A general and efficient 2-amination of pyridines and quinolines

Article abstract of DOI:10.1021/jo070189y

(Chemical Equation Presented) Pyridine N-oxides were converted to 2-aminopyridines in a one-pot fashion using Ts₂O-t-BuNH₂ followed by in situ deprotection with TFA. The amination proceeded in high yields, excellent 2-/4-selectivity, and with good functional group compatibility. 2-Amino (iso)quinolines were also obtained in the same manner. Combined with the simple oxidation of pyridines to pyridine N-oxides, this method provides a general and efficient way for amination of 2-unsubstituted pyridines.

Full text of DOI:10.1021/jo070189y

this is usually done by chlorination of pyridine N-oxides with
poor 2,4-regioselectivity and/or low yields.6,7 The most direct
approach would start with 2-unsubstituted pyridines. The
Chichibabin reaction1b,c,8 gives 2-aminopyridines directly from
sodium amide and pyridines, but it is very limited in scope with
unsatisfactory yields and poor functional group tolerance due
to the strongly basic conditions and high temperatures.9
A General and Efficient 2-Amination of Pyridines
and Quinolines
Jingjun Yin,* Bangping Xiang,* Mark A. Huffman,
Conrad E. Raab, and Ian W. Davies
Department of Process Research, Merck Research Laboratories,
P.O. Box 2000, Rahway, New Jersey 07065
Pyridine N-oxides 2 are readily available via oxidation of
pyridines under a variety of different conditions.10 Abramovich
first reported use of imidoyl chlorides to convert pyridine
N-oxides to 2-amidopyridines.11 Synthesis of 2-amidopyridines
from secondary amides or 2-amido(iso)quinolines from primary
amides via in situ generation of imidoyl chlorides or benzoyl
isocyanates has also been reported recently.12 For the synthesis
of 2-aminopyridines, 4-chloro-2,2-dimethyl-2H-1,3-benzoxazine
can be used because the resulting amidopyridine product can
be readily converted to 2-aminopyridines.13 However, this
reagent requires a two-step synthesis,13b and the release of the
2-amino group requires a separate step.
jingjun_yin@merck.com; bangping_xiang@merck.com
ReceiVed January 30, 2007
Pyridine N-oxides were converted to 2-aminopyridines in a
one-pot fashion using Ts2O-t-BuNH2 followed by in situ
deprotection with TFA. The amination proceeded in high
yields, excellent 2-/4-selectivity, and with good functional
group compatibility. 2-Amino (iso)quinolines were also
obtained in the same manner. Combined with the simple
oxidation of pyridines to pyridine N-oxides, this method
provides a general and efficient way for amination of
2-unsubstituted pyridines.
On the other hand, after reacting with an electrophile to form
3, the 2-position is highly activated for nucleophile addition. If
ammonia serves as the nucleophile, 2-aminopyridines 4 could
be obtained. Very few examples of direct conversion of (iso)-
quinoline N-oxides to 2-amino(iso)quinolines are known, and
they give 60-70% yields mostly using NH4OH-TsCl.14
(5) (a) Lang, F.; Zewge, D.; Houpis, I. N.; Volante, R. P. Tetrahedron
Lett. 2001, 42, 3251. (b) Vedejs, E.; Trapencieris, P.; Suna, E. J. Org. Chem.
1999, 64, 6724.
(6) Even complete 4-chlorination is known: (a) Alca´zar, J.; Alonso, J.
M.; Bartolome´, J. M.; Iturino, L.; Matesanz, E. Tetrahedron Lett. 2003,
44, 8983. For other examples: (b) Yamanaka, H.; Araki, T.; Sakamoto, T.
