General and mild preparation of 2-aminopyridines

Article abstract of DOI:10.1021/ol102301u

A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine-N-oxides is presented as a mild alternative to S_NAr chemistry. A variety of amines and heterocyclic-N-oxides participate effectively in this transformation which uses the phosphonium salt, PyBroP, as a means of substrate activation.

Full text of DOI:10.1021/ol102301u

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5254-5257
General and Mild Preparation of
2-Aminopyridines
Allyn T. Londregan,* Sandra Jennings, and Liuqing Wei
CVMED Medicinal Chemistry, Pfizer Inc., Eastern Point Road,
Groton, Connecticut 06340, United States
allyn.t.londregan@pfizer.com
Received September 24, 2010
ABSTRACT
A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from the corresponding pyridine-N-oxides is presented
as a mild alternative to SNAr chemistry. A variety of amines and heterocyclic-N-oxides participate effectively in this transformation which uses
the phosphonium salt, PyBroP, as a means of substrate activation.
2-Aminopyridines are ubiquitous features in small molecule
chemotherapeutics.1 Typical syntheses of 2-aminopyridines
Scheme 1. Syntheses of 2-Aminopyridines
require a nucleophilic displacement of the corresponding
2-halopyridines with an amine (Scheme 1). Yields for this
transformation, particularly on unactivated 2-halopyridines,
are frequently low and in most cases require high temper-
atures and pressures.2 Palladium- and copper-catalyzed
aminations can enhance yields and do offer attractive
alternatives to SNAr chemistry, but these preparations usually
require harsh reaction conditions as well as substrate-specific
ligands.3 Aminations at a late stage in a synthesis are often
not possible due to substrate decomposition or incompat-
ibility under the above conditions. For these reasons, new
and mild methods for the preparation of 2-aminopyridines
are desirable.
(1) (a) Hilton, S.; Naud, S.; Caldwell, J.; Boxall, K.; Burns, S.; Anderson,
V. E.; Antoni, L.; Allen, C. E.; Pearl, L. H.; Oliver, A. W.; Aherne, G. W.;
Garrett, M. D.; Collins, I. Bioorg. Med. Chem. 2010, 459. (b) Yonezawa,
S.;Tamura,Y.;Kooriyama,Y.;Sakaguchi,G.PCTInt.Appl.WO2010047372,
2010. (c) Steinig, A. G.; Mulvihill, M. J.; Wang, J.; Werner, D. S.; Weng,
Q.; Kan, J.; Coate, H.; Chen, X. U.S. Pat. Appl. US2009197862, 2009. (d)
Aicher, T. D.; Boyd, S. A.; Chicarelli, M. J.; Condroski, K. R.; Hinklin,
R. J.; Singh, A. PCT Int. Appl. WO 2008118718, 2008.
Another increasingly popular synthetic approach to 2-ami-
nopyridines employs pyridine-N-oxides in place of the
corresponding 2-halopyridines.4 Treatment of pyridine-N-
oxide (4) with an activating agent (A-X ) Ts2O, TsCl,
Ac2O, etc.) enhances the electrophilic character of the
2-position (5), thus allowing for nucleophilic addition of the
(2) (a) Goldstein, D. M.; Gong, L.; Michoud, C.; Palmer, W. S.; Sidduri,
A. PCT Int. Appl. WO 2008028860, 2008. (b) Kling, A.; Backfisch, G.;
Delzer, J.; Geneste, H.; Graef, C.; Hornberger, W.; Lange, U. E. W.;
Lauterbach, A.; Seitz, W.; Subkowski, T. Bioorg. Med. Chem. 2003, 11,
1319–1341.
(4) (a) Keith, J. M. J. Org. Chem. 2010, 75, 2722–2725. (b) Storz, T.;
Bartberger, M. D.; Sukits, S.; Wilde, C.; Soukup, T. Synthesis 2008, 2,
201–214. (c) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies,
I. W. J. Org. Chem. 2007, 72, 4554–4557.
(3) (a) Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423–
17429. (b) Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109–4112.
10.1021/ol102301u  2010 American Chemical Society
Published on Web 10/19/2010

