One-pot synthesis of substituted pyrimidine derivatives from acetylenedicarboxylate, amine and orthoformate

Article abstract of DOI:10.1055/s-0030-1258034

Substituted pyrimidine derivatives with a disubstituted pattern are produced in a novel one-pot reaction from diethyl(methyl)acetylenedicarboxylate, amine, and trimethyl(ethyl)orthoformate under solvent-free conditions using ZnCl₂ catalyst. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258034

LETTER
2311
One-Pot Synthesis of Substituted Pyrimidine Derivatives from
Acetylenedicarboxylate, Amine and Orthoformate
S
ynthesis of Subst
r
itute
d
Py
a
rimidine
D
s
erivativesampattu S. Nagarajan, Boreddy S. R. Reddy*
Industrial Chemistry Laboratory, Central Leather Research Institute, Adyar, Chennai 600 020, India
Fax +91(44)24911589; E-mail: induchem2000@yahoo.com
Received 28 June 2010
acetate. Hua Cao and co-workers12 reported the synthesis
of pyrimidine from electron-deficient alkynes, amines,
and formaldehyde under catalyst-free conditions. Func-
tionally polysubstituted furans via copper-catalyzed dom-
ino rearrangement of diethyl but-2-ynedioate with
alkynols were also reported.13 Herein, we wish to report
our investigation of a new one-pot reaction which in-
volves acetylenedicarboxylate, amine, and orthoformate
for the synthesis of disubstituted pyrimidine compounds
using ZnCl2 as a catalyst under solvent-free condition
(Scheme 1).
Abstract: Substituted pyrimidine derivatives with a disubstituted
pattern are produced in a novel one-pot reaction from diethyl(meth-
yl)acetylenedicarboxylate, amine, and trimethyl(ethyl)orthofor-
mate under solvent-free conditions using ZnCl2 catalyst.
Key words: solvent-free conditions, diethyl acetylenedicarboxy-
late, trimethyl orthoformate, pyrimidine
Multicomponent reactions (MCR) are one-pot processes
in which three or more easily accessible components react
to form a single product. MCR offer significant advantag-
es over conventional linear-type synthesis as they are flex-
ible, convergent, and atom-efficient. They have become
an important area of research in organic, medicinal, and
combinatorial chemistry.1–3 According to current synthet-
ic requirements, effective and environmentally benign
multicomponent procedures are particularly welcome.4
Pyrimidines and their analogues found both in various bi-
ologically active natural compounds and designed medic-
inal agents represent an important class of nitrogen-
containing heterocycles.5 Specifically, tetrahydropyrimi-
dines containing an amino acid unit have attracted much
attention due to their interesting properties such as musca-
rinic agonist activity,6 protein–nucleic acid interaction,7
antiviral activity,8 and anti-inflammatory activity.9 Struc-
ture–activity relationship (SAR) studies of the tetrahydro-
pyrimidine derivatives showed that the substituent groups
on the ring play a critical role in their biological activi-
ties.10 Diethyl acetylenedicarboxylate is an exceptionally
versatile compound used extensively as a reactant or reac-
tion intermediate. It exhibits unique reactivity since the
strongly electron-withdrawing carbonyl groups activate
the triple bond, their multiple bonds are suitable for nu-
cleophilic addition, and is also having a good leaving
group for substitution. The acetylene group along with
one or two ethyl groups can take part in a condensation re-
action to give a variety of addition products and heterocy-
clic compounds. Trimethyl orthoformate is an important
substrate for the design of new multicomponent reactions
in medicinal, industrial, and agricultural chemistry. Re-
cently, Konakahara et al.11 reported 4,5-disubstituted
pyrimidine derivatives by ZnCl2-catalyzed three-compo-
nent coupling reaction involving a variety of functional-
ized enamines, triethylorthoformate, and ammonium
O
CO2R1
R2
ZnCl2
N
+
NH2
R2
CH(OR3)3
2
+
solvent-free
R1O2C
N
R2
4
OR3
CO2R1
2
1a R1 = Et
3a R3 = Et
1b R1 = Me
3b R3 = Me
Scheme 1 Synthesis of pyrimidine derivatives
When a mixture of diethyl acetylenedicarboxylate, trime-
thyl orthoformate, and an excess of aromatic amine was
stirred using Lewis acid for three hours, the expected di-
substituted pyrimidine derivatives 4a–p were isolated in
more than 50% yield after workup.
