J . Org. Chem. 1999, 64, 93-100
93
Novel Asym m etr ic Syn th esis of Atr op isom er ic 6-Ar yl P yr a zin on es
via a n Un u su a l Ch ir a lity Tr a n sfer P r ocess
J ohn Tulinsky,1 B. Vernon Cheney, Stephen A. Mizsak, William Watt, Fusan Han,
Lester A. Dolak, Thomas J udge, and Ronald B. Gammill*,†
Structural, Analytical and Medicinal Chemistry, Pharmacia & Upjohn, Inc.,
Kalamazoo, Michigan 49001-0199
Received J une 18, 1998
Cyclization of (S,S)-R-[(1-phenylethyl)amino]-R-(2-iodophenyl)acetonitrile with (COCl)2 in toluene
or chlorobenzene afforded the atropisomeric pyrazinone (aS,S) 6-(2-R-iodophenyl)-3,5-dichloro-1-
(1-phenylethyl)-2(1H)-pyrazinone in 57% yield. With smaller ortho substituents (F, Cl, CH3, CF3,
OCH3) on the aromatic ring, mixtures of atropisomers were obtained from the cyclization reaction.
All of the individual atropisomers prepared were stable at room temperature. All but the o-fluoro-
substituted atropisomers were stable at elevated temperatures. This paper describes a stereose-
lective synthesis of pyrazinones and suggests a mechanism for formation via an interesting transfer
of chirality.
In tr od u ction
pounds, efficient and expedient methods of synthesis
remain the gatekeepers for the delineation of new and
interesting chemical and biological properties of such
molecules.
Chiral atropisomeric compounds are of considerable
interest due to their presence in a number of biologically
active natural and synthetic products and their utility
as directing groups in asymmetric synthesis.2 The inter-
esting physical, chemical, and biological properties of
these compounds is reflected and to a vast extent con-
trolled by the relative conformation of the two aromatic
rings.2,3 In principle, heteroaryl-aryl atropisomers3b offer
certain opportunities for structural and physical change
that are not available in the more classical biphenyl
systems. For example, heteroatoms provide an opportu-
nity to probe a wide variety of geometric and electronic
situations unavailable in the biphenyl system.3 Despite
many recent advances in the asymmetric synthesis of
chiral biphenyl and heteroaryl-aryl atropisomeric com-
Pyrazinones 1 and 2 are recently discovered ligands
at Pharmacia & Upjohn that bind to a new site on the
1
GABAA/chloride ionophore complex.6a,b In the H NMR
spectra of pyrazinones 1 and 2, the methylene hydrogens
(3) (a) For reviews and papers discussing axially chiral heteroaro-
matics, see: Gallo, R.; Roussel, C.; Berg, U. In Advances in Heterocyclic
Chemistry; Katritzky, A. R., Ed.; Academic Press: San Diego, 1988;
Vol. 43, p 173. Roussel, C.; Adjimi, M.; Chemlal, C.; Djafri, A. J . Org.
Chem. 1988, 53, 5076. Dogan, I.; Pustet, N.; Mannschreck, A. J . Chem.
Soc., Perkin Trans. 2 1993, 1557. (b) For specific examples and leading
references of heterocyclic systems, see: for N-aryl-4-thiazoline-2-
thiones, Roussel, C.; Djafri, A. New J . Chem. 1986, 10, 399. For the
anaesthetic ketamine, the tranquilizer etaqualone, and the anthelm-
intic praziquantel: Mannschreck, A.; Koller, H.; Wernick, R.; Kontakte,
Darmstadt 1985, 1, 40. For examples of flavins: Shinkai, H.; Nakao,
H.; Kuwahara, I.; Miyamoto, M.; Yamaguchi, T.; Manabe, O. J . Chem.
Soc., Perkin Trans. 1 1988, 313. For N-aryl-4-pyridones: Mintas, M.;
Orhanovic, Z.; J akopcic, K.; Koller, H.; Stuhler, G.; Mannschreck, A.
Tetrahedron 1985, 41, 229. For N-arylpyrroles: Vorkapic-Furac, J .;
Mintas, M.; Burgemeister, R.; Mannschreck, A. J . Chem. Soc., Perkin
Trans. 2 1989, 713. For the anticonvulsant and hypnotic methaqua-
lone: Mannschreck, A.; Koller, H.; Stuhler, G.; Davies, M. A.; Traber,
J . Eur. J . Med. Chem. 1984, 19, 381. For N-aryl-2(1H)-quinolones and
N-aryl-6(5H)-phenanthridones: Mintas, M.; Mihaljevic, N.; Koller, H.;
Schuster, D.; Mannschreck, A. J . Chem. Soc., Perkin Trans. 2 1990,
619. (c) For a recent report on the atroposelective thermal reactions of
axially twisted amides and imides, see: Curran, D. P.; Qi, H.; Geib, S.
J .; DeMello, N. C. J . Am. Chem. Soc. 1994, 116, 3131.
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Dekker, Inc.: New York, 1993. Ariens, E. J . Trends Pharm. Sci. 1993,
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K.; Level, L. A.; Morrone, J . M.; Ryan, K.; Schmidt, A. W.; Schulz, D.
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† Current Address: Central Research Division, Pfizer, Inc., Groton,
CT 06340.
(1) Postdoctoral Research Scientist 1993-95. Current address:
Discovery Research, Cell Therapeutics, Inc., 201 Elliott Ave W., Seattle,
WA 98119.
(2) The term atropisomerism refers to optical isomerism resulting
from restricted rotation about a single bond. Biphenyls represent but
one example of this type of isomerism. (a) For a general discussion of
atropisomeric compounds, see: Oki, M. In Topics in Stereochemistry;
Allinger, N. L., Eliel, E. L., Wilen, S. H., Eds.; J ohn Wiley and Sons:
New York, 1983. Eliel, E. L. Stereochemistry of Carbon Compounds;
McGraw-Hill: New York, 1995. For recent asymmetric syntheses of
atropisomeric compounds, see: Lipshutz, B. H.; Liu, Z.; Kayer, F.
Tetrahedron Lett. 1994, 5567. Feldman, K. S.; Ensel, S. M.; Minard,
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Rajagopalan, T. G.; Desai, H. K.; Kartha, G.; Chen, S. K.; Nakanishi,
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10.1021/jo9811930 CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/15/1998