Synthesis of heavily substituted 2-aminopyridines by displacement of a 6-methylsulfinyl group

Article abstract of DOI:10.1021/jo801303v

(Chemical Equation Presented) 2-Aminopyridines, with a variety of polar 6-substituents, were elaborated by displacement of a methylsulfinyl group from the 6-position of the pyridine ring. The requisite 6-thiomethyl pyridines were synthesized by reaction o

Full text of DOI:10.1021/jo801303v

SCHEME 1. Classical Hantzsch Pyridine Synthesis
Synthesis of Heavily Substituted
2-Aminopyridines by Displacement of a
6-Methylsulfinyl Group
Simon J. Teague*
Department of Medicinal Chemistry, AstraZeneca R&D
Charnwood, Bakewell Road, Loughborough, U.K.
SCHEME 2. 6-Methylsulfinyl 2-Aminopyridine Synthesis
simon.teague@astrazeneca.com
ReceiVed June 26, 2008
2-Aminopyridines, with a variety of polar 6-substituents,
were elaborated by displacement of a methylsulfinyl group
from the 6-position of the pyridine ring. The requisite
6-thiomethyl pyridines were synthesized by reaction of 2-(1-
phenylethylidene)propanedinitriles with dimethyl N-cyanodi-
thioiminocarbonate.
These difficulties were overcome by elaborating a 6-thio-
methylpyridine by the unusual condensation of 2-(1-phenyleth-
ylidene)propanedinitrile (1) with dimethyl N-cyanodithioimi-
nocarbonate (2) (Scheme 2).2 Deprotonation at the γ-position
of the ethylidene nitrile with potassium carbonate results in
displacement of thiomethoxide from the iminocarbamate and
cyclization. The resulting N-cyanodihydropyridine intermediate
was then converted to the required aminopyridine (3) by addition
of piperidine.
Surprisingly, the aminopyridine (3) could be brominated
selectively, even in the presence of the electron-rich 4-(4′-
methoxyphenyl) substituent, using NBS in DMF, giving the
5-bromopyridine (4). Negishi coupling of the aminopyridyl
5-bromide failed when the 6-position was substituted.3 A search
for such couplings where the steric demand is high suggested
the use of σ-allylpalladium complexes. Heck reactions, though
possible with lower alkenes, such as isobutene, are rare and
experimentally challenging. This led to selection of isobutenyl
transfer by in situ fragmentation of a homoallyl alcohol. The
published procedure4 was adapted to use the commercially
available 2,4-dimethyl-4-pentene-2-ol (5) to give the 5-alkenyl
pyridine (6). Hydrogenation of the rather hindered olefin, in
the presence of a 6-thiomethyl group, proved to be possible
but troublesome. A mixture of the required product (7) and the
6-H compound (8) together with starting material was isolated
with all the catalysts attempted. The methane thiol, which was
liberated, proved to be a very effective catalyst poison, resulting
in both prolonged reaction times and heavy catalyst loadings.
Incorporating the required alkyl substituent into the initial
dinitrile was attractive but unprecedented. Homologation would
Modulation of the physical properties of unacceptably lipo-
philic lead molecules by introduction of polar moieties at
solvent-exposed positions is a common problem for medicinal
chemists. In a recent in-house study, 2-aminopyridines with
polar 6-substituents were required. The scope for variation of
the 4-methoxyphenyl substituent in the screening hit was limited,
and the 5-isobutyl group was an absolute requirement for
biological activity. This led to an intense focus upon variation
of the remaining 6-substituent.
4-Aryl pyridines have diverse biological activities,1 and a
number of routes for their synthesis have been developed. Initial
approaches, employing classical Hantzsch-type condensation-
dehydrogenation reactions of ketones with an aryl aldehyde,
malononitrile, and ammonia suffer from poor yields, regio-
chemical difficulties, and intolerance to polar functionality
(Scheme 1). Only symmetrical, cyclic ketones perform well;
unsymmetrical aliphatic ketones give much lower yields of
difficult to separate regioisomers. Methyl ketones predominantly
gave the 6-alkyl regioisomer, whereas for this work, the 5-alkyl
isomer was required.
(1) (a) Blonanserin: Heading, C. E. Curr. Opin. Cent. Periph. NerV. Syst.
InVest. Drugs 2000, 2, 79–84. (b) Cerivastin: Mcclellan, K. J.; Wiseman, L. R.;
Mctavish, D. Drugs 1998, 55, 415–420. (c) FR 76830: Kuno, A.; Sakai, H.;
Sugiyama, Y.; Takasugi, H. Chem. Pharm. Bull. 1993, 41, 156–162. (d) WIN
58161: Coughlin, S. A.; Danz, D. W.; Robinson, R. G.; Klingbeil, K. M.;
Wentland, M. P.; Corbett, T. H.; Waud, W. R.; Zwelling, L. A.; Altschuler, E.;
et al. Biochem. Pharmacol. 1995, 50, 111–116.
(2) Peseke, K.; Suarez, J. Q. Z. Chem. 1983, 23, 404–405.
(3) Walters, I. A. S. Tetrahedron Lett. 2006, 47, 341–344.
(4) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2006, 128, 2210–2211.
10.1021/jo801303v CCC: $40.75
Published on Web 10/15/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9765–9766 9765