Similarly, various aromatic amines reacted well under
identical reaction conditions to give the corresponding
disubstituted pyrimidine derivatives. Aromatic amines
with electron-donating groups give moderate to good
yields of disubstituted pyrimidines. On the other hand,
amines with stronger electron-withdrawing groups such
as nitro group resulted in very low yield of disubstituted
pyrimidine, along with a gummy material whose structure
could not be elucidated. Aliphatic amines such as ethyl
and n-propyl amines were employed in the MCR. The
reaction was found to be sluggish (4o and 4p) compared
with other aromatic amines. The disubstituted pyrimidine
1
derivatves 4a–p were fully characterized by H, 13C
NMR, MS spectra and elemental analysis. The influence
of the ratio of the components was investigated using a
typical reaction of p-methoxyaniline, and the optimum
reaction conditions were given in the general procedure.
Trimethyl orthoformate was replaced by triethyl orthofor-
mate affording 4m in ca. 64% yield compared to trimethyl
orthoformate 4n in 63% yield. Similar results were ob-
served in each case and nearly the same yields were ob-
SYNLETT 2010, No. 15, pp 2311–2313
x
x
.x
x
.2
0
1
0
Advanced online publication: 12.08.2010
DOI: 10.1055/s-0030-1258034; Art ID: G18910ST
© Georg Thieme Verlag Stuttgart · New York

2312
A. S. Nagarajan, B. S. R. Reddy
LETTER
tained. Trimethyl or triethyl orthoformate each have a
single proton that can facilitate cleavage of the methoxy
group and thereby the MCR proceeds easily. But, dimeth-
yl acetal does not undergo MCR even under stringent con-
ditions such as heating the reaction (up to 100 °C) and
acetonitrile as a solvent. Hydroamination takes place be-
tween substituted amine and an active triple bond present
in the dialkyl acetylenedicarboxylate. Dimethyl fumarate
or maleate does not undergo MCR reaction due to the ab-
sence of active triple bond for hydroamination. To explain
the mechanism of this one-pot multicomponent tandem
reaction, we have proposed a plausible reaction course as
illustrated in Scheme 2.
Table 1 One-Pot Synthesis of Pyrimidine Derivatives
Entry R1
R2
R3
Product Time Yield
(h)
3
2
2
1
3
1
3
2
2
2
3
2
3
3
3
3
(%)
65
56
71
59
63
67
69
80
72
73
27
67
64
63
60
61
1
2
Me
3,4-F2C6H3
Et
4a
4b
4c
4d
4e
4f
Et
4-MeOC6H4
Me
Et
3
Et
2-Cl-4-BrC6H3
2,5-Et2C6H3
4
Me
Me
Et
Me
Et
5
2,4,6-Me3C6H2
2,4,6-Br3C6H2
2-Br-4-FC6H3
2-Cl-4-BrC6H3
6
Et
7
Me
Et
Me
Me
4g
4h
4i
The first step is the formation of the reaction intermediate
A, through a hydroamination step. This is followed by a
Lewis acid promoted two-component ester amidation to
give the intermediate C. ZnCl2 coordination with the
orthoester is followed by a reaction of the activated acetal
with the intermediate C, which leads to the formation of
D which is subsequently transformed to E with the liber-
ation of methanol. When the reaction of 1 equivalent acet-
ylenedicarboxylate 1, 2 equivalent amine 2, and 1
equivalent of orthoester 3 was conducted in solvent-free
conditions in the presence of ZnCl2 at room temperature
for 3 hours, the desired disubstituted pyrimidine 4 was ob-
tained in a 56–80% yield. All the reactions required 1–3
hours to complete the intermolecular coupling and subse-
quent intramolecular cyclization. Most reactions proceed-
ed cleanly to produce the corresponding disubstituted
pyrimidine derivatives 4a–p in moderate to good yields
(Table 1).
