Viehe's salt in a novel one pot synthesis of pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2004.12.069

A series of pyrimidine derivatives are synthesized from N-substituted lactams, and Viehe's salt. A short reaction sequence, good yields of the targeted heterocyclic compounds (44-67%), as well as their convenient isolation and purification are the distinc

Full text of DOI:10.1016/j.tetlet.2004.12.069

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1177–1179
VieheÕs salt in a novel one pot synthesis of pyrimidines
Alexander S. Kiselyov*
Small Molecule Drug Discovery, Chemical Diversity, 11558 Sorrento Valley Rd., San Diego, CA 92121, USA
Received 1 November 2004; revised 13 December 2004; accepted 15 December 2004
Available online 8 January 2005
Abstract—A series of pyrimidine derivatives are synthesized from N-substituted lactams, and VieheÕs salt. A short reaction sequence,
good yields of the targeted heterocyclic compounds (44–67%), as well as their convenient isolation and purification are the distinct
advantages of the reported protocol.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Synthesis of polysubstituted pyrimidines received sub-
stantial attention due to the pronounced activity as
anti-inflammatory and analgetic agents.1 Several reports
in the literature describe the application of these sub-
strates for the treatment of hypoxemia,2 neuronosis,3
and neuropathy.4 In our medicinal chemistry program,
we required a robust approach to a diverse set of the title
heterocycles. Retrosynthetic analysis of the targeted
molecules suggested that these may be accessed from
the corresponding lactams by treatment with VieheÕs salt
followed by the reaction of the resultant iminium dichlo-
rides with amidines in the presence of base (Scheme 1).
A variety of heterocyclic ring systems have been con-
structed using VieheÕs salt. These include the derivatives
of 4-pyrone,5 2-pyrone,6 pyrimidine,7 1,3-oxadiazin-6-
one,8 thiazole,9 pyrazole,10 various fused heterocycles,11
and nonaromatic species.12 The proposed reaction se-
quence allows for the introduction of four elements of
diversity into the resultant molecules, including: (1) R2
substituent originating from the amidine input; (2)
amino functionality resulting from the nucleophilic aro-
matic substitution of the NMe2 group;13 (3) and (4)
both the size of the fused aliphatic ring, as well as the
R1 substituent resulting from the lactam.
In the initial study, we synthesized a set of pyrimidines
with varying R1, and R2 substituents. Three commer-
cially available N-substituted 2-pyrrolidinones 1a–c
(R1 = Me, cyclohexyl, and Ph) were selected for the
preparation of 2 followed by their reaction with a set
of seven amidinium salts. The results of these experi-
ments are summarized below (Table 1).
Addition of dry DMF to the reaction mixture proved
to be highly beneficial in increasing the yields of the
targeted heterocycles. This may be attributed to the
improved solubility of amidines in the toluene/DMF
(2:1) solvent mixture. Larger ratios of toluene/DMF did
not affect the outcome of the cyclization. Similar
reactions conducted in toluene/dioxane, toluene/THF,
2
NH2 HX
NH2
N
R3
N
R3'
N
N
N
R3
R3'
N
R2
Base
Cl
Cl
N
H
Cl
Cl
Viehe's salt
N
O
3
n
N
R1
n
n
N
R1
n
N
R1
R2
N
R1
R2
1
N
4
Scheme 1.
Keywords: Pyrimidines; Iminium salts; Amidines; Condensations.
*
Tel.: +1 858 794 4860; fax: +1 858 794 4931; e-mail: ask@chemdiv.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.069

1178
A. S. Kiselyov / Tetrahedron Letters 46 (2005) 1177–1179
Table 1. Yields of pyrimidines 3a–n14
NH2 HCl
N
Cl
Cl
toluene, 80oC
R2
NH2
N
N
Cl
Cl
Cl
Hunig's base
toluene/DMF (2:1), 80oC
N
( )n
( )n
O
N
( )n
N
N
R2
N
R1
R1
2
Cl
R1
3a-n
1a-c
Compound, 3
n
R1
R2
Yield, %
48
a
1
Me
b
c
1
1
Me
Ph
62
58
Cl
d
e
1
1
64
56
CF3
O
Ph
Ph
N
f
1
1
64
67
OMe
g
Ph
OCF3
Ph
h
i
2
2
Me
Me
48
55
Cl
j
2
2
Ph
Ph
Ph
51
62
k
O
N
O
l
2
Ph
54
m
n
2
2
Bn
Bn
48
44
N
Bn
or toluene/MeCN systems furnished lower yields of pyrim-
idines (15–35%), along with considerable amount of tar
products. Guanidines reacted with the intermediate
iminium species 2 to afford the corresponding 2-amino-
pyrimidines (Table 1, entry e). A similar reaction
sequence performed with the N-substituted derivatives
of 2-pyrimidinone yielded the corresponding 6,6-fused
pyrimidines 3h–n in good yields (44–62%, Scheme 2).
tube to furnish products of formal nucleophilic aromatic
substitution of the NMe2 group 4a–e in 48–61% yields
(Scheme 2).13
In summary, we have developed a practical proce-
dure for the synthesis of polysubstituted pyrimidines
from N-substituted lactams, and VieheÕs salt.
A
short reaction sequence, good yields of title compounds
(44–67%), as well as their ready isolation, and purifi-
cation are the distinct advantages of the reported
protocol.
Pyrimidines 3b, 3h, and 3j react with piperidine and N-
methylbenzylamine in dry DMF at 140 ꢁC in a sealed

