A convenient method for the preparation of highly substituted 1101 pyrimidines: Synthesis of tri- and tetra-subsituted pyrimidines from 1,3-dicarbonyl compounds and N,N,N′-tris-(trimethylsilyl)amidines

Article abstract of DOI:10.1002/jhet.5570390542

A modification of the Pinner pyrimidine synthesis has been developed that utilizes trimethylsilyl amidines and results in greatly improved yield of highly substituted pyrimidines.

Full text of DOI:10.1002/jhet.5570390542

Sep-Oct 2002
A Convenient Method for the Preparation of Highly Substituted
Pyrimidines: Synthesis of Tri- and Tetra-Subsituted Pyrimidines from
1,3-Dicarbonyl Compounds and N,N,N'-Tris-(Trimethylsilyl)amidines.
Usha Ghosh and John A. Katzenellenbogen*
1101
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL 61801
Received May 1, 2002
A modification of the Pinner pyrimidine synthesis has been developed that utilizes trimethylsilyl
amidines and results in greatly improved yield of highly substituted pyrimidines.
J. Heterocyclic Chem., 39, 1101 (2002).
Introduction.
compound. The rate-limiting step in this double condensa-
tion reaction is thought to be the dehydration of the various
hydroxy-hydropyrimidine intermediates [12]. The substi-
tuted 1,3-dione precursors, we found, were often sensitive
to the basic conditions typically used in this condensation
[7]. Therefore, we sought to modify this reaction so that it
would proceed under milder conditions and in a manner
such that the dehydration steps would be facilitated. To
reduce the need for base and to accelerate the dehydra-
tions, we selected an N,N,N'-tris-(trimethylsilyl)amidines
as an amidine equivalent (Scheme 1b). These silyl
amidines, which are readily prepared by a known method
(Scheme 1c) [13], are much less basic than unsubsituted
amidines. Also, because the dehydration step with these
The biological importance of pyrimidine compounds is
well known [1], and, as a consequence, considerable atten-
tion has been devoted to developing practical syntheses of
variously substituted pyrimidines [2,3]. Among the possi-
ble disconnection strategies, the condensation of a three-
carbon unit (typically a 1,3-dione or enone) with an N-
C=N fragment (typically an amidine) is widely used for
the direct preparation of the pyrimidine nucleus (the
Pinner method) [4]. However, this method works best for
the synthesis of pyrimidines having relatively low degrees
of substitution. In the case of highly substituted pyrim-
idines, use of the Pinner method generally requires longer
reaction time and often results in poor yields [5-7].
We have been interested in the development of novel lig-
ands for the estrogen receptor that are chemically simple
and amenable to combinatorial synthesis. In the process of
our work in this area, we sought to prepare a number of
highly substituted diazenes, including some tetrasubstituted
pyridines [8]. We were able to prepare some of the pyrim-
idines of interest to us by the condensation of a ketone with
two equivalents of an aryl nitrile in presence of trifluo-
romethanesulfonic anhydride [9], a method that shows
good regioselectivity when the ketone component is enoliz-
able in only one direction. This approach, however, is not
suitable for the preparation of 2,4,5-tris-aryl- and 2,5-bis-
aryl-pyrimidines. When we explored another known
method involving the condensation of 1,3-dicarbonyl com-
pounds with aromatic aldehydes in presence of ammonium
acetate [10], a route which goes via a dihydropyrimidine
intermediate, we obtained the desired pyrimidines, but only
in unacceptably low yields. Therefore, we sought to
develop a better, more general method for the synthesis of
these highly substituted pyrimidines.
In this report, we describe our development of a modifi-
cation of the Pinner pyridimine synthesis that uses silyl-
substituted amidines in place of amidines. This method
can be used in a convenient manner for the synthesis of
various tri- and tetrasubstituted pyrimidines in good yields.
Results and Discussion.
In the Pinner pyrimidines synthesis [4,6,11] (Scheme
1a), an amidine is condensed with a 1,3-dicarbonyl

1102
U. Ghosh and J. A. Katzenellenbogen
Vol. 39
N-trimethyl silyl analogs would produce hexamethyldis-
iloxane rather than water, we anticipated that the conden-
sation reaction would be driven in the forward direction by
the silyl substitution.