8
9
Et
2,6-Br2-4-MeC6H2 Me
2,6-Br2-4-MeC6H2 Et
10
11
12
13
14
15
16
Me
Me
Et
4j
4-O2NC6H4
Et
4k
4l
2-MeO-5-MeC6H3 Me
2-MeO-5-MeC6H3 Et
2-MeO-5-MeC6H3 Me
Me
Me
Me
Et
4m
4n
4o
4p
Et
Et
n-Pr
Me
Thus, we have demonstrated a simple and efficient syn-
thesis of substituted pyrimidine derivatives via a ZnCl2-
catalyzed three-component coupling reaction of a func-
tionalized amine (aliphatic and aromatic) with an orthoe-
ster and disubstituted acetylenedicarboxylate. This has
proven to be a facile and practical method for the prepara-
tion of a pyrimidine skeleton.
OR1
CO2R1
R2
hydroamination
O
+
NH2
NH
R2
CO2R1
A
Acknowledgment
O
A. S. Nagarajan thanks the (CSIR, SRF) for generous financial as-
sistance.
R2
R2 NH2
N
OR1
R1O2C
N
R2
OR3
ZnCl2
References and Notes
O
E
(1) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39,
3168. (b) Ramon, D. J.; Yus, M. Angew. Chem. Int. Ed.
2005, 44, 1602.
R1O2C
NH
R2
B
– R3 OH
(2) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(3) Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org. Chem.
amidation
2003, 4101.
ZnCl2
OR3
(4) (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471.
(b) Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.
(5) (a) Looper, R. E.; Runnegar, M. T. C.; Williams, R. M.
Angew. Chem. Int. Ed. 2005, 44, 3879. (b) Kobayashi, J.;
Kanda, F.; Ishibashi, M.; Shigemori, H. J. Org. Chem. 1991,
56, 4574. (c) Skinner, G. S.; Wunz, P. R. J. Am. Chem. Soc.
1951, 73, 3814.
(6) (a) Messer, W. S. Jr.; Abuh, Y. F.; Liu, Y.; Periya Samy, S.;
Ngur, D. O.; Edgar, M. A. N.; El-Assadi, A. A.; Sbeih, S.;
Dunbar, P. G.; Roknich, S.; Rho, T.; Fang, Z.; Ojo, B.;
O
O
N
H
R2
N
R2
R3O
OR3
N
••
H
OR3
R1O2C
NH
R2
C
R1O2C
OR3
R2
R3OH
D
Scheme 2 A plausible mechanism for preparation of pyrimidine
derivatives
Synlett 2010, No. 15, 2311–2313 © Thieme Stuttgart · New York

LETTER
Zhang, H.; Huzl, J. J.; Nagy, P. I. J. Med. Chem. 1997, 40,
Synthesis of Substituted Pyrimidine Derivatives
2313
of EtOAc–hexane (20:80 v/v). The product was further
purified by recrystallization from EtOAc and found to be
pure as indicated by TLC, 1H NMR and 13C NMR data.
Compound 4b: 1H NMR (500 MHz, DMSO-d6): d = 1.09 (t,
J = 6.9 Hz, 3 H), 3.77 (s, 6 H), 3.95 (s, 3 H), 4.13 (q, J = 7.6
Hz, 2 H), 5.29 (s, 1 H), 6.80–6.81 (m, 5 H), 6.88–6.90 (m, 4
H). 13C NMR (125 MHz, DMSO-d6): d = 14.2, 55.5, 59.8,
61.1, 62.0, 92.0, 114.3, 121.3, 123.4, 129.8, 133.6, 139.7,
149.5, 157.0, 164.4, 169.9. LCQ-MS (ESI): m/z (%) = 412.
Anal. Calcd for C22H24N2O6: C, 64.07; H, 5.87; N, 6.79.
Found: C, 64.19; H, 5.79; N, 6.91.
1230. (b) Messer, W. S. Jr.; Abuh, Y. F.; Ryan, K.;
Shepherd, M. A.; Schroeder, M.; Abunada, S.; Sehgal, R.;
El-Assadi, A. A. Drug Dev. Res. 1997, 40, 171. (c) Zhang,
H.; Ojo, B.; Huang, X. P.; Edgar, M. A. N.; El-Assadi, A. A.;
Baril, D.; Lynch, K.; Wahidy, S.; Messer, W. S. Life Sci.
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B.; Huzl, J. J.; Smith, D. A.; El-Assadi, A. A.; Sbeih, S.;
Ngur, D. O.; Periyassamy, S.; Hoss, W.; Messer, W. S. Jr.
J. Med. Chem. 1994, 37, 2774. (e) Dunbar, P. G.; Durant,
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Periyasamy, S.; Hoss, W.; Messer, W. S. Jr. J. Med. Chem.
