A general and versatile synthesis of 2-alkyl-4-aminopyridines

Article abstract of DOI:10.1016/S0040-4039(01)00081-8

A versatile two-step synthesis of 2-alkyl-4-aminopyridines from commercially available cis-1-methoxy-1-buten-3-yne is described. Acylation of the yne derivative followed by amination and cyclization in ammonia produced the desired substituted pyridines in high yield.

Full text of DOI:10.1016/S0040-4039(01)00081-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1847–1849
A general and versatile synthesis of 2-alkyl-4-aminopyridines
Vidyadhar B. Hegde,a,* James M. Rengaa and John M. Owenb
aDiscovery Research, Dow AgroSciences, Dow Venture Center, 9330 Zionsville Road, Indianapolis, IN 46268-1054, USA
bProcess Research, Dow AgroSciences, Dow Venture Center, 9330 Zionsville Road, Indianapolis, IN 46268-1054, USA
Received 29 November 2000; accepted 29 December 2000
Abstract—A versatile two-step synthesis of 2-alkyl-4-aminopyridines from commercially available cis-1-methoxy-1-buten-3-yne is
described. Acylation of the yne derivative followed by amination and cyclization in ammonia produced the desired substituted
pyridines in high yield. © 2001 Elsevier Science Ltd. All rights reserved.
2-Alkyl-4-aminopyridines 1 are key intermediates for
the preparation of N-(3-chloro-2-ethylpyridin-4-yl)-
arylacetamides, potent inhibitors of mitochondrial elec-
tron transport which show broad spectrum control of
insects, mites and nematodes.1 Although numerous syn-
theses of 2,6-dialkyl-4-aminopyridines have been
reported,2 practical, scalable routes for the preparation
of 2-alkyl-4-aminopyridines are lacking. For example,
direct amination of haloalkylpyridines is reported,3 but
the relative inaccessibility of 4-halo-2-alkylpyridine
makes this an unattractive approach.4 Alternatively, the
classical entry, and most commonly used method, into
this structural type involves the reduction of the 4-
nitro-2-alkylpyridine N-oxides. Aside from problems
associated with the isolation of the product, the yield in
our hands was poor and variable (5–33% yield).5
Although these methods have general applicability they
are often difficult to perform on a large scale and,
moreover, lack versatility to accommodate a variety of
substituents. Accordingly, an efficient and scalable syn-
thesis of a wide assortment of 2-substituted 4-aminopy-
ridines was required for the analog synthesis and
sample preparation for field studies.
Retrosynthetically, 2-alkyl-4-aminopyridine
1 arises
from the cyclization of the enamino derivative, as
depicted in Scheme 1. The enamino moiety presumably
can be generated from the attack of ammonia on the
ketoalkyne 2 in a Michael fashion. This ketoalkyne
should be readily obtainable from cis-1-methoxy-1-
buten-3-yne 36 and an anhydride using known metala-
tion chemistry, as illustrated in Scheme 2.7
Scheme 1.
Scheme 2.
Keywords: aminopyridines; cis-1-methoxy-1-butyn-3-yne; acetylenic ketones.
* Corresponding author. E-mail: vbhegde@dowagro.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00081-8

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V. B. Hegde et al. / Tetrahedron Letters 42 (2001) 1847–1849
Table 1. Acylation of cis-1-methoxy-1-buten-yne
Table 2. Aminolysis of 2c
R
Substratea
Yieldb
Purity % GC
Conditions
Yields (isolated)a
2a
2b
2b
2c
2d
2e
2f
Me
CF3
CF3
Et
C2F5
i-Pr
CycloPr
t-Bu
A
A
C
A
A
A
B
97
80
82
96
81
98
95
80
45c
95
69
88
94
90
91
89
90
1c
5
40–100°C
20–30°C
75–80°C, 50% EtOH
50–55°C, 10% THF
50–55°C, 50% HCONH2
88% (68%)
79% (55%)
37%
76%
90%
12%
15%
19%
19%
6%
2g
2h
A
D
(CH2)3OH
a Performed at 0.1 mol scale.
a A=(RCO)2O, B=RCOCl, C=RCON(OCH3)CH3, D=butyrolac-
tone.
With the acetylenic ketone 2c in hand, focus was
directed toward the transformation of 2c into 1c
(Scheme 3). High pressure aminolysis of ketone 2c in
methanol at 100–130°C for 14 h (100 psi) gave an 82%
isolated yield of 4-amino-2-ethylpyridine 1c.9 When the
reaction was run in ethanol at 130°C, a slow conversion
(40 h) occurred and a poor yield (45%) resulted, sug-
gesting that the choice of solvent is critical. It was also
observed during scale-up that higher temperatures were
not tolerated, resulting in lower yields. Consequently,
the optimal yield was obtained when aminolysis was
performed at 100°C (100 psi) for 14 h.
b Yields are crude oils of listed GC purities and were of sufficient
purity to be converted to the corresponding alkyl aminopyridines.
These oils were often distilled for analytical sample.
c Isolated yield, considerable decomposition occurred during Kugel-
rohr distillation.
Metalation of 3 at −78°C, followed by treatment with
propionic anhydride, produced the acetylenic ketone 2c
(R=Et) in 76% isolated yield after Kugelrohr distilla-
tion.8 The major contaminant was identified as the
bisacetylene 4, formed by the attack of the lithium
acetylide on the acetylenic ketone 2c. The inverse addi-
tion of the lithium acetylide of 3 to the anhydride at
−78°C gave essentially quantitative yield of 2c, totally
eliminating the formation of 4. Although the substitu-
tion of ethyl propionate for propionic anhydride gave
only 5% of 2c, the lithium acetylide of 3 could be added
to more reactive acylation reagents to prepare a variety
of substituted acetylenic ketones (2a–h), as listed in
Table 1.
To further simplify the process, the aminolysis was
performed in aqueous ammonia at atmospheric pres-
sure under a variety of conditions (Table 2). Although
the desired compound 1c10 was obtained in good yield,
it was contaminated with a dimer product 5.
The formation of this dimer can proceed via pathway A
or B, as illustrated in Scheme 4. To determine the
Scheme 3.
Scheme 4.

