Synthesis of aminopyridines from 2-fluoropyridine and lithium amides

Article abstract of DOI:10.1016/j.tetlet.2004.06.132

Lithium amides promote the amination of 2-fluoropyridine under mild reaction conditions, providing 2-aminopyridines in good yields and purity. Treatment of 2-fluoropyridine with 1 equiv of lithium amide at room temperature affords complete conversion afte

Full text of DOI:10.1016/j.tetlet.2004.06.132

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6417–6420
Synthesis of aminopyridines from 2-fluoropyridine and lithium
amides
a
Lubov Pasumansky, Armando R. Hernandez, Soya Gamsey, Christian T. Goralski
a
a
b
´
and Bakthan Singarama,
*
aDepartment of Chemistry and Biochemistry, University of California––Santa Cruz, Santa Cruz, CA 95064, USA
bDowpharma, The Dow Chemical Company, Midland, MI 48674, USA
Received 11 June 2004; accepted 30 June 2004
Available online 20 July 2004
Abstract—Lithium amides promote the amination of 2-fluoropyridine under mild reaction conditions, providing2-aminopyridines
in good yields and purity. Treatment of 2-fluoropyridine with 1equiv of lithium amide at room temperature affords complete con-
version after 2h. To our knowledge, this is the first study of lithium amide-promoted amination of fluoropyridines that are not fur-
ther activated by electron-withdrawinggroups.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Aminopyridines have been shown to be biologically ac-
tive molecules. There are several aminopyridine-based
pharmaceuticals, which are used to treat a range of dis-
orders.1 Additionally, because of their chelatingabili-
ties, aminopyridines are commonly used as ligands in
inorganic and organometallic chemistry.2 If substituted
Scheme 1. Reaction of 2-Fluoropyridine with LAB.
with optically active groups, they could potentially serve
as chiral auxiliaries or chiral ligands in asymmetric reac-
by coordination to boron duringthe reaction. To check
this hypothesis, we treated 2-fluoropyridine with
BH3ÆSMe2 to form a 2-fluoropyridine-borane complex.
We then reacted the complex with lithium dipropyl-
amide (formed from dipropylamine and n-BuLi) at
0ꢁC (Scheme 2). Interestingly, 2-dipropylaminopyridine
was isolated from this reaction in 50% yield.
tions. For these reasons, aminopyridines are valuable
synthetic targets. The methods, which currently exist
for the synthesis of aminopyridines from halopyridines
include nucleophilic aromatic substitution reactions
(SNAr) with free amines under high pressure3 and/or
high temperature.4 Several years ago, Buchwald and
others have demonstrated transition metal-catalyzed
cross-couplingof bromo and chloropyridines with
amines as an efficient route to aminopyridines.5
Recently, we have disclosed a method of converting2-
fluoropyridines to aminopyridines with lithium amino-
borohydrides (LAB) (Scheme 1).6 This method is also
applicable to 2-chloro and 2-bromopyridines.
This result intrigued us since it is known that sterically
hindered lithium amides such as LDA, do not promote
amination of 2-halopyridines. Rather, these reactions re-
sult in ortho-lithiation.7 To test the generality of this
Our investigations regarding a possible mechanism for
the reaction of 2-fluoropyridine with LAB reagent led
us to hypothesize that the pyridine could be activated
Keywords: Aminopyridines; 2-Fluoropyridine; Lithium amides.
*
Scheme 2. Reaction of 2-fluoropyridine with BMS and lithium
dipropylamide.
Correspondingauthor. Tel.: +1-831-459-3154; fax: +1-831-459-
2935; e-mail: singaram@chemistry.ucsc.edu
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.132