1993, 36, 842.
Compound 4h: 1H NMR (500 MHz, DMSO-d6): d = 1.15 (t,
J = 6.8 Hz, 3 H), 3.73 (s, 3 H), 4.18 (q, J = 6.8 Hz, 2 H), 5.56
(s, 1 H), 6.62 (s, 1 H), 6.64 (s, 1 H), 7.22–7.24 (m, 3 H),
7.49–7.50 (m, 2 H). 13C NMR (125 MHz, DMSO-d6): d =
14.4, 31.0, 60.4, 62.4, 97.3, 116.2, 122.3, 126.6, 130.1,
130.6, 131.2, 132.3, 136.9, 142.1, 146.2, 163.6, 169.1. LCQ-
MS (ESI): m/z = 578. Anal. Calcd for C20H16Br2Cl2N2O4: C,
41.48; H, 2.79; N, 4.84. Found: C, 41.57; H, 2.93; N, 4.72.
Compound 4i: 1H NMR (500 MHz, DMSO-d6): d = 1.13 (t,
J = 6.9 Hz, 3 H), 2.19 (s, 6 H), 3.76 (s, 3 H), 4.11 (q, J = 6.8
Hz, 2 H), 5.61 (s, 1 H), 7.18 (s, 2 H), 7.33 (s, 3 H). 13C NMR
(125 MHz, DMSO-d6): d = 14.4, 20.5, 60.1, 62.0, 92.4,
108.7, 121.9, 129.4, 132.2, 132.7, 135.7, 138.5, 139.6,
148.2, 162.6, 170.0. LCQ-MS (ESI): m/z = 696.1. Anal.
Calcd for C22H20Br4N2O4: C, 37.96; H, 2.90; N, 4.02. Found:
C, 37.85; H, 3.00; N, 4.13.
(7) Malin, G.; Iakobashvili, R.; Lapidot, A. J. Biol. Chem. 1999,
274, 6920.
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2006, 49, 445. (b) Zhou, S.; Kern, E. R.; Gullen, E.; Cheng,
Y. C.; Drach, J. C.; Matsumi, S.; Mitsuya, H.; Zemlicka, J.
J. Med. Chem. 2004, 47, 6964.
(9) Pattarini, R.; Smeyne, R. J.; Morgan, J. I. Neuroscience
2007, 145, 654.
(10) (a) Nair, A. C.; Jayatilleke, P.; Wang, X.; Miertus, S.; Welsh,
W. J. J. Med. Chem. 2002, 45, 973. (b) De Lucca, G. V.;
Liang, J. J. Med. Chem. 1999, 42, 135.
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4111.
(12) Huo, C.; Xiujum, W.; Huanfeng, J.; Qiuhua, Z.; Min, Z.;
Haiyang, L. Chem. Eur. J. 2008, 14, 11623.
(13) Sasada, T.; Kobayashi, F.; Skai, N.; Konakahara, T. Org.
Lett. 2009, 11, 2161.
Compound 4p: 1H NMR (500 MHz, CDCl3): d = 0.85 (t,
J = 7.6 Hz, 6 H), 0.95 (t, J = 7.6 Hz, 3 H), 1.52–1.67 (m, 4
H), 3.10 (t, J = 7 Hz, 2 H), 3.38 (t, J = 6.9 Hz, 2 H), 3.70 (s,
3 H), 4.06 (q, J = 6.8 Hz, 2 H), 5.52 (s, 1 H), 6.86 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 11.3, 11.4, 11.5, 21.9,
22.1, 29.8, 39.2, 61.1, 62.0, 83.7, 129.1, 140.0, 167.7, 172.8.
LCQ-MS (ESI): m/z = 284.2. Anal. Calcd for C14H24N2O4:
C, 59.13; H, 8.51; N, 9.85. Found: C, 59.02; H, 8.48; N, 9.86.
(14) General Procedure for Pyrimidine
To a stirred mixture of acetylenedicarboxylate 1 (2 mmol),
amine 2 (4 mmol), and orthoformate 3 (2 mmol), ZnCl2 (0.5
mol%) was added successively at r.t. with vigorous stirring
for 1–3 h. The precipitated solid was purified with a mixture
Synlett 2010, No. 15, 2311–2313 © Thieme Stuttgart · New York

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