In our preliminary attempts with this modification of the
Pinner method, we found that the reaction of dibenzoyl-
methane with an aryl N,N,N'-tris-(trimethylsilyl)benzami-
dine in the presence anhydrous KF [14], a catalyst selected
to assist the silyl transfer process, did not give the required
pyrimidine (Scheme 2, entry 1). However, when we
replaced this anhydrous salt with other forms of KF
(entries 2-4), yields increased. The yield with ammonium
(Scheme 3). We found that pyridine worked better as a
solvent than DMF or acetonitile, and we also found that
using half of an equivalent of the amine salt worked best
for tri-substituted systems, whereas for the preparation of
tetra-substituted pyrimidines, a full equivalent of salt was
preferred. The yields for tri-substituted pyrimidines were
74-89%, and for tetra- substituted pyrimidines were 42-
78%, depending on substituents.
bifluoride (NH •HF ) was 40% (entry 5). This result sug-
4
2
gested that activation of the 1,3-dicarbonyl component
might also be also required to facilitate this reaction.
Conclusion.
We have developed a general method for the synthesis of
tri- and tetra-substituted pyrimidines in high yield, using
1,3-dicarbonyl compounds and N,N,N'-tris-(trimethylsi-
lyl)amidines in place of amidines, which are typically used
in the Pinner pyrimidine synthesis.
On this basis, we the investigated amine salts, namely
EXPERIMENTAL
MeNH •HCl, Me NH•HCl, and NH Cl, and we found that
2
2
4
the reaction proceeds well without the presence of fluoride
ion (Scheme 2, entries 6-7). For the synthesis of tri-subsi-
tuted pyrimidines, all of these salts gave good yields, but
All reaction using water or air sensitive reagents were con-
ducted under dry inert gas atmosphere with dry solvents.
Pyridine and hexane were distilled from CaH under N and
2
2
for the tetra-subsituted pyrimidines, only NH Cl worked
4
stored over CaH until used. THF, dichloromethane, diethyl ether
2
well, presumably because it is the least bulky.
and toluene were obtained dry from solvent delivery system
designed by J.C. Meyer using activated neutral alumina under
dry Argon. All the reagents purchased from Aldrich Chemicals
and Lancaster were used without further purification. The 1,3-
diones are prepared according to a literature procedure [8]. All
reactions were monitored by TLC (Merck, 0.25 mm silica gel
Accordingly, we chose NH Cl as being most general for
4
the synthesis of pyrimidines. Using this salt with 1,3-dike-
tones and N,N,N'-tris-(trimethylsilyl)benzamidines in pyri-
dine under reflux for 24-38 hours, we obtained the corre-
sponding pyrimidines in moderate to good yields

Sep-Oct 2002
A Convenient Method for the Preparation of Highly Substituted Pyrimidines
1103
1
(281 mg, 83%). mp 140-141 °C (lit. [8] m.p. 135-136 °C); H
glass plates containing F-254 indicator), which were visualized
under UV light (254 nm), iodine vapor, or by using a phospho-
molybdic acid indicator spray. Flash column chromatography
[15] was performed using Woelm 32-63 µm silica gel packing.
NMR (CDCl , 500 MHz): δ 8.70 (2H, AA'XX', J = 9.00 &
3
AX
J
= 2.14 Hz), 8.28 (4H, AA'XX', J = 6.64 & J
= 2.14
AA'
AX
AA'
Hz), 7.96 (1H, s, HC(5) pyrimidine), 7.58-7.50 (6H, m, (C4
1
13
&C6)-Ph), 7.05 (2H, AA'XX', J = 9.00 & J
= 2.14 Hz) and
H NMR and C NMR spectra were recorded on Varian
AX
AA'
13
3.92 (3H, s, OMe); C NMR (CDCl , 125 MHz): δ 164.65,
164.26, 161.85, 137.65, 130.82, 130.71, 130.12, 128.89, 127.27,
113.73, 109.66 and 55.36. MS (EI, 70 eV) m/z 338 (M , 100%),
U400 or U500 spectrometers, and spectra chemical shifts (δ) are
reported in parts per million (ppm) downfield from internal
tetramethylsilane or by reference to proton resonances resulting
from incomplete deuteration of the NMR solvent. Coupling con-
stants are reported in Hertz. Electron ionization (EI) spectra were
obtained using a Finnigan-MATCH5 spectrometer at 70 eV.