V. B. Hegde et al. / Tetrahedron Letters 42 (2001) 1847–1849
1849
Scheme 5.
mechanism leading to the dimer formation, a crossover
experiment was performed (Scheme 5). This involved
the aminolysis of acetylenic ketone 2c in the presence of
1e in ammonium hydroxide. If pathway [A] were opera-
tive, attack of 1e on 2c in a Michael fashion followed
by cyclization would give a dimer with an isopropyl
group on the aminopyridine 6. However, GC/MS analy-
sis of the aminolysis reaction indicated dimer 5 and 1c
as the products formed with the recovery of the unre-
acted 1e. This result supports the formation of 5 via
pathway [B], with carbonꢀcarbon bond formation
occurring prior to pyridine ring formation.
was separated by recrystallization. Reaction of dihydroxy-
pyridine with phenyl phosphonic dichloride at 200°C
gave the dichloropyridine, which on treatment with
ammonia at 200°C gave 4-amino-3-chloro-2-ethylpyridine
in 20% overall yield.
5. Reduction was carried out using iron in acetic acid at
100°C.
6. Distilled before use from commercially available material
supplied by Aldrich as a 50 wt% solution in methanol–
water (4:1).
7. Crimmins, M. T.; O’Mahoney, R. J. Org. Chem. 1990,
55, 5894.
8. A solution of n-BuLi (1.6 or 2.5 M, 0.11 mol) was added
to a freshly distilled 3 (bp 122–124°C, 8.2 g, 0.1 mol) in
THF (200 mL) at −78°C over a 45 min period under
nitrogen. After 1.0 h, the resulting suspension was added
via cannula to a solution of an appropriate anhydride or
acid chloride (0.1 mol) in THF and stirred for an addi-
tional 1.5 h. After quenching with aq. NH4Cl, the reac-
tion mixture was extracted with diethyl ether. The
organic layer was dried over Na2SO4, filtered and concen-
trated. The crude oils were acceptable for conversion to
the aminopyridines 1, but they were often purified by
Kugelrohr distillation or by chromatography for analyti-
In conclusion, we have described a direct and efficient
preparation of 2-alkyl-4-aminopyridines 1. This method
was used for preparing analogs of pyridine carboxam-
ides, samples in excess of 100 g for field studies and
radiolabeled samples for biological studies.11 The read-
ily available anhydrides, acid chlorides and lactones
and the versatility of the metalation and aminolysis
make this method an attractive approach for the prepa-
ration of 2-alkyl-4-aminopyridines 1.
1
References
cal sample. Data for 2c: H NMR (CDCl3, 300 MHz) l
1.12 (t, 3H, J=2.4 Hz), 2.55 (q, 2H, J=2.5 Hz), 3.83 (s,
3H), 4.62 (d, 1H, J=2.1 Hz), 6.55 (d, 1H, J=2.1 Hz);
EI-MS m/z 138 (M+), 109; anal. calcd for C8H10O2: C,
69.53; H, 7.30. Found: C, 69.35; H, 7.33.
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1
10. Data for 1c: H NMR (CDCl3, 300 MHz) l 1.23 (t, 3H,
J=7.7 Hz), 2.67 (q, 2H, J=7.7 Hz), 4.2 (bs, 2H), 6.34
(dd, 1H, J=2.3, 5.6 Hz), 6.38 (d, 1H, J=2.3 Hz), 8.11 (d,
1H, J=5.6 Hz); EI-MS m/z 121 (M+), 94, 80; anal. calcd
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68.81; H, 8.43; N, 22.71.
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