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L. Pasumansky et al. / Tetrahedron Letters 45 (2004) 6417–6420
Table 1. Aminopyridines obtained from the reaction of 2-fluoropy-
ridine–borane complex and lithium amide
reaction, we reacted three other lithium amides with the
2-fluoropyridine-borane complex. These results are sum-
marized in Table 1.
Entry
1
Amide
Product
Yield (%)
62
In order to determine the importance of pre-activating
2-fluoropyridine with BH3, we also performed the reac-
tion in the absence of BMS. When 2-fluoropyridine was
reacted with lithium pyrrolidide, we were pleasantly sur-
prised to find that 2-pyrrolidinopyridine was obtained in
80% yield. Although we found no prior examples of sim-
ple lithium amides promotingnucleophilic substitution
reactions of 2-fluoropyridine, it was recently reported
that 2- and 4-cyanopyridines can be aminated with lith-
ium amides in the presence of CsF.8
2
3
34
35
To determine the scope of this amination method, a
series of primary and secondary lithium amides were
reacted with 2-fluoropyridine to generate the corre-
spondingaminopyridines ( Table 2).9 It is important to
note that this methodology is complementary to the
reaction of 2-fluoropyridine with LAB reagents. We
found that monoalkylaminopyridines can be synthesized
from primary lithium amides (Table 2, entries 5, 8 and
9), whereas these products were difficult to obtain using
primary amine-derived LAB reagents.
By usingenantiomerically pure lithium amides in this
reaction, the synthesis of chiral aminopyridines has been
achieved. When optically pure limonene-derived amino
Table 2. Reactions of 2-fluoropyridine with various lithium amides
Entry
1
Amide
Product
Yield (%)a
80
2
3
4
82
85
83
5
40
6
7
64
82
8
64
9
10b
a Isolated yields.
b 2equiv of n-BuLi was used, the product was purified by flush column chromatography (15% EtOAc/Hex).

L. Pasumansky et al. / Tetrahedron Letters 45 (2004) 6417–6420
Table 3. Reactions of 2-fluoropyridine with free amines
6419
alcohol ((1S,2S,5R)-2-amino-2-methyl-5-(prop-1-en-2-
yl)cyclohexanol) was treated with n-BuLi (2equiv) and
reacted with 2-fluoropyridine, the aminopyridine prod-
uct was isolated in low yield after column chromatogra-
phy (Table 2, entry 9). This low yield is most likely due
to steric hindrance from the methyl group. Conversely,
when nonsterically demanding( R)-(+)-a-methylbenzyl-
amine (Table 2, entry 8) was used in the same manner,
the chiral aminopyridine product was obtained in 60%
yield.
Entry Fluoropyridine Amine
1
Product
Yield (%)a
60b 12c
To determine the scope of this methodology, we at-
tempted to extend the reaction to other halopyridines.
Interestingly, when we reacted 2-chloro and 2-bromopyr-
idine with lithium amides we observed openingof the py-
ridine ring( Scheme 3).
2
3
15b
––
––
NRb,c
A literature search revealed that a similar type of pyr-
idine ringopeningreaction has been observed during
the reaction of trialkylboranes with 2-bromo-6-lithiopyr-
idine, as well as duringirradiation of pyridine N-oxide
in the presence of secondary amines.10 A proposed expla-
nation for our result is described mechanistically in
Scheme 4.
NRb,c
4
5
62
The reaction of lithium amides with 2-fluoropyridine is
an efficient route to 2-aminopyridines. It is possible
however, to obtain 2-aminopyridines from the reaction
of free amines with 2-fluoropyridine if the amine is
exceptionally nucleophilic, or if the pyridine ringis fur-
ther activated by electron-withdrawingsubstituents. 11 It
has been reported that azetidine, a highly nucleophilic
amine, reacts with 2-fluoropyridine at room temperature
to give the corresponding aminopyridine in 50% yield.12
Similarly, we found that by treating2-fluoropyridine
with pyrrolidine at room temperature, the aminopyr-
idine product is obtained in 60% yield. Less nucleophilic
amines do not react with 2-fluoropyridine even after ex-
tended reflux (Table 3, entry). We observed that very
activated pyridines, such as 2-fluoro-4-trifluoromethyl-
pyridine, react with free amines to generate aminopyr-
idines. Usingthis substrate, even less nucleophilic
free amines can be used to synthesize aminopyridines.13
Table 3 summarizes the results obtained from reactions
involvingfree amines and 2-fluoropyridines.
6
86
a Isolated yields.
b The reaction was run neat.
In conclusion, we have described mild and convenient
method for the synthesis of 2-aminopyridines from 2-
fluoropyridine and various lithium amides. Both pri-
mary and secondary lithium amides have been shown
to be effective in these simple amination reactions. Using
this method, we have successfully synthesized enantio-
merically pure aminopyridines, which can serve as
potential ligands in asymmetric reactions.
Acknowledgements
We would like to thank Lacie Hirayama for technical
support and NIH (#GM07910) for financial support
for A.H.
Supplementary data
Scheme 3. Reaction of lithium amides with 2-bromo and 2-chloropyr-
idines.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2004.06.132.
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