A novel three-component one-pot pyrimidine synthesis based upon a coupling-isomerization sequence

Article abstract of DOI:10.1021/ol006046e

(Equation presented) 246-Tri(hetero)aryl-substituted pyrimidines can be readily synthesized in a three-component one-pot process based upon a coupling-isomerization sequence of an electron-poor (hetero)aryl halide and a terminal propargyl alcohol subseque

Full text of DOI:10.1021/ol006046e

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1967-1970
A Novel Three-Component One-Pot
Pyrimidine Synthesis Based upon a
Coupling−Isomerization Sequence†
Thomas J. J. Mu1ller,* Roland Braun, and Markus Ansorge
Department Chemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13 (Haus F), D-81377 Mu¨nchen, Germany
tom@cup.uni-muenchen.de
Received May 11, 2000
ABSTRACT
2,4,6-Tri(hetero)aryl-substituted pyrimidines can be readily synthesized in a three-component one-pot process based upon a coupling−
isomerization sequence of an electron-poor (hetero)aryl halide and a terminal propargyl alcohol subsequently followed by a cyclocondensation
with amidinium salts.
The pyrimidyl heterocyclic core 1 is a widespread subunit
in numerous natural products and, ultimately, in the pyri-
midine and purine bases as constituting the ribo- and
deoxyribonucleosides.1 Besides the strong deactivation of
pyrimidines toward electrophilic substitution and the facili-
tated reactivity in nucleophilic additions and substitutions,1a,f,2
this class of heterocycles could become increasingly impor-
tant as an interesting structural coordinating substitute ligand
for pyridyl units in supramolecular metallo-gridlike archi-
tectures3 and in novel inorganic/organic hybrid types of
molecular wires.4
† In memoriam, Professor Dr. Rudolf Gompper (1926-1999).
(1) For reviews, see: (a) Brown, D. J. In The Chemistry of Heterocyclic
Compounds, Vol. 16, The Pyrimidines; Weissberger, A., Ed.; Wiley-
Interscience: New York, 1970. (b) Lister, J. H. In The Chemistry of
Heterocyclic Compounds, Vol. 24, Fused Pyrimidines, Part II, The Purines;
Weissberger, A.; Taylor, E. C., Eds.; Wiley-Interscience: New York, 1971.
(c) Hoffmann, M. G. In Houben-Weyl, Methoden der Organischen Chemie,
Vol. E9; Schaumann, E., Ed.; G. Thieme Verlag: Stuttgart, 1996. (d) Hurst,
D. T. In An Introduction to the Chemistry and Biochemistry of Pyrimidines,
Purines and Pteridines; Wiley: Chichester, 1980. (e) Bojarski, J. T.;
Mokrosz, J. L.; Barto´n, H. J.; Paluchowska, M. H. AdV. Heterocycl. Chem.
1985, 38, 229. (f) Brown, D. J. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, New York,
Toronto, Sydney, Paris, Frankfurt, 1984; Vol. 3, Chapter 2.13.
(2) (a) Eicher, T.; Hauptmann, S. Chemie der Heterocyclen; Georg
Thieme Verlag: Stuttgart, New York, 1994; pp 398. (b) Gilchrist, T. L.
Heterocyclenchemie; Neunhoeffer, H., Ed.; Wiley-VCH: New York, 1995;
pp 270.
Furthermore, a number of synthetic pharmacophores with
antibacterial,5 antimicrobial, antifungal,6 and antimycotic7
activities are based upon the pyrimidyl structural motifs 1
and 2.
(4) (a) Harriman, A.; Ziessel, R. Coord. Chem. ReV. 1998, 171, 331. (b)
Harriman, A.; Ziessel, R. Chem. Commun. 1996, 1707.
(5) Ahluwalia, V. K.; Kaila, N.; Bala, S. Indian J. Chem., Sect. B 1987,
26B, 700.
(6) El-Hashash, M. A.; Mahmoud, M. R.; Madboli, S. A. Indian J. Chem.,
Sect. B 1993, 32B, 449.
(3) (a) Lehn, J.-M. Supramolecular Chemistry-Concepts and Perspec-
tiVes; VCH: Weinheim, 1995; Chapter 9. (b) Hanan, G. S.; Volkmer, D.;
Schubert, U. S.; Lehn, J.-M.; Baum, G.; Fenske, D. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1842. (c) Semenov, A.; Spatz, J. P.; Mo¨ller, M.; Lehn,
J.-M.; Sell, B.; Schubert, D.; Weidl, C. H.; Schubert, U. S. Angew. Chem.,
Int. Ed. 1999, 38, 2547.
(7) Keutzberger, A.; Gillessen, J. Arch. Pharm. (Weinheim, Ger.) 1985,
318, 370.
10.1021/ol006046e CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/06/2000

