Barbituric acid initiated rearrangement of 2,2'-pyridil into 5,5'-(2-pyrilidine)bisbarbituric acid.

Article abstract of DOI:10.1021/ol017305i

[reaction: see text] In the study of the barbituric acid initiated 2,2'-pyridil rearrangement, a very efficient synthetic procedure (isolated yield 80-90%) for the preparation of useful 2-pyrilidenes 3 was developed.

Full text of DOI:10.1021/ol017305i

ORGANIC
LETTERS
2002
Vol. 4, No. 5
811-813
Barbituric Acid Initiated Rearrangement
of 2,2′-Pyridil into
5,5′-(2-pyrilidine)bisbarbituric Acid
,†
Branko S. Jursic,* Donna M. Neumann,† Kenneth L. Martin,‡ and
Edwin D. Stevens†
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148,
and Department of Chemistry, Berry College, Mt. Berry, Georgia 30165
bsjcm@uno.edu
Received December 27, 2001
ABSTRACT
In the study of the barbituric acid initiated 2,2′-pyridil rearrangement, a very efficient synthetic procedure (isolated yield 80−90%) for the
preparation of useful 2-pyrilidenes 3 was developed.
Derivatives of barbituric acid have attracted the attention of
researchers in synthetic organic chemistry, as well as
medicinal chemistry, for a long time as a result of their
exceptionally diverse biological activity.1 It was demonstrated
that some barbituric acid derivatives have new and very
interesting biological activities that stand apart from previous
medical utilization of barbituric acid derivatives.2 An even
higher interest in this research area was elevated by a recent
discovery that aromatic pyrilidenes, which structurally
resemble 5,5′-pyrilidenebisbarbituric acids, have very potent
immuno-modulating activity.3 To be able to fully evaluate
these inhibitory activities, a general synthetic route for the
preparation of these compounds must be developed. While
the preparation of a wide variety of 5,5′-(3-pyrilidene) and
5,5′-(4-pyrilidene)bisbarbituric acids and their ammonium
salts4 can be accomplished through the condensation of
pyridinecarbaldehyde and the corresponding barbituric acid,
the condensation between 2-pyridinecarbaldehyde and bar-
bituric acid yields unique pyridinium-barbiturate ylides. The
reaction is unique in many ways because of the fact that
ylide 25 is prepared by the dimerization of the condensation
intermediate 16 (Scheme 1).
Scheme 1. Preparation of Ylide 2
† University of New Orleans.
‡ Berry College.
(1) There are many diseases that are treated with barbituric acid
derivatives alone or in combination with some other chemotherapeutics.
(a) Goth, A. Medical Pharmacology, 4th ed.; C. V. Mosby Company: St.
Louis, 1968. Burger’s Medicinal Chemistry and Drug DiscoVery; Wolff,
M. E., Ed.; Wiley: New York, 1997; Vols. 1-5. (b) Rastaldo, R.; Penna,
C.; Pagliaro, P. Life Sci. 2001, 69, 729. (c) Aiken, S. P.; Brown, W. M.
Front. Biosci. 2000, 5, 124. (d) Ghansah, E.; Weiss, D. S. Neuropharma-
cology 2001, 40, 327. (e) Levine, B. Princ. Forensic Toxicol. 1999, 185.
(2) (a) Oliva, A.; Zimmermann, G.; Krell, H.-W. Barbituric Acid
DeriVatiVes with Antimetastatic and Antitumor ActiVity; International Patent
WO 98/58925, 1998. (b) Gulliya, K. S Uses for Barbituric Acid Analogues;
U.S. patent 943,385, 1997.
Considering that 5,5′-(2-pyrilidene)bisbarbituric acid 3
cannot be prepared in this way, we have searched for a
2-pyridinecarbaldehyde synthetic equivalent. In many chemi-
10.1021/ol017305i CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/05/2002