Elemental analysis was performed by the Microanalytical
Service Laboratory at the University of Illinois, Urbana-
Champaign. Melting points (uncorrected) were recorded on a
Thomas-Hoover Electrothermal Apparatus. All final compounds
were obtained in chromatographically homogenous form.
3
+
339 (29%), 102 (44%).
2,4,6-Tris-(4'-methoxyphenyl)pyrimidine (3c).
This material was prepared, according to the general proce-
dure, from 1,3-(4'-methoxyphenyl)-1,3-dione 1c (284 mg, 1
mmol), amidine 2 (550 mg, 1.5 mmol), and dimethyl ammonium
chloride (32 mg, 0.6 mmol) in dry pyridine (10 ml), with reflux
for 38 hours. After collection of the solid product by filtration
and crystallization from hexane-ethyl acetate, we obtained
General Method for Pyrimidine Synthesis.
1
pyrimidine 3c (294 mg, 74%); mp 174-175 °C; H NMR (CDCl ,
3
The silylamidine, N,N,N'-tris-(trimethylsilyl)-4-methoxyben-
zamidine, was prepared according to a literature procedure [13],
by the reaction of anisonitrile and (Me Si) NLi•OEt in ether to
500 MHz): δ 8.66 (2H, AA'XX', J = 9.00 & J
= 2.14 Hz),
AX
AA'
8.23 (4H, AA'XX', J = 9.00 & J
= 2.14 Hz), 7.80 (1H, s,
AX
AA'
HC(5) pyrimidine), 7.04 (6H, AA'XX', J = 9.00 & J
= 2.14
3
2
2
AX
AA'
13
afford the adduct Ar(NLi)N(SiMe ), which was then heated with
Hz), 3.89 (3H, s, OMe) and 3.89 (3H, s, 2 OMe); C NMR
3
Me SiCl in toluene to give the product in 76% yield (Scheme 1c).
(CDCl , 125 MHz): δ 163.91, 163.76, 161.71, 161.64, 131.14,
3
3
This amidine (1.5 mmol) was then added dropwise at room tem-
perature to a stirred solution of 1,3-diketone (1 mmol) and
ammonium chloride (0.6-1 mmol) in dry pyridine (10 ml) under
dry inert atmosphere. The reaction mixture was refluxed for 24-
38 hours, and after completion of the conversion (as determined
by TLC analysis), the reaction mixture was cooled and ice-water
was added with stirring. The precipitate was collected by filtra-
tion, washed, and then dried, or the product was extracted with
ethyl acetate (2x 10 ml). Extracts were washed with 2 N HCl (2
x 5 ml), brine (5 ml), and then dried over anhydrous Na SO .
130.19, 129.98, 128.66, 114.11, 113.63, 107.85, 55.36 and 55.31;
MS (EI, 70 eV) m/z 398 (M , 100%), 132 (16%).
+
Anal. Calcd. for C H N O : C, 75.36; H, 5.57; N, 7.03.
25 22
2 3
Found: C, 74.92; H, 5.51; N, 6.79.
5-Propyl-2,4,6-tris-(4'-methoxyphenyl)pyrimidine (3d).
This material was prepared, according to the general proce-
dure, from 1,3-bis-(4'-methoxyphenyl)-2-propyl-1,3-dione 1d
(50 mg, 0.153 mmol), amidine 2 (85 mg, 0.23 mmol), and
dimethyl ammonium chloride (7 mg, 0.15 mmol) in dry pyridine
(5 ml), with reflux for 38 hours. After isolation of the solid prod-
uct by filtration and recrystallization from ethanol, we obtained
2
4
Solvents were removed under vacuum, and the products were
purified by flash column chromatography over silica gel using
hexane-ethyl acetate or by recrystallization.