Synthetically, condensation reactions of 1,3-dicarbonyl
compounds (and synthetic equivalents) with amidines or
amidinium salts allow a broad access to substituted pyrim-
idines 1.2,8 However, pyrimidines with a 2,4,6-triaryl sub-
stitution pattern (2) are constructed in stepwise procedures.2
Therefore, we set out to develop a novel pyrimidine
synthesis, preferentially in a straightforward highly conver-
gent manner, that also can be conducted as a one-pot process.
Here, we wish to communicate a facile one-pot synthesis of
2,4,6-tri(hetero)aryl-substituted pyrimidines (2) based upon
a coupling-isomerization sequence with a subsequent cy-
clocondensation/aromatization with amidinium salts.
dinucleophilic components with the initially formed enone
functionality, followed by a subsequent oxidative aromati-
zation of the intermediate dihydropyrimidines, pyrimidines
are readily formed (Scheme 2). In particular, the mild
Scheme 2. Retrosynthetic Concept for a Three-Component
Pyrimidine Synthesis
Recently, we found that palladium/copper-catalyzed cross-
coupling reactions of electron-poor halogen-substituted π-sys-
tems and 1-aryl prop-2-yn-1-ols do not furnish the expected
propargyl alcohols but rather give the isomeric enone
components.9 Mechanistically, this isomerization occurring
after the cross-coupling reaction is purely base-catalyzed and
opens a new access to electron-deficient propenones. With
this powerful tool for the construction of chalcones (1,3-
diaryl propenones) in hand and considering the mild reaction
conditions for the Sonogashira coupling reaction, we have
developed a novel one-pot pyrazoline synthesis (Scheme 1).9
reaction conditions of Sonogashira couplings11 not only allow
the presence of sensitive functional groups without tedious
protection and deprotection steps but also are advantageous
for base-mediated processes such as cyclocondensations. In
addition, this strategy could also be extended to a combi-
natorial approach to 2,4,6-triaryl-substituted pyrimidines (2).
Thus, we have submitted p-iodo nitrobenzene (3a) or
4-bromo pyridine (3b), several aryl propynols 4,12 and
amidinium salts 513 to the reaction conditions of the
Sonogashira coupling in a boiling mixture of triethylamine
and THF.14 In all cases the isolated products were the beige-
to-yellow pyrimidines 6 in 41-70% yield (Table 1).15 In
neither case was the expected dihydropyrimidine found,
regardless of whether the reaction has been performed under
an anaerobic or aerobic atmosphere. As already shown for
the one-pot synthesis of pyrazolines, the electron-withdraw-
Scheme 1. One-Pot Pyrazoline Synthesis Based upon a
Coupling-Isomerization Sequence
(11) (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, H.
Synthesis 1980, 627. (b) Sonogashira, K. In Metal Catalyzed Cross-coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998;
p 203.
(12) The propynols 4 were synthesized according to Krause, N.; Seebach,
D. Chem. Ber. 1987, 120, 1845.
(13) The amidinium salts 5 were synthesized according to a modification
of the Pinner reaction; see: Schaefer, F. C.; Peters, G. A. J. Org. Chem.
1961, 26, 412.
Since the cyclocondensation of amidinium salts with
chalcones (1,3-diaryl propenones) to give pyrimidines is a
well documented reaction,10 retrosynthetically, an extension
of the coupling-isomerization-based methodology to the
synthesis of pyrimidines can be easily envisioned. Upon
cyclocondensing amidines or amidinium salts as suitable 1,3-
(14) Typical Procedure (6g, entry 7). To a magnetically stirred solution
of 0.25 g (1.00 mmol) of 4-iodo nitrobenzene (3a), 22 mg (0.02 mmol) of
Pd(PPh3)2Cl2, and 2 mg (0.01 mmol) of CuI in a degassed mixture of 10
mL of THF and 5 mL of triethylamine under nitrogen was added a solution
of 145 mg (1.05 mmol) of 1-(3-thienyl)-propyn-1-ol (4d) in 10 mL of THF
dropwise at room temperature over a period of 30 min. The mixture was
heated to reflux temperature for 16 h. After the mixture cooled to room
temperature, 165 mg (1.00 mmol) of 2-thienyl amidinium chloride (5a)
was added and the reaction mixture was heated to reflux temperature for
48 h. After cooling the solvents were removed in vacuo, and the residue
was dissolved in dichloromethane and filtered through a short pad of silica
gel. The solvents were evaporated in vacuo, and the residue was recrystal-
lized from dichloromethane/pentane to give 255 mg (70%) of analytically
pure 6a as a beige powder.
(8) For an efficient repetitive synthesis of (oligo)pyrimidines based upon
vinamidinium salt amidine condensations, see: Gompper, R.; Mair, H.-J.
Polborn, K. Synthesis 1997, 696
(9) Mu¨ller, T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem., Int. Ed. 2000,
39, 1253.
(10) (a) Dodson,; Seyler, J. Org. Chem. 1951, 16, 461. (b) Al-Hajjar, F.
H.; Sabri, S. S. J. Heterocycl. Chem. 1982, 19, 1087. (c) Simon, D.; Lafont,
O.; Farnoux, C. C.; Miocque, M. J. Heterocycl. Chem. 1985, 22, 1551. (d)
Boykin, D. W.; Kumar, A.; Bajic, M.; Xiao, G.; Wilson, W. D.; Bender,
B. C.; McCurdy, D. R.; Hall, J. E.; Tidwell, R. R. Eur. J. Med. Chem.
1997, 32, 965.
(15) All compounds have been characterized spectroscopically and by
correct elemental analysis.
1968
Org. Lett., Vol. 2, No. 13, 2000