Chem. Pharm. Bull. 1988, 36, 2244. (c) Klemm, L. H.; Louris, J. N.;
Boisvert, W.; Higgins, C.; Muchiri, D. R. J. Heterocycl. Chem. 1985, 22,
1249. (d) Miura, Y.; Takaku, S.; Nawata, Y.; Hamana, M. Heterocycles
1991, 32, 1579. (e) Bremner, D. H.; Dunn, A. D.; Wilson, K. A. Synthesis
1992, 6, 528. (f) Ohta, A.; Takahashi, N.; Shirokoma, Y. Heterocycles 1990,
30, 875. (g) Itoh, T.; Ono, K.; Sugawara, T.; Mizuno, Y. J. Heterocycl.
Chem. 1982, 19, 513.
(7) Deprotonation at the 2-position with a strong base followed by
halogenation is known, but with limited scope. For examples: (a) Cuperly,
D.; Gros, P.; Fort, Y. J. Org. Chem. 2002, 67, 238. (b) Mathieu, J.; Gros,
P.; Fort, Y. Chem. Commun. 2000, 951. (c) Imahori, T.; Uchiyama, M.;
Sakamoto, T.; Kondo, Y. Chem. Commun. 2001, 2450.
2-Aminopyridines and analogues constitute an important
class of compounds in organic synthesis and drug discovery.1
During SAR investigations in the drug discovery process,
derivatization of a 2-unsubstituted pyridine moiety in a complex
molecule to the corresponding 2-aminopyridine is often desired
but only achieved with a long sequence and low efficiency.2
One of the most widely used amination methods is substitution
of 2-halopyridines and analogues with ammonia or an equivalent
under high temperature (150-250 °C) and pressure3 or under
Pd4- or Cu5-catalyzed conditions. However, to use this approach,
a halogen atom must be installed at the 2-position first, and
(8) Chichibabin, A. E.; Zeide, O. A. J. Russ. Phys. Chem. Soc. 1914,
46, 1216.
(1) (a) Scriven, E. F. V. In ComprehensiVe Heterocyclic Chemistry, Part
2; Boulton, A. J., McKillop, A., Eds.; Pergamon: New York, 1984; Vol.
2, pp 165-314. (b) Leffler, M. T. Org. React. 1942, 1, 91. (c) McGill, C.
K.; Rappa, A. AdV. Heterocycl. Chem. 1988, 44, 1-79.
(9) Direct amination of nitropyridines with NH3/KMnO4 or via vicarious
nucleophilic substitution has been reported. (a) Wozniak, M.; Baranski, A.;
Szpakiewicz, B. Liebigs Ann. Chem. 1991, 875. (b) Seko, S.; Miyake, K.
Chem. Commun. 1998, 1519. (c) Makosza, M.; Bialecki, M. J. Org. Chem.
1998, 63, 4878. (d) Bakke, J. M.; Svensen, H.; Trevisan, R. J. Chem. Soc.,
Perkin Trans. 1 2001, 376.
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Bull. 1986, 34, 2013. (b) Jain, S. L.; Sain, B. Chem. Commun. 2002, 1040.
(c) Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetrahedron 1997, 53,
15877. (d) Fields, J. D.; Kropp, P. J. J. Org. Chem. 2000, 65, 5937.
(11) (a) Abramovich, R. A.; Singer, G. M. J. Am. Chem. Soc. 1969, 91,
5672. (b) Abramovich, R. A.; Singer, G. M. J. Org. Chem. 1974, 39, 1795.
(c) Abramovich, R. A.; Rogers, R. B. J. Org. Chem. 1974, 39, 1802. (d)
Abramovich, R. A.; Pilski, J.; Konitz, A.; Tomasik, P. J. Org. Chem. 1983,
48, 4391. (e) Abramovitch, R. A.; Wang, Y.-X. Heterocycles 1987, 26,
2065.
