Nucleophilic amination of methoxypyridines by a sodium hydride-iodide composite

Article abstract of DOI:10.1039/C8CC05979A

A new protocol for nucleophilic amination of methoxypyridines and their derivatives was developed using sodium hydride (NaH) in the presence of lithium iodide (LiI). The method offers a concise access to various aminopyridines which are potentially of medicinal interest.

Full text of DOI:10.1039/C8CC05979A

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Nucleophilic amination of methoxypyridines by a sodium hydride-
iodide composite
Jia Hao Pang,a Atsushi Kaga,a and Shunsuke Chiba*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new protocol for nucleophilic amination of methoxypyridines amine functionality onto the pyridine rings.7-9 However, these
and their derivatives was developed using sodium hydride (NaH) methods have thus far been proven successful only for the C2-
in the presence of lithium iodide (LiI). The method offers a concise and C4-amination in terms of the regioselectivity due to the
access to various aminopyridines which are potentially of inherent reactivity of the pyridines or pyridyne
medicinal interest.
intermediates.10,11
The pyridine ring is one of the most essential aromatic
heterocycles found in small molecule pharmaceuticals and
agrochemicals.1 Therefore, it is highly important to exploit
new methods to construct substituted pyridines and to install
functionality of interest onto the pyridine ring, while inherent
electron-deficient and basic nature of pyridines often hampers
development of versatile reaction tools to construct and
functionalize them.
Especially, installation of amine
functionality (i.e. amination of pyridines) offers a direct access
to aminopyridines, which are utilized as an important core of
various pharmaceutical drugs.2 At present, the state-of-the-art
approach for synthesis of aminopyridines involves transition-
metal-catalyzed amination of halopyridines (Scheme 1a).3,4
Electrophilic amination of pyridyl metal nucleophiles with N-
electrophiles such as hydroxylamine derivatives (typically
under Cu catalysis)5 and radical imidation/amination of
pyridines under redox catalysis have proven promising as an
alternative method (Scheme 1b and c).6 On the other hand,
the recent rigid guideline to the level of residual transition-
metal contamination in the pharmaceutical ingredients
attracts attention to the needs for transition-metal-free
processes. In this context, nucleophilic aromatic substitution
of (pseudo)halopyridines with amine nucleophiles, that
proceed via the SNAr mechanism or via the corresponding
pyridyne intermediates, is one of the reliable way to install
Scheme 1. Amination of pyridines.
We recently disclosed that unprecedented use of sodium
hydride (NaH) by its solvothermal treatment with sodium
iodide (NaI) or lithium iodide (LiI). The resulting NaH-iodide
composites could show hydride-donor reactivity, enabling
hydrodecyanation, reduction of amides into aldehydes, and
hydrodehalogenation of bromo- and iodoarenes as well as
dearylation of arylphosphine oxides.12 During these studies,
we observed that the pyridine rings, which are often
susceptible to the common hydride reagents,13 are tolerated in
the reductive transformations in the presence of the NaH-
iodide composite (Scheme 2a and 2b). We also found that
nucleophilic amination of methoxyarenes was enabled by the
NaH-iodide composite (Scheme 2c).14,15 Stimulated by these
discoveries, we wondered if the NaH-iodide composite is
capable of functionalizing methoxypyridines through
a.Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, Singapore 637371,
Singapore.
Electronic Supplementary Information (ESI) available: Electronic Supplementary
Information (ESI) available: Experimental details, including procedures, syntheses nucleophilic amination without undesired collapse of the
and characterization of new compounds; 1H and 13C NMR spectra. See
DOI: 10.1039/x0xx00000x
pyridine ring. Optimization of the reaction conditions, scope
and limitation, and synthetic application of the nucleophilic
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amination of methoxypyridines by the NaH-LiI system are opening of the morpholine adduct 3ad followed by hydrolysis
described herein (Scheme 2D).
of the resulting enol intermediate (see ESI for more details).
This ring-fragmentation of the morpholine moiety was
prevented using cis-2,6-dimethylmorpholine (2e), affording
3ae as a sole product. Amination with piperazines took place
efficiently (for 3af
-
3ah). It is of worthy to note that the
2g proceeded
reaction with cis-2,6-dimethylpiperazine
(
)
selectively at the less hindered site, while double amination
took place with none-substituted piperazine (2h). Unique
chemoselectivity was observed in the reaction with 4-
hydroxypiperidine (2i), that affords amination product 3ai
keeping
a
free hydroxyl group intact. Use of 4-
aminopiperidines 2j and 2k gave the corresponding amination
products 3aj and 3ak, respectively, in good yields. Acyclic
secondary amines 2l and 2m also worked smoothly. The
reaction of 1,3-propanediamine 1n with 2.1 equiv of 1a
afforded bis-pyridyl adduct 3an in 61% yield. We found that
the reaction of n-butylamine
(2o) provides 3-aminated
pyridine 3ao in 61% yield through nucleophilic substitution of
the 3-methoxy group along with formation of Chichibabin
amination product, 2-aminopyridine 3ao’ in 7% yield,16