1
pyrimidine 3d (28 mg, 42%); mp 139-140 °C (lit. [8] 135 °C); H
NMR (CDCl , 500 MHz): δ 8.49 (2H, AA'XX', J = 9.00 &
3
AX
4,6-Bis-methyl-2-(4'-methoxyphenyl)pyrimidine (3a).
J
= 2.19 Hz), 7.62 (4H, AA'XX', J = 8.79 & J
= 2.19
AA'
AX
AA'
This material was prepared, according to the general proce-
dure, from pentane-2,4-dione 1a (200 mg, 2 mmol), amidine 2
(1.1 g, 3 mmol), and dimethyl ammonium chloride (64 mg, 1.2
mmol) in dry pyridine (15 ml) with reflux for 24 hours. Isolation
of the water-soluble product by extraction, furnished, after
recrystallization from hexane-ethyl acetate, pyrimidine 3a (382
Hz), 7.03 (4H, AA'XX', J = 8,79 & J
= 2.19 Hz), 6.99 (2H,
AX
AA'
AA'XX', J = 9.00 & J
= 2.14 Hz), 3.92 (3H, s, OMe), 3.89
AX
AA'
(3H, s, OMe), 3.86 (3H, s, OMe), 2.84 (2H, t, J = 7.81 Hz,
CH CH ), 1.15 (2H, quint, J = 7.56 & 7.81 Hz, CH CH CH )
2
2
2
2
3
13
and 0.59 (3H, t, J = 7.56 Hz, CH CH ); C NMR (CDCl , 125
2
3
3
MHz): δ 166.63, 163.09, 161.42, 160.74, 160.03, 132.39, 130.69,
130.34, 129.78, 129.10, 127.20, 113.84, 113.68, 113.58, 55.42,
55.33, 55.29, 30.45, 22.77 and 13.88; MS (EI, 70 eV) m/z 440
1
mg, 89%); mp 91-92 °C; H NMR (CDCl , 500 MHz): δ 8.42
3
(2H, AA'XX', J = 9.00 & J
= 2.14 Hz), 7.00 (2H, AA'XX',
AX
AA'
+
J
= 9.00 & J
= 2.14 Hz), 6.87 (1H, s, HC(5) pyrimidine),
(M , 87%), 439 (49%), 133 (100%).
AX
AA'
13
3.88 (3H, s, OMe) and 2.53 (6H, s, 2 CH ); C NMR (CDCl ,
3
3
4-Propyl-2,5,6-tris-(4'-methoxyphenyl)pyrimidine (3e).
125 MHz): δ 166.59, 163.88, 161.51, 130.78, 129.78, 117.25,
+
113.72, 55.28 and 24.12; MS (EI,70 eV) m/z 214 (M , 100%),
This material was prepared, according to the general proce-
dure, from 1,2-bis-(4'-methoxyphenyl)-hexane-1,3-dione 1e (30
mg, 0.092 mmol), amidine 2 (51 mg, 0.14 mmol), and dimethyl
ammonium chloride (5 mg, 0.09 mmol) in dry pyridine (5 ml),
with reflux for 38 hours. After isolation of the solid product by
filtration and crystallization from ethanol, we obtained pyrimi-
135 (41%), 199 (32%).
Anal. Calcd. for C H N O: C, 72.87; H, 6.59; N, 13.07.
13 14
2
Found: C, 72.79; H, 6.60; N, 12.93.
4,6-Bis-phenyl-2-(4'-methoxyphenyl)pyrimidine (3b).
1
This material was prepared, according to the general proce-
dure, from dibenzoylmethane 1b (225 mg, 1 mmol), amidine 2
(550 mg, 1.5 mmol), and dimethyl ammonium chloride (32 mg,
0.6 mmol) in dry pyridine (10 ml), with reflux for 24 hours.