(2) For examples: (a) Song, Y. H.; Clizbe, L.; Bhakta, C.; Teng, W.;
Li, W.; Wong, P.; Huang, B.; Sinha, U.; Park, G.; Reed, A.; Scarborough,
R. M.; Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2002, 12, 2043. (b) Lam, P.
Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M. J.; Galemmo, R. A.;
Fevig, J. M.; Teleha, C. A.; Alexander, R. S.; Smallwood, A. M.; Rossi,
K. A.; Wright, M. R.; Bai, S. A.; He, K.; Luettgen, J. M.; Wong, P. C.;
Knabb, R. M.; Wexler, R. R. J. Med. Chem. 2003, 46, 4405.
(3) For examples: (a) Taylor, E. C.; Corvetti, A. J. J. Org. Chem. 1954,
19, 1633. (b) Ikemoto, T.; Kawamoto, T.; Wada, H.; Ishida, T.; Ito, T.;
Isogami, Y.; Miyano, Y. o.; Mizuno, Y.; Tomimatsu, K.; Hamamura, K.;
Takatani, M.; Wakimasu, M. Tetrahedron 2002, 58, 489. (c) Gudmundsson,
K. S.; Johns, B. A. Org. Lett. 2003, 5, 1369. (d) Kuramochi, T.; Kakefuda,
A.; Yamada, H.; Tsukamoto, I.; Taguchi, T.; Sakamoto, S. Bioorg. Med.
Chem. 2005, 13, 4022.
(12) (a) Manley, P. J.; Bilodeau, M. T. Org. Lett. 2002, 4, 3127. (b)
Couturier, M.; Caron, L.; Tumidajski, S.; Jones, K.; White, T. D. Org. Lett.
2006, 8, 1929.
(13) For examples: (a) Wachi, K.; Terada, A. Chem. Pharm. Bull. 1980,
28, 465. (b) Ujjainwalla, F.; Walsh, T. F. Tetrahedron Lett. 2001, 42,
6441.
(4) (a) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417. (b) Mathes,
B. M.; Filla, S. A. Tetrahedron Lett. 2003, 44, 725. (c) Bolm, C.; Frison,
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3767.
10.1021/jo070189y CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/15/2007
4554
J. Org. Chem. 2007, 72, 4554-4557

TABLE 1. Amination of Pyridine N-Oxidea
SCHEME 1
entry
A-B
solvent
conv (%)
4a/5
4a/10a
1
2
TsCl
Ts2O
TsCl
Ts2O
Ts2O
AcCl
AcCl
MsCl
Ms2O
Ts2O
Ts2O
Ts2O
Ts2O
Ts2O
TsCl
TsCl
TsCl
TsCl
Ts2O
Ts2O
Ts2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
61
60
61
25
27
0
0
0
16
68
5
0.46
0.48
0.46
0.17
0.18
0
0
0
-
0.58
0.02
0.05
0.80
0.76
0.15
0.80
0.38
0.61
1.3
19
14
12
3.8
4.5
-
3b
4b
5c
6b
HoweVer, the corresponding reaction with pyridine N-oxides
has failed (Vide infra).15 The inefficiency of this process is due
to multiple side reactions. First, it is difficult to efficiently form
the highly activated species 3 as a stable intermediate.16 Once
formed, 3 is exposed to the attack of the counterion B- (B )
Cl,6 TsO,6d,17 AcO18) at the 2- and 4-positions to give 6 and 7
as byproducts (vide infra). If the amine nucleophile is added
before the activating reagent, reaction between the two reagents
to give 5 becomes a major side reaction. Additionally, further
reaction of product 4 with 3 or the activating reagent signifi-
cantly lowers the yield.15During the course of the process
development of a drug candidate, we needed an efficient and
convenient method to convert a 2-unsubstituted pyridine moiety
to a 2-aminopyridine moiety. Here we wish to report a general
and efficient method to introduce a 2-amino group to 2-unsub-
stituted pyridines and (iso)quinolines.