amine under relatively mild conditions. Unfortunately, side
reactions are quite common, including addition at the
4-position, counteranion (X-) addition at the 2- and 4-posi-
tion, and amination of the activating agent directly with the
amine nucleophile. Several clever solutions to these prob-
lematic side reactions appeared in the literature4a,c recently
that carefully modulate reaction conditions to minimize side
products. In these optimized cases, however, the amine
substrate scope is narrow, thus limiting broad applicability.
Table 1. Reaction Optimization for the Amination of
Pyridine-N-oxide with Cyclohexylaminea
entry
additive
base
solvent
temp (°C)
yield
We were interested in expanding and improving the
reactivity of amines with pyridine-N-oxides while minimizing
some of the more common side reactions. Since most of the
reaction side products were due to the activating agent, we
began our search for suitable alternatives. Phosphorus
oxychloride and related reagents, when combined with
pyridine-N-oxides, affect nonregioselective chlorination of
the 2- and 4-position in a manner similar to the activating
agents shown above.5 In these cases, the strength of
phosphorus-oxygen bond formation provides a strong
thermodynamic drive for reaction completion. We surmised
that we could take advantage of this same principle with
more specific phosphonium salts. Although most commonly
used as amide coupling reagents,6 phosphonium salts (Py-
BroP,7 BroP, PyBOP, and BOP)8 have also been shown to
activate carbon-oxygen bonds for nucleophilic displacement
reactions.9 Additionally, phosphorus activated carbon-oxygen
bonds can function as effective partners in cross-coupling
reactions.10 To our knowledge, however, there have been
no reports of phosphonium salt activation of pyridine-N-
oxides.
1
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
PyBroP
BroP
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
DBU
2,6-lutidine
NEt3
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
DMF
EtOAc
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
25
25
25
25
0f25
70
25
25
25
25
25
25
25
25
25
25
82
75
41
69
55
53
n/re
62
70
n/r
40
78
83
n/r
n/r
n/r
2b
3c
4d
5
6
7
8
9
10
11
12
13
14
15
16
PyBop
BOP
Ph3PBr2
a Unless otherwise noted, all reactions were conducted at 0.25 M
concentration with 6 (1.00 equiv), 7 (1.25 equiv), base (3.75 equiv), and
additive (1.30 equiv). b 1.00 equiv of 7. c 5.00 equiv of 7. d 0.10 M
concentration. e No reaction.
(entry 16) were ineffective. Nontrialkylamine bases (entries
10 and 11) performed poorly under the reaction conditions.
A solvent screen demonstrated that dichloromethane (0.25
M) gave the highest yields (entries 1, 4, and 7-9). Interest-
ingly, elevated temperature (entry 6) had a detrimental effect
on the observed yield. Under our optimized conditions, we
used N-oxide 6 as the limiting reagent with a small excess
of 7 (1.25 equiv), PyBroP (1.30 equiv), and a 3-fold excess
of iPr2EtN (3.75 equiv) compared to the amine nucleophile.
The reactions were complete in 5-15 h at room temperature.
The order of reagent addition had no impact on observed
yields.
We next applied the optimized reaction conditions to a
variety of amine nucleophiles (Table 2). When pyridine-N-
oxide 6 was combined with each amine in dichloromethane
and treated with iPr2EtN and PyBroP, we were pleased to
obtain the corresponding 2-aminopyridines in modest to
excellent yields. In none of these instances did we observe
reaction at the 4-position of the pyridine-N-oxide. As shown
in Table 2, primary and secondary aliphatic amines were
very effective nucleophiles (entries 1-6).11 Ammonia (entry
15) also showed modest reactivity under our conditions. The
steric bulk of the amine had little impact on the reaction
outcome, as t-butylamine performed well (entry 12). Ami-
nations with allylic and benzylic amines (entries 7 and 8)
proceeded smoothly as did those with heterocyclic amines
To assess the feasibility of using phosphonium salts as a
means to introduce amines onto pyridine-N-oxides, we
attempted the coupling of pyridine-N-oxide 6 with cyclo-
hexylamine 7 (Table 1). When a basic mixture of 6 and 7
was treated with PyBroP (bromo-tris-pyrrolidino-phospho-
nium hexafluorophosphate), we were delighted to obtain 8
as the major product of the reaction. Remarkably, no addition
at the 4-position of the pyridine-N-oxide was observed. After
reaction optimization, we found that Hunig’s base (iPr2EtN)
and dichloromethane as a base/solvent pair worked most
effectively (entry 1). PyBroP and the closely related BroP
(entry 13) were the only phosphonium salts that afforded
the desired product. Although BroP (83%) slightly outper-
formed PyBroP (82%), we chose not to use BroP due to the
generation of carcinogenic HMPA as a byproduct (vide
infra). Hydroxybenzotriazole-based phosphonium salts (en-
tries 14 and 15) and bromo-triphenylphosphonium bromide
(5) (a) Alcazar, J.; Alonso, J. M.; Bartolome, J. M.; Iturino, L.; Matesanz,
E. Tetrahedron Lett. 2003, 44, 8983–8986. (b) Yamanaka, H.; Araki, T.;
Sakamoto, T. Chem. Pharm. Bull. 1988, 36, 2244–2247.
(6) Han, S.; Kim, Y. Tetrahedron 2004, 60, 2447–2476.
(7) Castro, B.; Coste, J. PCT Int. Appl. WO90/10009, 1990.
(8) Abbreviations: PyBroP ) bromo-tris-pyrrolidino-phosphonium hexaflu-
orophosphate; BroP ) bromo-tris-dimethylamino-phosphonium hexafluo-
rophosphate; PyBOP ) benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium
hexafluorophosphate; BOP ) benzotriazole-1-yl-oxy-tris-dimethylamino-
phosphonium hexafluorophosphate.
(9) Wan, Z.; Wacharasindhu, S.; Levins, C. G.; Lin, M.; Keiko Tabei,
K.; Mansour, T. S. J. Org. Chem. 2007, 72, 10194–10210.
(10) Kang, F.; Sui, Z.; Murry, W. V. J. Am. Chem. Soc. 2008, 130,
11300–11302.
(11) For entry 6, as anticipated, no racemization and no protecting-group
degredation occurred. Chiral purity was determined on a Chiralpak AD
Column, 5% IPO/heptanes with 0.1% DEA, 210 nm, 1 mL/min flow rate,
and compared to a racemic standard.
Org. Lett., Vol. 12, No. 22, 2010
5255