After collection of the insoluble precipitate by filtration and crys-
tallization from hexane-ethyl acetate, we obtained pyrimidine 3b
dine 3e (18 mg, 45%); mp 129-130 °C (lit. [8] 130-131 °C); H
NMR (CDCl , 500 MHz): δ 8.56 (2H, AA'XX', J
= 9.00 &
3
AX
J
1.93 Hz), 7.41 (2H, AA'XX', J = 8.79 & J
= 1.94 Hz),
AA' =
AX
AA'
7.05 (2H, AA'XX', J
= 8,79 & J
= 2.14 Hz), 7.00 (2H,
AX
AA'
AA'XX', J = 8.79 & J = 1.93 Hz), 6.89 (2H, AA'XX', J
=
=
AX
AA'
AX
8.79 & J
= 1.95 Hz), 6.76 (2H, AA'XX', J = 9.00 & J
AA'
AX AA'

1104
U. Ghosh and J. A. Katzenellenbogen
Vol. 39
2.14 Hz), 3.88 (3H, s, OMe), 3.86 (3H, s, OMe), 3.85 (3H, s,
OMe), 2.65 (2H, t, J = 7.50 Hz, CH CH ), 1.78 (2H, quint, J =
Acknowledgment.
2
2
We are grateful for support of this research through a research
grant from the National Institutes of Health (PHS 5R37
DK15556). NMR spectra were obtained in the Varian Oxford
Instrument Center for Excellence in NMR Laboratory. Funding
for this instrumentation was provided in part from the W. M.
Keck Foundation, the National Institutes of Health (PHS 1 S10
RR104444-01), and the National Science Foundation (NSF CHE
96-10502). Mass spectra were obtained on instruments sup-
ported by grants from the National Institute of General Medical
Sciences (GM 27029), the National Institutes of Health (RR
01575), and the National Science Foundation (PCM 8121494).
7.5 & 7.3 Hz, CH CH CH ) and 0.91 (3H, t, J = 7.30 Hz,
2
2
3
13
CH CH ); C NMR (CDCl , 100 MHz): δ 169.33, 162.91,
2
3
3
162.02, 161.49, 159.85, 158.78, 131.54, 131.47, 131.38, 131.06,
129.79, 129.41, 128.52, 113.98, 113.66, 113.10, 55.16, 55.13,
+
55.14, 37.33,21.90 and 14.05; MS (EI, 70 eV) m/z 440 (M ,
56%), 439 (38%), 411 (100%).
4,6-Bis-methyl-5-ethyl-2-(4'-methoxyphenyl)pyrimidine (3f).
This material was prepared, according to the general proce-
dure, from 3-ethyl-2,4-pentanedione 1f (256 mg, 2 mmol), ami-
dine 2 (1.1 g, 3 mmol), and ammonium chloride (108 mg, 2
mmol) in dry pyridine (15 ml), with reflux for 38 hours. After
isolation of the water-soluble product by extraction and after
purification by flash column chromatography, we obtained
pyrimidine 3f (377 mg, 78%). mp 80-81 °C (hexane-ethyl
REFERENCES AND NOTES
*
Address Correspondence to: John A. Katzenellenbogen,
1
acetate); H NMR (CDCl , 500 MHz): δ 8.36 (2H, AA'XX', J
Department of Chemistry, University of Illinois, 600 S. Mathews Ave.,
Urbana, IL 61801, e-mail: jkatzene@uiuc.edu; (217) 333-6310
(phone); (217) 333-7325 (fax).
[1] J. A. Joule, G. Smith and K. Mills, Heterocyclic Chemistry,
Third Edition; Chapman & Hall, 1994.
[2] G. W. Kenner and A. Todd, Heterocyclic Compounds; R. C.
Elderfield: New York, 1957; Vol. 6.
[3] D. J. Brown, The Chemistry of Heterocyclic Compounds;
A. Weissberger: New York, 1962; Vol. 16.
[4] D. J. Brown, In The Pyrimidines; A. Weissberger, E. C.
Taylor Eds., John Wiley and Sons: New York, 1962; pp 116.
