precatalysts which are, easily acivated and ensure
formation of the catalytically active monoligated Pd(0) species: (a)
Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008,
130, 6686. (b) Fors, B, P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2008, 130, 13552. (c) Lee, B. K.; Biscoe, M. R.;
Buchwald, S. L. Tetrahedron Lett. 2009, 50, 3672.
(16) (a) Jonckers, T. H. M.; Maes, B. U. W.; Guy, L. F.; Dommisse,
L.; Dommisee, R. Tetrahedron 2001, 57, 7027. (b) Yin, J; Zhao, M. M.;
Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481. (c) Usui., S;
Suzuki, T.; Hattori, Y.; Etoh, K.; Fujieda, H.; Nishizuka, M.; Imagawa,
M.; Nakagawa, H.; Kohda, K.; Miyata, N. Bioorg. Med. Chem. Lett.
2005, 15, 1547. (d) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc.
2008, 130, 6586.
Org. Lett., Vol. 13, No. 8, 2011
1985

Table 1. Variation of Reaction Parameters for the Coupling of
Morpholine to 3-Halo-2-aminopyridinea
Table 2. Cross-Coupling of 3-Bromo-2-aminopyridine with
Secondary Cyclic Aminesa
entry
X
catalyst
temp [°C]
solvent
yieldb
1
2
Br
Br
Br
Br
Br
Cl
Pd2dba3/L3
Pre-L3
65
65
65
rt
THF
71
THF
83 (85)c
3
Pd2dba3/L9
Pre-L3
THF
71
68
11
76
0
4
THF
5
Pd2dba3/L9
Pre-L3
rt
THF
6
65
65
90
90
65
THF
7
Cl
Pd2dba3/L9
Pd2dba3/L3
Pd2dba3/L3
Pd(OAc)2/L3d
THF
8
Br
Br
Br
dioxane
toluene
THF
82
0
9
10
51
a Reaction conditions: 3-halo-2-aminopyridine (1 mmol), morpho-
line (1.5 mmol), Pd2dba3 (2 mol %)/ligand (8 mol %), LiHMDS (2.5
mmol), solvent (2.5 mL) or 3-halo-2-aminopyridine (1 mmol), morpho-
line (1.5 mmol), Pre-L3 (4 mol %), LiHMDS (2.5 mmol), solvent (2.5
mL). b Yields [%] were determined by GC analysis using dodecane as an
internal standard. c Reaction was analyzed after 5 h reaction time.
d Pd(OAc)2 (4 mol %) was used.
a Reaction conditions: 3- bromo-2-amino pyridine (1 mmol), amine
(1.5 mmol), Pre-L3 (4 mol %), LiHMDS (2.5 mmol, 1 M in THF), 65 °C,
12 h. b Isolated yields [%] are an average of two runs. c 3-Chloro-
2-aminopyridine was used. d Reaction was run at room temperature.
2-aminopyridine were well tolerated, whereas substitution
in position 4 was deleterious (Figure 2).
at 65 °C. Replacing THF with dioxane and increasing the
reaction temperature from 65 to 90 °C delivered compar-
able results (Table 1, entries 1 and 8), though no product
formation was observed in toluene (Table 1, entry 9).
When initiating the reaction with a Pd-source in a higher
oxidation state, only 51% yield was obtained [Pd(OAc)2,
Table 1, entry 10].17 Alternative bases, such as NaOtBu,
K3PO4, Cs2CO3, K2CO3, or Na2CO3 proved to be ineffec-
tive in the coupling reaction and 2.5 equiv of LiHMDS
were determined to be optimal.18
With these optimized reaction conditions in hand we set
out to investigate the scope of the reaction with regard to
the secondary cyclic amine coupling partner. High yields
were obtained for a range of substituted morpholines (Table
2, entries 1À4) and piperidines (Table 2, entries 8À11);
pyrrolidines were coupled in moderate yields (Table 2,
entries 6À7). The ability to perform the reaction at room
temperature proved important in the case of the Boc-
protected piperazine as the yield was increased from 39
to 65% by lowering the reaction temperature (Table 2,
entry 5). Substituents in positions 5 and 6 on the 3-bromo-
Figure 2. Amination of substituted 2-amino-3-bromopyridines;
for reaction conditions see Table 2.
In contrast to the cross-coupling of secondary amines,
BrettPhos-precatalyst (Pre-L8) outperformed RuPhos-
precatalyst (Pre-L3) and Pd2dba3/BrettPhos (L8) in the
coupling of 3-bromo-2-aminopyridine with a branched
primary amine such as cyclopentylamine, yielding 8a in
78% (Table 3, entry 1), compared to only 47 and 66%,
respectively. Benzylamine and linear primary amines also
proved to be competent under these reaction conditions
yielding the corresponding products in moderate to good
yields (Table 3, entries 3À5).