SCHEME 3. 5-Alkyl Aminopyridine Synthesis and Sulfinyl
Displacement
Experimental Section
Compound 7. 2-Amino-4-(4-methoxyphenyl)-5-(2-methylpro-
pyl)-6-(methylsulfanyl)pyridine-3-carbonitrile. Potassium carbon-
ate (0.20 g, 1.45mmol) was added in one portion to a stirring
solution of 2-(1-(4-methoxyphenyl)-4-methylpentylidene)propane-
dinitrile (0.32 g, 1.26 mmol) and dimethyl N-cyanodithioiminocar-
bonate (0.18 g, 2.19 mmol) in DMF (5 mL) at ambient temperature.
The resulting heterogeneous solution was stirred at ambient
temperature for 18 h. Piperidine (0.2 mL, 2.02 mmol) was added,
and the reaction mixture was stirred at 60 °C for 12 h. The reaction
mixture was diluted with water and extracted with dichloromethane.
The organic layer was dried over sodium sulfate, filtered, and
evaporated to afford crude product. The crude solid was triturated
with ethanol and isolated by filtration. Drying under vacuum gave
TABLE 1. Nucleophilic Displacement of the 6-Sulfinyl Group
1
the product as an off white solid (0.19 g, 0.56 mmol, 46%): H
NMR (CDCl3) δ 7.15 (d, 2H), 6.97 (d, 2H), 5.01 (s, 2H), 3.84 (s,
3H), 2.51 (s, 3H), 2.2 (d, 2H), 1.8 (m, 1H), 0.64 (d, 6H); 13C NMR
(CDCl3) δ 165.7, 160.8, 158.1, 153.4, 131.2, 130.00, 124.2, 118.5,
115.00, 88.6, 56.3, 37.7, 29.0, 23.5, 14.9; exact mass MH+
328.1487; formula C18H22N3OS requires MH+ 328.1484; deviation
0.3 ppm; HPLC purity 91.4%.
Compound 10. 2-Amino-4-(4-methoxyphenyl)-5-(2-methyl-
propyl)-6-(methylsulfinyl)pyridine-3-carbonitrile. Sulfide (0.120
g, 0.35 mmol) in dichloromethane (10 mL) was treated with
m-chloroperbenzoic acid (0.1 g, ∼70%, 0.41 mmol). The reaction
was instantaneous. Ethyl acetate (40 mL) was added to the reaction
mixture, which was then washed with saturated aqueous sodium
bicarbonate. The organic extract was dried over magnesium sulfate
and evaporated. The residue was triturated with ether giving a white
be expected to affect the balance between R and γ alkylation
through both steric and electronic factors.
1
solid (0.11 g, 0.31 mmol, 88%): H NMR (CDCl3) δ 7.2 (br d,
2H), 6.99 (br d, 2H), 5.32 (s, 2H), 3.82 (s, 3H), 2.82 (s, 3H),
2.8-2.6 (m, 2H), 1.4 (m, 1H), 0.67 (m, 6H); 13C NMR (CDCl3) δ
163.9, 160.3, 158.2, 157.3, 130.0, 129.7, 127.5, 124.1, 115.5, 114.3,
95.9, 55.3, 39.2, 35.1, 30.6, 22.2, 21.8; exact mass MH+ 328.1487;
formula C18H22N3O2S requires MH+ 344.1483; deviation 0.4 ppm;
HPLC purity 86.6%.
Pleasingly, the reaction with the homologated dinitrile (9)
preceded as required to give 7 directly (Scheme 3). Displacement
of the thiomethyl group was unsuccessful. Oxidation of 7 to
the sulfoxide 10 was clean with no trace of over oxidation to
