One-pot synthesis of polysubstituted pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2005.01.068

A series of polysubstituted pyrimidines were synthesized from in situ generated α,β-unsaturated imines and the corresponding amidine or guanidine derivatives in a convenient one-pot procedure.

Full text of DOI:10.1016/j.tetlet.2005.01.068

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1663–1665
One-pot synthesis of polysubstituted pyrimidines
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Rd., San Diego, CA 92121, USA
Received 16 December 2004; revised 10 January 2005; accepted 13 January 2005
Available online 29 January 2005
Abstract—A series of polysubstituted pyrimidines were synthesized from in situ generated a,b-unsaturated imines and the
corresponding amidine or guanidine derivatives in a convenient one-pot procedure.
Ó 2005 Elsevier Ltd. All rights reserved.
Synthesis of polysubstituted pyrimidines received sub-
stantial attention due to their pronounced physiological
activity. Several reports in the literature describe the
application of these substrates for the treatment of hy-
R
R
Ar2
N
Ar2
N
1
Ar2
NH
O
CN
R
R
R'
2
3
4
poxemia, neuronosis, and neuropathy. Notably, bcr-
TM
Abl kinase inhibitor Gleevec contains a 2,4-substituted
Ar1
NH2
Ar1
R'
Ar1
5
pyrimidine core. Preclinical data from several research
labs indicate continuing interest in polysubstituted pyr-
imidines as potential anti-tumor agents. Pyrimidine
derivatives has been used in coordination chemistry,
specifically as ligands for metal-cage complexes, in par-
Scheme 1.
6
mized reaction conditions include application of dry
THF or dioxane as solvents, as well as thorough temper-
ature control of the reaction mixtures, especially at the
earlier stages of reagent addition. We attribute this to
the formation of unstable aza-Wittig species 2b that un-
dergo smooth reaction with aldehydes to result in the
reactive imine species 3. Addition of polar solvents
(DMF, NMP, N-methyl morpholine; 20–50 vol %) to
better solubilize amidine or guanidine species did not
affect the outcome of the reaction.
7
8
ticular with lanthanides, and ruthenium.
In our medicinal chemistry program, we required a ro-
bust approach to a diverse set of the title heterocycles.
Among wide variety of synthetic approaches available
9
for the assembly of pyrimidine ring, we have focused
1
0–12
on a,b-unsaturated imines as starting materials.
The feasibility of generating these reactive species in situ
1
0
in the synthesis of substituted pyridines, E-allylic
1
1
12
As a further development of this protocol, we studied
the effect of phosphonate substitution on the reaction
amines, and a,b-unsaturated ketones is well docu-
mented (Scheme 1).
(
Table 2).
Initially, we studied reaction of a,b-unsaturated imines
with several amidines and guanidines (Table 1).
1
3
Application of substituted phosphonates in this reaction
sequence allowed for the introduction of a substituent in
the position 5 of the pyrimidine ring. However, it also
reduced the overall yield of the resulting pyrimidines
We believe that the described transformations proceed
1
0–12
via the initial formation of a,b-unsaturated imines
that undergo nucleophilic attack by a bi-dentate nucleo-
5a–g. For example, the best yields of the targeted pyrim-
idines 5 were consistently achieved with ethyl phosphon-
3
phile (amidine or guanidine). This step is then followed
by elimination of ammonia and aromatization to yield
0
ate (R = Me, entries 5a–c). Increasing steric bulk from
Me (entry 5b) to Ph (entries 5e and 5f) or i-Bu (entry
1
4
the observed polysubstituted pyrimidines 4a–l. Opti-
5g) reduced the yield of the targeted products from
57% to 22–39%, respectively. The latter reactions
also resulted in a number of high-molecular weight
products along with the desired compounds 5. Identified
components of the reaction mixtures included the
Keywords: Pyrimidines; Amidines; Condensations.
*
Tel.: +1 858 794 4860; fax: +1 858 794 4931; e-mail: ask@
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0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.068