7
8
9
-
-
8.6
12
-
10
11
12
13
14d
15d
16
17
18
19
20e
21d,e,f
MeCN
DMF
8
-
EtOAc
EtOAc
EtOAc
CHCl3
DCE
PhCF3
PhCF3
PhCF3
PhCF3
87
74
20
79
55
74
84
60
100
18
43
48
14
16
30
22
25
59
0.66
0.83
a Reaction conditions: to a solution of 0.25 mmol of 2a and 4.5 equiv
of t-BuNH2 in 2.5 mL of solvent was added 1.75 equiv of activating reagent
A-B at rt. Most reactions gave no further conversion after 15 min (those
with TsCl took a few hours). b Activating reagent was added before
t-BuNH2. c Ts2O was aged with 2a for 30 min before adding t-BuNH2.d Run
at 0 °C. e 5 mL of solvent/mmol 2a. f 6 equiv of t-BuNH2 and 2.5 equiv of
Ts2O were used.
Not surprisingly,15 when we attempted the amination of
pyridine N-oxide with TsCl-NH4OH in CHCl3 or CH2Cl2,14
only ∼10% of the desired product was obtained with a large
amount of TsNH2 and Py2NTs due to dimerization and further
tosylation of the product. We set out to study the reaction
parameters, such as the activating reagent, solvent, and par-
ticularly the ammonia surrogate R1NH2, hoping a bulky yet
cleavable R1 group such as tert-butyl would disfavor the
undesired byproducts 5-9 (Table 1).
Indeed, when pyridine N-oxide was treated with 1.75 equiv
of TsCl and 4.5 equiv of t-BuNH2 in CH2Cl2, a clean reaction
was observed with ∼61% conversion. Very little dimerization
or tosylation byproduct was observed. Note that the inexpensive
t-BuNH2 also served as the base for this reaction. Very
importantly, in contrast to poor 2-/4-selectivity in chlorination
reactions,6 a very good 2-/4-regioselectivity was obtained with
this amination (entry 1). The only major side reaction is direct
reaction between activating reagent and the amine to form 5,
so the ratio between the desired product 4a and 5 was used to
monitor the efficiency under different conditions. Unfortunately,
the 4a/5 ratio was only 0.46 in this case. Use of Ts2O19 gave
similar results (entry 2). To minimize the reaction between two
reagents, we attempted to form activated species 3 in the absence
of amine nucleophile, but premixing the N-oxide with TsCl or
Ts2O followed by amine addition gave no improvement (entries
3-5).20 Other activating species such as AcCl, MsCl, or Ms2O
were ineffective (entries 6-9).
A solvent screen revealed that EtOAc gave a high 4a/5 ratio,
while MeCN or DMF was ineffective (entries 10-13). The 2-/
4-amination selectivity was improved to >40/1 when the
reaction was run at 0 °C with Ts2O or TsCl, but this also resulted
in lower ratios of 4a/5, likely due to limited solubility of 2a in
EtOAc (entries 14 and 15). Combination of TsCl and CHCl3
also gave a high 4a/5 ratio (entry 16). The highest 4a/5 ratio
was achieved at 1.3/1 with Ts2O-PhCF3 (entry 19). Complete
conversion and high 2-/4-selectivity (∼59/1)21 were finally
achieved at 0 °C with larger amounts of reagents (entry 21).
Lower 4a/5 ratio was due to the higher concentration (entry 19
vs 20), which is important for a more efficient one-pot process.
(14) (a) Glennon, R. A.; Slusher, R. M.; Lyon, R. A.; Titeler, M.;
McKenney, J. D. J. Med. Chem. 1986, 29, 2375. (b) Miura, Y.; Takaku,
S.; Fujimura, Y.; Hamana, M. Heterocycles 1992, 34, 1055. (c) Storz, T.;
Marti, R.; Meier, R.; Nury, P.; Roeder, M.; Zhang, K. Org. Process Res.