cal reactions the phenyl moiety of a molecule can be
substituted with pyridine without altering the side chain
reaction. If this is true for benzil (PhCOCOPh), then the
corresponding pyridine synthetic equivalent (PyCOCOPy)
might be used for the preparation of 3. There is an abundance
of literature reports indicating the transformation of benzyl
benzoates or even benzaldehydes into benzil derivatives.7 If
it is possible to enforce the reverse benzil reaction of a
pyridine analogue, then 2,2′-bipyridil can be used as a
synthetic equivalent for 2-pyridinecarbaldehyde.8
One can envision at least two pathways in the preparation
of 5,5′-(2-pyrilidene)bisbarbituric acid; one through elimina-
tion of picolinic acid and formation of intermediate 1,
followed by the addition of barbituric acid to the newly
formed double bond, and the other by simple nucleophilic
substitution of the picolinic acid moiety of ester 3 with
barbituric acid (Scheme 4). Depending on solvent and
Scheme 4. Proposed Reaction Scheme for Preparation of 3
Based on the benzil model, the acid-catalyzed rearrange-
ment mechanism proposed for the conversion of 2,2′-pyridil
into 5,5′-(2-pyrilidene)bisbarbituric acid 3 is presented in
Scheme 2. It is expected that the most energy-demanding
Scheme 2. Preparation of Pyrilidene 3
temperature, both of these reactions occur. If the reaction is
performed for a few hours in refluxing methanol, the only
product of the condensation is 5,5′-(2-pyrilidene)bisbarbituric
acid 3 in more than 80% isolated yield.11 In the extended
time experiment at room temperature it seems that the
reaction goes through either elimination-addition, or the
elimination-addition and nucleophilic substitution reactions
compete, because both 2 and 3 are isolated from the reaction
mixture.12
transformation should be the rearrangement of keto alcohol
A into ester 3. The third step in the transformation (4 f 3)
is nucleophilic substitution by barbituric acid on ester 4.
Ester 4 (Scheme 2) can also be represented in its
Zwitterionic structure II9 (Scheme 3), which in many ways
To determine the validity of our reaction mechanism we
performed NMR reaction-following experiments at room
Scheme 3. Zwitterionic Thiamin and Barbiturate Models
(8) It is interesting to note that there is a lack of benzil-benzylic acid
rearrangements. We believe that this is due to the fact that the base present
is too weak to promote rearrangement, but with the addition of a strong
base the rearrangement might occur.
(9) Zwitterion II might be prepared through the rearrangement of reactive
intermediate B as shown in Scheme 2.
(10) For thiamin action in biological systems, see: (a) Bruce, T. C.;
Benkovic, S. J. Bioorganic Mechanisms; W. A. Benjamin: New York, 1966;
Vol. 2, Chapter 8. (b) Reed, L. J. Acc. Chem. Res. 1974, 7, 40. (c) Nakanishi,
I.; Itoh, S.; Fukuzumi, S. Chem. Eur. J. 1999, 5, 2810. (d) Nakanishi, I.;
Itoh, S.; Suenobu, T.; Fukuzumi, S. Chem. Commun. 1997, 1927. (e)
Shinkai, S.; Yamashita, Kusano, Y.; Manabe, O. J. Am. Chem. Soc. 1982,
104, 563.
resembles the thiamin model I often present in nature.10 We
believe that this model is also involved as an intermediate
in the preparation of 5,5′-(2-pyrilidene)bisbarbituric acid.
(11) Typical Procedure for Preparation of Pyrilidenes 3. Preparation
of 5,5′-(2-pyrilidene)bis(1,3-dimethylbarbituric acid). A methanol (400 mL)
solution of 2,2-pyridil (212 mg; 1 mmol) and 1,3-dimethyl barbituric acid
(468 mg; 3 mmol) was refluxed for 5 h. The dark reaction mixture was
concentrated (∼50 mL volume) at atmospheric pressure and left at room
temperature in an open beaker overnight. The crystalline product was slurred
in cold methanol (∼10 mL), separated by filtration, washed with cold
methanol (3 × 10 mL), and dried at 90 °C for 30 min to afford 350 mg
(87%) of pure product. If necessary, further purification of the product can
be accomplished by crystallization from acetic acid. 1H NMR (DMSO-d6)
δ 8.587 (1H, d, J ) 5.2 Hz), 8.411 (1H, t, J ) 7.1 Hz), 7.885 (1H, d, J )
(3) For instance, see: Veniaminovich, V. Salts of 5,5′-Arylidenebisbar-
bituric and 5,5′-Arylidenebis(2-thiobarbituric) Acid and 5,5′-Arylidenebis-
(2-thiobarbituric) Acid HaVing an Antibacterial, Anti-Chlamydial, AntiViral
and Immuno-Modulating ActiVity; International Patent WO 99/25699, 1999.
(4) Neumann, D. M.; Jursic, B. S.; Stevens, E. D. Manuscript in
preparation
(5) Jursic, B. S.; Neumann, D. M.; Moore, Z.; Stevens, E. D. J. Org.
Chem. Manuscript submitted.
(6) Jursic, B. S. J. Heterocycl. Chem. 2001, 38, 655 and references
therein.
5.4 Hz), 7.818 (1H, t, J ) 7.1 Hz), 6.334 (1H, s), 3.133 ppm (12H, s); 13
C
NMR (DMSO-d6) δ 159.384, 155.976, 147.913, 142.451, 137.564, 122.386,
120.609, 81.156, 32.045, 24.514 ppm. ES 424 (M + Na)+. Anal. Calcd
For C18H19N5O6 (MW 401.37): C, 53.75; H, 4.83; N, 17.33. Found: C,
53.86; H, 4.77; N 17.45.
(7) (a) O-Benzoylbenzaldehyde cyanohydrin has been found to form
benzil in DMF in a base-catalyzed reversible reaction. Zheng, Z.-R.; Kjaer,
N. T.; Lund, H. Acta Chem. Scand. 1998, 52, 362. (b) For base-catalyzed
rearrangement of symmetrically substituted benzils, see: Bowden, K.;
Williams, K. D. J. Chem. Soc., Perkin Trans. 2 1994, 77 and references
therein.
(12) From a closed-bottle mixture of 2,2-pyridil (2 mg) and 1,3-
dimethybarbituric acid (5 mg) in methanol (1 mL) after standing at room
temperature for 30 days a single crystal was grown. The crystal (1.7 mg)
contains both 2 and 3. Through comparison of the H NMR signals for 2
(doublet at 9.003 ppm) and 3 (doublet at 8.587 ppm) the ratio of products
1
is 32:68.
812
Org. Lett., Vol. 4, No. 5, 2002