whereas that of bulkier cyclohexylamine (2p) gave nucleophilic
amination product 3ap in 56% yield as a sole product.
Scheme 2. Molecular Transformations by NaH-iodide composite
We commenced our studies with the reactions of 3-
methoxypyridine (1a) and piperidine (2a) (Table 1). The
reaction of 1a with 2 equiv of 2a in the presence of NaH (5
equiv) and NaI (2 equiv) in THF at 60 °C gave 3-(piperidin-1-
yl)pyridine (3aa) in 7% yield with incomplete conversion (37%)
even after stirring for 24 h (Entry 1). We found that use of LiI
(2 equiv) in place of NaI dramatically enhanced the reaction
efficiency, resulting in full conversion within 8 h to provide 3aa
in 88% yield (Entry 2). This protocol could be performed
efficiently in a large (50 mmol) scale. It should be noted that
the reaction was not mediated only with NaH (Entry 3).
Table 1 Optimization of the reaction conditions
Entry
Additive
Time [h]
Yield [%]
Conversion [%]c
1
2
3
NaI
LiI
–
24
8
7
88 (92)b
0
37
>99
23
24
a The reactions were conducted using 0.5 mmol of 3-methoxypyridine (1a) and 1
mmol of piperidine (2a) in THF (0.5 mL: 1 M) and isolated yield of 3aa were noted
b
c
above. Isolated yield in 50 mmol scale. 1H NMR yields based on an internal
standard.
Having optimized the reaction conditions with the NaH-LiI
system, we investigated C3-amination of 3-methoxypyridine
a
(
1a) using various amines
2
(Scheme 3). Installation of Scheme 3. Screening of amines
2
.
The reactions were conducted using 0.5
in THF (0.5 mL: 1 M)
were noted above. b The reaction was
conducted using 1 mmol of 1a and 0.5 mmol of amine and isolated yield of
was calculated based on amine
C The reaction was conducted using 7 equiv of
NaH and 2 equiv of LiI at 90 C in sealed tube.
mmol of 3-methoxypyridine (1a) and 1 mmol of amines
2
aliphatic nitrogen-heterocycles such as pyrrolidine (for 3ab
)
and isolated yields of 3-aminopyridines
3
and azepane (for 3ac) worked smoothly. The reactions of
morpholine (2d) afforded not only morpholine adduct 3ad but
also ethanolamine adduct 3ad’ in 32% and 55% yields,
respectively. Formation of 3ad’ occurred presumably via
2
3
2.
°
deprotonation at the
α-oxy position and subsequent ring-
2 | J. Name., 2012, 00, 1-3
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We next searched a scope and limitation of pyridine pyrrolidine (2b) to afford
derivatives
Amination of even 2/4-alkoxypyridines commonly requires afford 3sa in 81% yield, while moderate efficiency was
assist of an electron-withdrawing group (EWG) such as a nitro observed in the second C5-amination of 3sa to (Scheme 6b).
6
in 79% yield. The first amination of
1
using piperidine 2a as a nucleophile (Scheme 4). 2,5-dimethoxypyridine (1s) took place exclusively at C2 to
7
group on the pyridine ring.17 On the other hand, our protocol Sequential diamination could be conducted on 3,5-
with the NaH-LiI system enabled amination at either C2- or C4- dimethoxypyridine (1t) in good yields (Scheme 6c).
position smoothly without the assist of EWG (for 3ba and 3ca).
We also confirmed that NaH alone does not mediate the C2/4
amination. We found that the methyl and phenyl substituents
in various positions do not affect the efficiency of the present
amination (for 3da
-3ma). This protocol was found applicable
to the amination of 1-(5-methoxypyridin-2-yl)-1H-indole (1n
)
Scheme 5 Sequence of directed C-H phenylation and nucleophilic amination of 3-
methoxypyridine (1a).
and 2-methoxyquinoline (1o) as well as 4- and 6-methoxy-1-
phenyl-1H-pyrrolo[2,3-b]pyridines (1p and 1q).
Scheme 4. Screening of methoxypyridines
using 0.5 mmol of methoxypyridines and 2 equiv of piperidine (2a) with NaH (5
1.
a All the reactions were conducted
1
equiv) and LiI (2 equiv) in THF (0.5 mL: 1 M) at 60 °C. Isolated yields of the
products were noted above.
The methoxy group on the pyridine ring can be used as a
directing group for deprotonative ortho-metallation, thus
capable of further installation of functionality through the
reactions of the resulting pyridyl metal species with various
electrophiles.18 For example, it was recently reported by
Daugulis that the methoxy group on 1a can be used for the
directed lithiation followed by arylation at the C4 position to
Scheme 6 Sequential amination of dimethoxypyridines 1r
based on the recovery of 3sa
, 1s and 1t.
a 76% yield
.
This work demonstrates new use of the NaH-iodide
composite for unprecedented nucleophilic amination of
methoxypyridines to prepare aminopyridine derivatives in a
concise fashion. Further investigation on use of the NaH-
iodide composite to explore other types of molecular
transformations is ongoing in our laboratory.
afford
together with our current amination protocol for synthesis of
4-phenyl-3-(piperidin-1-yl)pyridine ( ).
4
(Scheme 5).17a We took advantage of this method
5
We found that the present procedure is amenable to
sequential double amination of dimethoxypyridines (Scheme
6). For example, mono-amination of 2,6-dimethoxypyridine
This work was financially supported by Nanyang
Technological University and the Singapore Ministry of
Education (Academic Research Fund Tier 1: RG10/17).
(
1r) with piperidine (2a) was attained to give 3ra in 76% yield
(Scheme 6a), that can be followed by second-amination with
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A new protocol for nucleophilic amination of methoxypyridines and their
derivatives was developed using sodium hydride (NaH) in the presence of
lithium iodide (LiI).