the sulfone even with excess oxidizing agent.
Compound 11b. 2-Amino-4-(4-methoxyphenyl)-6-(methyl-
amino)-5-(2-methylpropyl)pyridine-3-carbonitrile. Sulfoxide (10
mg, 0.028 mmol) was heated to 80 °C in a sealed vial with
methylamine in methanol (1 mL, ∼25%) for 6 h. The reaction
mixture was evaporated and columned in ethyl acetate/isohexane
Displacement of sulfoxides from heteroaromatic and even
from phenyl rings is known, though this reaction is less used
than the analogous displacement of sulfones.5 Functionalized
primary amines were conveniently introduced by heating the
sulfoxide with the nucleophile to give compounds 11a-e (Table
1). Secondary amines were slow to displace the methylsulfinyl
group and produced a mixture of the required product 11d and
the thiomethyl pyridine (7) through concomitant deoxygenation
of the sulfoxide. Displacement with alcohols, which are much
less nucleophilic than amines, required deprotonation and
prolonged heating giving 11e.
1
(1:1) to give a white solid (6 mg, 0.018 mmol, 66%): H NMR
(CDCl3) δ 7.18 (d, 2H), 6.96 (d, 2H), 4.88 (s, 2H), 4.79 (s, H),
3.92 (s, 3H), 3.02 (d, 3H), 2.18 (dd, 2H), 1.5 (m, 1H), 0.66 (dd,
6H); 13C NMR (CDCl3) δ 159.3, 158.7, 158.6, 152.4, 130.1, 129.9,
119.0, 113.7, 109.2, 79.4, 55.2, 35.2, 28.7, 27.3, 22.6; exact mass
MH+ 311.1885; formula C18H23N4O requires MH+ 311.1872;
deviation 1.3 ppm; HPLC purity 97.5%.
The route made possible the synthesis of compounds with
aqueous solubility suitable for biological evaluation. However,
the localization of all polarity into only a small fraction of the
molecule is suboptimal, producing amphipathic molecules which
disrupt cellular systems nonselectively.
Acknowledgment. This work is dedicated to Prof. A. I.
Meyers. His love of creativity in heterocyclic chemistry has been
an enduring inspiration. His guidance, group members, and
location of work is a memory held dear.
Supporting Information Available: Experimental proce-
dures and analytical data for compounds 3, 4, 6, 7, 8, 9, 10,
and 11a-e are provided. This material is available free of charge
via the Internet at http://pubs.acs.org.
(5) On pyridines: (a) Hirokawa, Y.; Horikawa, T.; Kato, S. Chem. Pharm.
Bull 2000, 48, 1847–1853. (b) Furukawa, N.; Ogawa, S.; Kawai, T.; Oae, S.
J. Chem Soc., Perkin Trans. 1 1984, 8, 1839–1845. On quinolines: (c)
Maslankiewicz, M. J.; Maslankiewicz, A. Heterocycles 2007, 71, 175–180. On
a phenyl: (d) Clayden, J.; Stimson, C. C.; Keenan, M. Chem. Commun. 2006,
13, 1393–1394. Reviewed: (e) Furukawa, N. Sulf. Rep. 1986, 7, 47–88.
JO801303V
9766 J. Org. Chem. Vol. 73, No. 24, 2008