1664
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 1663–1665
Table 1.
OEt
P
O
NH
N
O
OEt
o
Ar -CHO
- 50 C
2
Ar1
Ar1
Ar -CN
o
1
o
-50 to 0 C,
THF, -78 C,
0 min
P
OEt
OEt
P
OEt
O
45 min
2
1
OEt
2
b
2
a
NH2
Ar2
Ar2
R
NH2 Cl
N
Hunig's base,
Ar1
N
R
Ar1
NH
o
0 C to reflux
4a-l
3
2 hrs
Entry, 4
mp, °C)
Ar
1
Ar
2
R
Yield, % Entry, 4
(mp, °C)
Ar
1
Ar
2
R
Yield, %
(
N
Cl
N
a (96–98)
Me
Me
67
71
g (172–173)
h (144–145)
58
60
N
F
b (108–109)
N
Me
N
O
F
F
F
O
c (133–135)
d (142–143)
73
i (212–214)
j (253–255)
55
58
HN
HN
F
N
N
COOMe 64
F
F
F
F
e (130–132)
f (128–130)
COOMe 61
k (230–232)
l (245–247)
54
56
N
N
HN
HN
F
N
68
N
N
OMe
Table 2.
NH2
R'
Ar2
OEt
Ar2
R'
NH
P
O
R'
Ar1
OEt
Ar -CHO
R
NH2 Cl
R'
2
N
Ar1
Ar -CN
1
o
-
30 to 40 C,
120 min
Hunig's base,
dioxane,
30 C, 30 min
P
OEt
OEt
N
R
Ar1
NH
o
O
40 C to reflux
o
-
6
hrs
1
2b'
3'
5a-g
0
Entry, 5 (mp, °C)
a (115–117)
Ar
1
Ar
2
R
R
Yield, %
52
Me
Me
Me
F
O
b (133–135)
c (172–174)
d (144–146)
e (167–169)
f (153–154)
Me
57
43
41
26
22
O
N
F
F
Me
F
F
F
O
Me
Me
O
O
O
O
OMe
O
F
N
g (170–172)
COOMe
39
F