electron-deficient anilines. To our knowledge, this is the only
report of amidation with an aniline onto a 2,6-unsubstituted
pyridine at room temperature.
We further examined the reaction of cyclohexylamine 7,
with a selection of pyridine- and quinoline-N-oxides under
our optimized conditions (Table 3). We were pleased to
Table 2. Amination of Pyridine-N-oxide with a Variety of
Aminesa
Table 3. Amination of Various Heterocyclic-N-oxides with
Cyclohexylaminea
a Reaction Conditions: Combine N-oxide 7 (1.00 equiv), cyclohexy-
lamine 7 (1.25 equiv), and iPr2EtN (3.75 equiv) in CH2Cl2 (0.25 M) and
add PyBroP (1.30 equiv) and stir for 15 h at room temperature. b 1:1 with
3-methyl isomer. c No reaction.
observe modest to good reactivity in all cases examined.
Electron-rich (entry 1) and electron-poor (entry 2) pyridine-
N-oxides showed comparable reactivity. Quinoline-N-oxides
worked well (entries 3 and 4), with isoquinoline-N-oxide
affording the 1-substituted regioisomer only.12 Reaction with
3-methylpyridine-N-oxide (entry 6) gave a 1:1 mixture of
addition products at the 2- and 6-positions, with no apparent
steric bias from the 3-methyl group. Although the majority
of the examples in Table 3 is derived from commercially
a Reaction Conditions: Combine N-oxide 6 (1.00 equiv), amine 1 (1.25
equiv), and iPr2EtN (3.75 equiv) in CH2Cl2 (0.25 M) and add PyBroP (1.30
equiv) and stir for 15 h at room temperature. b 1.0 M MeNH2 in THF. c 0.5
M NH3 in 1,4-dioxane.
(12) Examples of 1-position regioselectivity with isoquinoline-N-oxides
are known: (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127–
3129. (b) Abramovitch, R. A.; Rogers, R. B. Tetrahedron Lett. 1971, 22,
1951–1954.
(entries 13 and 14). Although the yields were attenuated,
we were pleased to observe reaction with electron-rich and
electron-neutral anilines (entries 9 and 10). With the excep-
tion of entry 11, we observed little or no reactivity with
(13) (a) Jain, S. L.; Sain, B. Chem. Commun. 2002, 1040–1041. (b)
Fields, J. D.; Kropp, P. J. J. Org. Chem. 2000, 65, 5937–5941. (c) Ferrer,
M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahedron 1997, 53, 15877–15888.
5256
Org. Lett., Vol. 12, No. 22, 2010

available N-oxides, the relative ease13 of converting pyridines
and quinolines to the corresponding pyridine- and quinoline-
N-oxides facilitates even larger potential diversity.
The proposed mechanism for this transformation is
outlined in Scheme 2. The reaction most likely proceeds via
entry 7) was observed under our standard reaction condtions.
Preformation of 12, as observed by the consumption of
PyBroP and N-oxide, followed by the addition of amine and
base, afforded the desired product as expected. Under no
-
circumstances did we observe counteranion (Br-, PF6 )
addition onto the pyridine. In this transformation, the
phosphonium salt works in excellent balance to activate and
eliminate, while remaining unreactive toward the amine
nucleophile.
Scheme 2. Proposed Reaction Mechanism
In conclusion, we have presented a general and facile
amination procedure for the synthesis of 2-aminopyridines,
which provides a mild alternative to traditional SNAr
chemistry. A diverse substrate scope combined with an
operationally simple procedure make this a useful methodol-
ogy. Further optimization of this procedure will continue in
our laboratory.
Acknowledgment. We thank Dr. David W. Piotrowski
(Pfizer Inc.) and Dr. David Hepworth (Pfizer Inc.) for their
advice and support in our research.
Supporting Information Available: Experimental details,
1
procedures, and H and 13C NMR data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
the activated pyridine complex 12. Subsequent basic rearo-
matization (13) affords the desired 2-aminopyridine 3 and
phosphoryltripyrrolidine 14, the only significant organic
byproduct of the reaction. The strong regiochemical prefer-
ence for 2-position addition may be attributed to a charge
association14 of the activated phosphonium complex 12 with
the incoming amine nucleophile 1. Whatever the source of
this effect, its strength cannot be overstated, as no addition
at the 4-position of 2,6-dimethylpyridine-N-oxide (Table 3,
OL102301U
(14) For a review on the regioselectivity of nucleophilic addition onto
activated pyridines see: Poddubnyi, I. S. Chem. Heterocycl. Compd. 1995,
31, 682–714. Hard-hard/soft-soft interactions during the nucleophilic
addition transition state are proposed to influence regioselectivity in addition
to activated pyridines and may work in concert with the proposed charge
interaction.
Org. Lett., Vol. 12, No. 22, 2010
5257