As mentioned above no synthesis of N3-arylated 2,3-
diaminopyridines has been described to date. A new
screen of catalysts revealed again BrettPhos-precatalyst
(Pre-L8) as the best system delivering 8f up to 66%
yield versus 42% when using Pd2dba3/BrettPhos (L8)
(Table 3, entry 6). Electron-rich anilines were coupled in
comparably high yields (Table 3, entries 7 and 8), elec-
tron-withdrawing groups were tolerated and in the case
(13) Buckley, R. B.; Christie, S. D. R.; Elsegood, M. R. J.; Gillings,
C. M.; Page, P. C. B.; Pardoe, W. J. M. Synlett 2010, 6, 939.
(14) Anderson, K. W.; Tundel, R. E.; Ikawa, T; Altman, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
(17) No product formation was observed without ligand or without
palladium source under the reaction conditions.
(18) For the role of LiHMDS as a base to enable Pd-catalyzed C,N-
cross coupling reactions in the presence of functional groups with acidic
protons, see: (a) Harris, M. C.; Huang, X.; Buchwald, S. L. Org. Lett.
2002, 4, 2885. (b) Charles, M. D.; Schultz, P.; Buchwald, S. L. Org. Lett.
2005, 7, 3965.
1986
Org. Lett., Vol. 13, No. 8, 2011

Table 3. Cross-Coupling of 3-Bromo-2-aminopyridine with
Primary Aminesa
Scheme 2. Sequential Pd-Catalyzed C,N-Cross Coupling of
3,5-Dibromo-2-aminopyridine
a Reaction conditions: 3-bromo-2-aminopyridine (1 mmol), amine
(1.5 mmol), Pre-L8 (4 mol %), LiHMDS (2.5 mmol, 1 M in THF), 65 °C,
12 h. b Isolated yields [%] are an average of two runs. c 3-Chloro-2-
aminopyridine was used.
a Isolated yields.
of para-chloroaniline no competitive coupling on the
chloride was observed (Table 3, entries 9 and 10).
Finally, as N3,N5-disubsituted 2,3,5-triaminopyridines
have been disclosed as important pharmacophores,3 we set
out to synthesize this scaffold using our methodology.
First, 3,5-dibromo-2-aminopyridine (9) was reacted with
morpholine following the general conditions (Scheme 2).
Three different products (10À12) were formed, the major
product being 2-morpholine-5-bromo-2-aminopyridine
(11)19 arising from preferred coupling in position 3.20,21
XPhos-precatalyst (Pre-L1) gave slightly better selectiv-
ity than RuPhos-precatalyst (Pre-L3) with respect to the
desired product 11 (1:8:1.6, 86% total yield vs 1:8.5:3, 75%
total yield). The ratio of the products was not altered by
shortening the reaction time or by performing the reaction
at room temperature. After isolating 2-morpholine-5-bro-
mo-2-aminopyridine (11), a second Pd-catalyzed C,N-
cross coupling reaction with piperidine was carried out.
From all precatalysts tested SPhos-precatalyst (Pre-L4)
performed best and provided product 13 in 71% yield.
In summary, we have identified reaction conditions for
the efficient Pd-catalyzed C,N-cross coupling of unpro-
tected 3-halo-2-aminopyridines with a range of primary
and secondary amines. Additionally, the method described
herein allowed for the synthesis of N3-arylated 2,3-diami-
nopyridines, which had been unprecedented to date. The
precatalysts derived from the ligands RuPhos and Brett-
Phos were identified as outstanding catalyst systems for
secondary amines and primary amines, respectively, which
is in accordance with recently identified trends.22
Acknowledgment. We thank Prof. Stephen L. Buchwald
(Massachusetts Institute for Technology) and Dr. Nick A.
Paras (Amgen Inc.) for insightful discussions. Felix Perez
thanks the National Institutes of Health Chemistry Biology
Interface Training program at UCLA for support.
Supporting Information Available. Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(19) Product configuration was confirmed by NOE experiment.
(20) The prefered C,N-cross coupling in position 3 is in accordance
with selectivities observed in C,C-cross couplingreactions: (a)Majumdar,
K. C.; Mondal, S. Tetrahedron Lett. 2007, 48, 6951. (b) Zhao, S.-B.;Cui, Q.;
Wang, S.-N. Organometallics 2010, 29, 998.
(21) For the origin of regioselectivity in Pd-catalyzed cross-coupling
reactions of polyhalogenated heterocycles, see: Legault, C. Y.; Garcia,
Y.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 12664.
(22) (a) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57. (b) Henderson, J. L.; McDermott,
S. M.; Buchwald, S. L. Org. Lett. 2010, 12, 4438. (c) Henderson, J. L.;
Buchwald, S. L. Org. Lett. 2010, 12, 4442.
Org. Lett., Vol. 13, No. 8, 2011
1987