temperature in solvents such as methanol, tetrahydrofuran,
acetic acid, chloroform, and dimethyl sulfoxide. Only in
DMSO is the reaction mixture a solution. In all other cases
a precipitate forms. From this experiment it is obvious that
the formation of ester 4 is required for high yield transforma-
tion of 2,2′-pyridil and barbituric acid into pyrilidine 3 and
picolinic acid (Figure 1). In prolonged DMSO experiments,
Figure 2. ORTEP of X-ray structure of 3.
In the crystalline state compound 3 has a Zwitterionic
structure with the positive charge located on the pyridinium
cation and the negative charge located almost equally on both
barbituric acids. In solution, both hydrogens in the 5- and
5′-positions of the two barbituric acids were not located
because one is on the pyridine ring and the other is involved
in hydrogen bonding interactions between two barbituric acid
moieties. The plane with the pyridinium ring is almost
perpendicular to the plane that separates the two barbituric
acid moieties. The C(1)-C(4) bond distance is 1.365 Å in
comparison with the C(1)-C(2) distance of 1.4275 Å and
the (C1)-C(7) distance of 1.5201 Å, indicating the strong
double bond character of the first two bonds and delocal-
ization of the negative charge. All atoms in the ring and ones
attached to the ring are basically in the ring plane.
Figure 1. 1H NMR (DMSO-d6) spectra over the course of the
reaction time.
a low field NMR aromatic compound is formed, which is
not detected when the preparation of compound 3 is
performed in methanol as a solvent.
To confirm the general applicability of this method in
preparation of a wide variety of useful 2-pyrilidenes,
preparations of derivatives with 1-phenylbarbituric acid,
1-methylbarbituric acid, 1-butylbarbituric acid, and barbituric
acid were performed. In all cases, the corresponding pyri-
lidine 3 was isolated in higher than 80% yield (we were not
able to detect any other side products). Structural properties
of 3 with R ) CH3 were determined using the usual
analytical methods as well as X-ray analysis. The X-ray
single crystal was obtained by slow crystallization from acetic
acid. The structure of compound 3 shows very interesting
structural properties (Figure 2).
Acknowledgment. We would like to thank the Louisiana
Board of Regents for their financial support (LEQSF(2001-
04)-RD-B12) for this work.
OL017305I
Org. Lett., Vol. 4, No. 5, 2002
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