[5] A. Bowman J. Chem. Soc., 494 (1937).
[6] C. Haley and A. C. Maitland J. Chem. Soc., 3155 (1951).
[7] J. C. Roberts J. Chem. Soc., 3065 (1952).
[8] U. Ghosh, D. Ganessunker, V. J. Sattigeri, K. E. Carlson, D.
S. Mortensen, B. S. Katzenellenbogen and J. A. Katzenellenbogen
Bioorg. Med. Chem., (In Press).
[9] A. G. Martinez, A. H. Fernandez, F. M. Jimenez, A. G.
Fraiale and L. R. Subramanian J. Org. Chem., 57, 1627 (1992).
[10] A. L. Weis and V. Rosenbach Tetrahedron Lett., 22, 1453
(1981).
[11] J. S. Gillespie, S. P. Acharya and R. E. Davis J. Heterocyclic
Chem. 9, 931 (1972).
3
AX
= 9.00 & J
= 2.14 Hz), 6.97 (2H, AA'XX', J = 9.00 & J
AA'
AX
AA'
= 2.14 Hz), 3.86 (3H, s, OMe), 2.67 (2H, q, J = 7.50 Hz,
CH CH ), 2.55 (6H, s, 2 CH ) and 1.16 (3H, t, J = 7.50 Hz,
2
3
3
13
CH CH ); C NMR (CDCl , 125 MHz): δ 164.23, 161.19,
2
3
3
160.86, 130.93, 129.85, 129.34, 113.68, 55.28, 21.89, 21.29 and
+
12.98. MS (EI, 70 eV) m/z 242 (M , 96%), 227 (100%), 134
(44%).
Anal. Calcd. for C H N O: C, 74.35; H, 7.49; N, 11.56.
15 18
2
Found: C, 74.35; H, 7.55; N, 11.56.
2,5-Bis-(4'-methoxyphenyl)-6-methyl-4-propylpyrimidine (3g).
This material was prepared, according to the general proce-
dure, from 2-(4'-methoxyphenyl)-hepane-2,4-dione 1g (234 mg,
1 mmol), amidine 2 (550 mg, 1.5 mmol), and dimethyl ammo-
nium chloride (54 mg, 1 mmol) in dry pyridine (10 ml), with
reflux for 38 hours. After isolation of the solid product by filtra-
tion and crystallization from ethanol, we obtained pyrimidine 3g
1
(209 mg, 60%); mp 134-135 °C (lit [8] 135-136 °C); H NMR
(CDCl , 500 MHz): δ 8.47 (2H, AA'XX', J = 8.79 & J =
3
AX
AA'
1.93 Hz), 7.12 (2H, AA'XX', J = 8.58 & J
= 1.93 Hz), 7.01
AX
AA'
(4H, AA'XX', J = 8.58 & J
= 2.14 Hz), 3.90 (3H, s, OMe),
AX
AA'
[12] A. R. Katritzky and T. I. Yousaf Can. J. Chem., 64, 2087
(1986).
[13] R. T. Boere, R. T. Oakley and R. W. Reed J. Organometallic
Chem., 331, 161 (1987).
[14] S. Brandl, R. Gompper and K. Polborn J. Prakt. Chem., 338,
451 (1996).
[15] W. C. Still, M. Kahn and A. Mitra J. Org. Chem., 43, 2923
(1978).
3.89 (3H, s, OMe), 2.54 (2H, t, J = 7.50 Hz, CH CH CH ), 2.34
2
2
3
(3H, s, CH ), 1.74 (2H, quint, J = 7.50 Hz, CH CH CH ) and
3
2
2
3
13
0.89 (3H, t, J = 7.50 Hz, CH CH ); C NMR (CDCl , 125
2
3
3
MHz): δ 167.79, 164.92, 162.01, 161.39, 158.98, 131.05, 130.41,
130.36, 129.66, 129.18, 114.10, 113.72, 55.31, 55.25, 37.15,
+
23.40, 21.84 and 14.00; MS (EI, 70 eV) m/z 348 (M 38%), 347
(22%), 320 (89%), 319 (100%).