Table 1. Three-Component Pyrimidine Synthesis Based upon a Coupling-Isomerization-Cyclocondensation Sequencea
a Reaction conditions: 1.0 equiv of the (hetero)aryl halide 3, 1.05 equiv of the propargyl alcohol 4, 0.02 equiv of (Ph3P)2PdCl2, 0.01 equiv of CuI, 1.0
equiv of the amidine hydrochloride 5; THF/NEt3 2:1 (10 mL/mmol halide). b Yields refer to isolated yields of compounds 6 after recrystallization estimated
to be g95% pure as determined by NMR spectroscopy and elemental analysis.
ing nature of the (hetero)aryl halide 3 is crucial for the
successful coupling-isomerization step.9 However, the sub-
stituents Ar1 and Ar2 on the pyrimidine ring can be electron-
rich (entry 5), electron-poor (entries 3 and 4), or heterocyclic
Org. Lett., Vol. 2, No. 13, 2000
1969

(entries 1, 4, 6, and 7), and even bromo substituents are
tolerated (entries 2, 5, 6, and 8).
poor (hetero)aryl halides with 1-aryl propargyl alcohols
giving rise to chalcones can be extended to a one-pot three-
component synthesis of 2,4,6-tri(hetero)aryl pyrimidines.
Since 2-pyridyl-substituted pyrimidines are bidentate ligands
for many late transition metals,3,4 ultimately a one-pot ligand
synthesis with subsequent complexation under self-organiza-
tion to oligometallic chains and grids can be easily envi-
sioned. Further studies directed to extend the one-pot
pyrimidine synthesis to dendritic and self-organizing struc-
tures are currently underway.
The proton and carbon NMR spectroscopic data support
the formation of the pyrimidine core, in particular, in the 1H
NMR spectra of 6 by the indicative appearance of the singlet
for the methine proton at C5 of the central pyrimidine ring
between δ 7.9 and 8.2. Furthermore, in the 13C NMR spectra
three quaternary signals can be found between δ 162 and
166, characteristic for sp2-hybridized quaternary carbon
centers adjacent to nitrogen atoms.16 The signals at lowest
field (δ 165 to 166) can be assigned to the C2 center, i.e.,
the amidine-type carbon atoms.16
Acknowledgment. The financial support of the Fonds
der Chemischen Industrie, Deutsche Forschungs-gemein-
schaft and the Dr.-Otto-Ro¨hm Geda¨chtnisstiftung is gratefully
acknowledged. We also wish to express appreciation to Prof.
H. Mayr for his generous support.
In conclusion, we could show that the mild reaction
conditions of the coupling-isomerization sequence of electron-
(16) Kalinowski, H.-O.; Berger, S.; Braun, S. 13C NMR Spektroskopie;
Georg Thieme Verlag: Stuttgart, New York, 1984; p 351.
OL006046E
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Org. Lett., Vol. 2, No. 13, 2000