A. S. Kiselyov / Tetrahedron Letters 46 (2005) 1663–1665
1665
corresponding a,b-unsaturated ketones (25–40% by LC
MS analysis, 20–30% isolated yields) that presumably orig-
inated from the nonreacted imines 3 . Our attempts to im-
prove the outcome of these reactions by further increasing
the temperature of the reaction (ca. 140 °C, sealed tube),
microwave irradiation of the reaction mixtures, addition
of polar solvents (DMF, NMP), or by applying varying
Helv. Chim. Acta 1990, 73, 1149; (c) Balzani, V.;
Bargmans, E.; Lehn, J. M.; Sabbatini, N.; Tetrode, R.;
Zeissel, R. Helv. Chim. Acta 1990, 73, 2083.
. (a) Brown, D. J. The Pyrimidines; Wiley Interscience:
New York, NY, 1984; (b) Brown, D. J. The Pyrim-
idines, Supplement II; Wiley Interscience: New York,
NY, 1985.
0
9
1
0. Kiselyov, A. S. Tetrahedron Lett. 1995, 36, 9297.
amount (2–10 equiv) of bases (HunigÕs base, Bu NF,
4
11. (a) Shin, W. S. S.; Lee, K.; Oh, D. Y. Tetrahedron Lett.
1995, 36, 281; (b) Palacios, F.; Garcia, J.; Ochoa de
Retana, A. M.; Oyarzabal, J. Heterocycles 1995, 41, 1915,
and references cited therein.
DABCO) were unsuccessful. In addition, no reaction
was observed with phosphonates containing electron-with-
0
drawing groups (Table 2, R = COOMe, CN).
1
2. Lee, K.; Oh, D. Y. Synthesis 1991, 213.
1
3. General experimental procedure: n-BuLi (2.5 M solution
in hexanes, 4 mL, 1 mM) was added by syringe to a
vigorously stirred solution of diethyl alkylphosphonate
In summary, we have described a convenient one-pot
approach to polysubstituted pyrimidine derivatives from
in situ generated a,b-unsaturated imines and the corre-
sponding amidine or guanidine derivatives. In addition,
pyrimidines with small alkyl substituents in position 5
are also accessible via this protocol by using properly
substituted alkylphosphonates.
(
(
1 mM) in dry THF for methyl phosphonate or dioxane
15 mL) under Ar at ꢀ78 °C. A solution of nitrile (1 mM)
in 5 mL of the same solvent was slowly added by syringe.
The resulting colorless to pale-yellow mixture was slowly
warmed to ꢀ50 °C and stirred for additional 30 min. A
solution of aldehyde (1 mM) in 5 mL of dry solvent (THF
or dioxane) was slowly added (5 min), and the resulting
mixture was allowed to warm upto room tem pe rature
(45 min). A mixture of amidine or guanidine (1 mM) and
HunigÕs base (1 mM) in dry solvent (5 mL) was introduced
to the reaction vessel and the resulting heterogeneous
solution was slowly brought to reflux (30 min). After this,
the reaction mixture was refluxed for an additional 100–
120 min until TLC (hexanes/ether, 1:1) and GC MS
analyses indicated absence of starting materials (nitrile
and aldehyde). The reaction mixture was then concen-
trated to 20 mL on rotavap, diluted with EtOAc (50 mL),
organic extract was washed twice with brine (30 mL),
dried over Na SO , concentrated to ca. 10 mL, cooled
References and notes
1
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2
3
4
5
. Yasuji, S.; Masaichi, H.; Kataoka, K.; Hoshina, K.;
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2
4
down in the freezer and triturated with cold ether. The
resulting crystals were collected, washed with ether and
recrystallized from EtOH and dried in vacuo to yield
analytically pure pyrimidines.
14. Representative examples: 4b: 71% yield,
(400 MHz, DMSO-d
1
H NMR
6
): d 1.98 (s, 3H, Me), 6.92 (m, 3H),
7.23 (m, 2H), 7.30 (d, 2H, J = 8.0 Hz), 7.68 (d, 2H,
J = 8.0 Hz), 7.98 (s, 1H). ESI MS: (M+1) 265, (Mꢀ1) 263;
HR ESI MS: Exact mass calcd for C H FN 264.1063,
1
7
13
3
3
found: 264.1086. Elemental analysis, calcd for C17H13FN :
C, 77.25; H, 4.96; N, 10.60. Found: C, 77.11; H, 5.11; N,
1
10.38; 4d: 64% yield, H NMR (400 MHz, DMSO-d ): d
6
2.98 (s, 3H, Me), 3.68 (s, 2H, CH ), 7.11 (m, 2H), 7.35 (m,
2
1H), 7.68 (d, 2H, J = 7.6 Hz, Py), 8.12 (s, 1H), 8.22 (d, 2H,
J = 7.6 Hz, Py); ESI MS: (M+1) 342, (Mꢀ1) 340; HR ESI
MS: Exact mass calcd for C H F N O : 341.0976,
6
. (a) Maquoi, E.; Sounni, N. E.; Devy, L.; Olivier, F.;
Frankenne, F.; Krell, H.-W.; Grams, F.; Foidart, J.-M.;
Noel, A. Clin. Cancer Res. 2004, 10, 4038; (b) Huang, M.;
Wang, Y.; Collins, M.; Mitchell, B. S.; Graves, L. M. Mol.
Pharmacol. 2002, 62, 463; (c) Von Bubnoff, N.; Veach, D.
R.; Miller, W. T.; Li, W.; Sanger, J.; Peschel, C.;
Bornmann, W. G.; Clarkson, B.; Duyster, J. Cancer Res.
1
8
13
2
3
2
found: 341.0884. Elemental analysis, calcd for:
C H F N O : C, 63.34; H, 3.84; N, 12.31. Found: C,
63.14; H, 3.96; N, 12.12; 5b: 57% yield, H NMR
1
8
13
2
3
2
1
(400 MHz, DMSO-d ): d 1.95 (s, 3H, Me), 2.03 (s, 3H,
6
2
Me), 2.95 (s, 2H, CH ), 6.88 (m, 2H), 7.05 (s, 1H), 7.28 (d,
2
003, 63, 6395.
2H, J = 8.0 Hz), 7.61 (d, 2H, J = 8.0 Hz); ESI MS: (M+1)
323, (Mꢀ1) 321; HR ESI MS: Exact mass calcd for
C H FN O : 322.1118, found: 322.1128. Elemental
7
8
. Alpha, B.; Lehn, J. M.; Perathoner, S.; Sabbatini, N.
Angew. Chem., Int. Ed. Engl. 1987, 26, 1266.
1
9
15
2
2
. (a) Beler, P.; De Cola, L.; Von Zelewsky, A. J. Chem. Soc.,
Chem. Commun. 1988, 1057; (b) Ziessel, R.; Lehn, J. M.
2 2
analysis, calcd for: C19H15FN O : C, 70.80; H, 4.69; N,
8.69. Found: C, 70.62; H, 4.82; N, 6.47.