DeV. 2004, 8, 663. (d) Couturier, M.; Le, T. Org. Process Res. DeV. 2006,
10, 534. (e) Gerster, J. F.; Lindstrom, K. J.; Miller, R. L.; Tomai, M. A.;
Birmachu, W.; Bomersine, S. N.; Gibson, S. J.; Imbertson, L. M.; Jacobson,
J. R.; Knafla, R. T.; Maye, P. V.; Nikolaides, N.; Oneyemi, F. Y.; Parkhurst,
G. J.; Pecore, S. E.; Reiter, M. J.; Scribner, L. S.; Testerman, T. L.;
Thompson, N. J.; Wagner, T. L.; Weeks, C. E.; Andre, J.-D.; Lagain, D.;
Bastard, Y.; Lupu, M. J. Med. Chem. 2005, 48, 3481.
(15) Solekhova, M. A.; Kurbatov, Y. V. Russ. J. Org. Chem. 2002, 38,
1192.
(16) Only methylated (A ) Me) or acylated [A ) Ac or RC(O)-]
N-oxides are observed. The formation of the former is low yielding (ref
6a); the latter was only used for Grignard addition: (a) Webb, T. R.
Tetrahedron Lett. 1985, 26, 3191. (b) Fakhfakh, M. A.; Franck, X.; Fournet,
A.; Hocquemiller, R.; Figade`re, B. Tetrahedron Lett. 2001, 42, 3847.
(17) Umemoto, T.; Tomizawa, G.; Hachisuka, H.; Kitano, M. J. Fluorine
Chem. 1996, 77, 161.
(19) Ts2O is readily available on both small and large scales.
(20) This might indicate a reversible activation of 2a by TsCl/Ts2O or a
preferred amine attack at the sulfur atom of activated species 3a. In the
case of Ts2O, small amounts of water might cause decomposition of Ts2O
and low conversion.
(18) (a) Kelly, T. R.; Bridger, G. J.; Zhao, C. J. Am. Chem. Soc. 1990,
112, 8024. (b) Bashir, M.; Kingston, D. G. I.; Carman, R. J.; Tassell, R. L.
v.; Wilkins, T. D. Heterocycles 1987, 26, 2877.
(21) The 2-/4-amination selectivity was improved significantly by
lowering the temperature from rt to 0 °C, but it is not clear how it was
affected by solvents and activating reagents.
J. Org. Chem, Vol. 72, No. 12, 2007 4555

TABLE 2. Direct 2-Amination of Pyridine N-Oxidesa
TABLE 3. Direct 2-Amination of (Iso)quinoline N-Oxidesa
a Reaction conditions: same as in Table 2 but with 2.0-2.3 equiv of
Ts2O.
rich and an electron-withdrawing group proceeded well. In
general, very little, if any, 4-amination was observed. In the
case of 3-picoline N-oxide, 2- and 6-amination products were
obtained in a 1.7/1 ratio (entry 3). A trisubstituted pyridine
N-oxide was also aminated very efficiently (entry 10). The
amination step typically took just a few minutes for completion;
the in situ deprotection with TFA required 2-6 h.
The one-pot amination method was readily expanded to
quinoline N-oxides and isoquinoline N-oxide (Table 3). Sub-
stituted quinoline N-oxides were selectively aminated at the
2-position in high yields (entries 1-3). These N-oxides typically
required slightly less Ts2O than the simple pyridine N-oxides.
For the isoquinoline N-oxide, if Ts2O was added for activation
in the absence of t-BuNH2, significant amounts of the tosylation
product (6) and other byproducts were observed within minutes
at rt. These byproducts were mostly eliminated if Ts2O was
added after t-BuNH2 (entry 4). Note that quinoline N-oxide 2k
was obtained via oxidation of quinoline with MCPBA, so the
sequence represents an efficient 2-amination of 2-unsubstituted
quinoline.
In summary, we have developed a general and efficient
method to convert pyridine N-oxides to 2-aminopyridines in a
one-pot process in high yields and high 2-/4-regioselectivity
(>50/1). The process uses commercially available reagents
t-BuNH2 and Ts2O and shows good functional group compat-
ibility. The use of t-BuNH2 was critical for shutting down side
reactions such as dimerization and tosylation of the product as
well as suppressing the reaction between the amine and the
activating reagent Ts2O. TFA treatment of the crude reaction
mixture effectively removed the t-Bu group. Starting with
2-unsubstituted pyridines or quinolines, simple oxidation fol-
lowed by this amination provides an efficient synthesis of
2-aminopyridines or 2-aminoquinolines.
a Reaction conditions: to a solution of 2.0 mmol of pyridine N-oxide
and t-BuNH2 (5-9 equiv) in PhCF3 (CH2Cl2 or CHCl3 might be added to
dissolve the substrates) at 5-12 °C (20 °C for entry 5) was added 2.0-4.3
equiv of Ts2O, 15 min; then TFA, 70 °C, 2-6 h (12 h for entry 9). Isolated
yields are reported. b Combined yield of inseparable isomers.
Compound 4a could be isolated at this point in 92% yield.
2-Aminopyridine was readily obtained by deprotection in neat
TFA. However, a more efficient one-pot process was realized
by adding TFA (2.5 mL/mmol) to the reaction mixture after
completion of tert-butyl amination followed by heating at 70
°C to provide 2-aminopyridine in 84% yield.
We also used HN(SiMe3)2 instead of t-BuNH2 as a more
readily cleavable ammonia surrogate, but the product was
hydrolyzed under the amination conditions to give the 2-ami-
nopyridine that reacted further with the N-oxide to give
significant amounts of dimers.22
Experimental Section
Representative Procedure for 2-Amination: To a solution
of pyridine N-oxide (190 mg, 2 mmol, 1.0 equiv) and tert-
butylamine (1.05 mL, 10 mmol, 5.0 equiv) in PhCF3 (10 mL)
Using the above optimized one-pot conditions, a variety of
substituted pyridine N-oxides could be directly aminated at the
2-position in high yields (Table 2). Functional groups such as
2- and 4-ester groups, chloro, methoxy, and pyridyl groups were
well tolerated. Amination of pyridine N-oxides with an electron-
(22) To prevent cleavage of TMS groups under reaction conditions, a
stronger organic base (e.g., i-Pr2NEt) was added to quench the TsOH, but
this resulted in unidentified impurities, possibly from the organic base adding
to the pyridine. We also noticed that NEt3 added to the 2-position when
combined with a pyridine N-oxide and Ts2O.
4556 J. Org. Chem., Vol. 72, No. 12, 2007

at 0 °C was added Ts2O (1.30 g, 4.0 mmol, 2.0 equiv) as a
solid in portions while maintaining the reaction temperature at
<5 °C. LC revealed incomplete conversion after 10 min. More
tert-butylamine (0.21 mL, 2.0 mmol, 1.0 equiv) was added
followed by Ts2O (0.33 g, 1.0 mmol, 0.5 equiv). Complete
conversion was obtained in 10 min. TFA (5 mL) was added to
the reaction mixture, which was then aged at 70 °C for 5 h.
The solution was concentrated to oil and diluted with water (5
mL) and CH2Cl2 (10 mL). The pH was adjusted to ∼10 with
50% aq NaOH (∼4 mL). The top aqueous layer was extracted
with CH2Cl2 (4 × 10 mL). The combined organic layers were
concentrated and chromatographed (SiO2, 2 × 20 cm, 1-3%
MeOH/CH2Cl2) to give 2-aminopyridine (158 mg, 84% yield).
NMR data matched those of commercial material. Note that, if
desired, it is also possible to crystallize the HCl salt of the
product from the crude product. See details in Supporting
Information.
Supporting Information Available: Experimental procedures
and characterization data for amination products (Tables 2 and 3).
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO070189Y
J. Org. Chem, Vol. 72, No. 12, 2007 4557