A. S. Kiselyov / Tetrahedron Letters 46 (2005) 1177–1179
1179
Cmpd
3b
R
n
Amine
HN
Yield of 4, %
a, 50
R1
R1'
Me
1
N
H
R1 R1'
N
N
N
10 fold excess
b, 48
3b
Me
1
N
H
Ph
Ph
DMF, sealed tube, 140oC
N
N
( )n
( )n
N
R
c, 54
d, 51
Me
Me
Ph
2
2
2
3h
N
HN
Ph
- HNMe2
Ph
N
4a-e
R
3
3h
3j
N
H
HN
e, 61
Scheme 2.
Quintela, J. M.; Peinador, C. Tetrahedron 1996, 52,
10497–10506; (e) Player, M. R.; Sowell, J. W., Sr. J.
Heterocycl. Chem. 1995, 32, 1537–1540; (f) Quintela, J.
M.; Peinador, C.; Moreira, M. J. Tetrahedron 1995, 51,
5901–5912; (g) Kokel, B. J. Heterocycl. Chem. 1994, 31,
845–855; (h) Kokel, B. J. Heterocycl. Chem. 1994, 31,
1185–1192.
References and notes
1. Dozorova, E. N.; Grizik, S. I.; Persianova, I. V.; Syubaev,
R. D.; Shvarts, G. Y.; Granik, V. G. Khim.-Pharm. Z.
1985, 19, 154.
2. Yasuji, S.; Masaichi, H.; Kataoka, K.; Hoshina, K.;
Yamazaki, N.; Kadota, T.; Yamaguchi, H. Japan Patent
WO 9105784, 1991.
3. Yokoyama, K.; Kato, S.; Kitahara, T.; Imuda, J.; Takei,
M.; Awaya, A.; Nakano, T.; Horigome, K.; Sasaki, T.
Japan Patent JP 01040469, 1989.
4. Awaya, A.; Nakano, T.; Kobayashi, H.; Tan, K.; Hori-
komi, K.; Sasaki, T.; Yokoyama, K.; Ohno, H.; Kato, K.
Japan Patent WO 8704928, 1987.
5. (a) Morris, J.; Wishka, D. G.; Luke, G. P.; Judge, T. M.;
Gammill, R. B. Tetrahedron 1997, 53, 11211–11222; (b)
Morris, J.; Luke, G. P.; Wishka, D. G. J. Org. Chem.
1996, 61, 3218–3220.
6. Bouvy, D.; Janousek, Z.; Viehe, H. G. Bull. Soc. Chim.
Belg. 1993, 102, 129–140.
7. (a) Neidlein, R.; Wang, Z. Synth. Commun. 1997, 27,
1223–1235; (b) Wang, Z.; Neidlein, R. Heterocycles 1998,
48, 1923–1930; (c) Lockhart, C. C.; Sowell, J. W., Sr. J.
Heterocycl. Chem. 1996, 33, 659–661.
8. (a) Decock-Plancquaert, M.-A.; Evariste, F.; Guillot, N.;
Janousek, Z.; Maliverney, C.; Merenyi, R.; Viehe, H. G.
Bull. Soc. Chim. Belg. 1992, 101, 313–321; (b) Neidlein, R.;
Meffert, P.; Sui, Z. Synthesis 1992, 443–446; (c) Neidlein,
R.; Sui, Z. Synthesis 1990, 959–961.
12. (a) Schlama, T.; Gouverneur, V.; Valleix, A.; Greiner, A.;
Toupet, L.; Mioskowski, C. J. Org. Chem. 1997, 62, 4200–
4202; (b) Bouvy, D.; Janousek, Z.; Viehe, H. G. Bull. Soc.
Chim. Belg. 1993, 102, 129–140; (c) Tinant, B.; Declercq,
J.-P.; Bouvy, D.; Janousek, Z.; Viehe, H. G. J. Chem. Soc.,
Perin Trans. 2 1993, 911–915; (d) Vovk, M. V.; Bratenko,
M. K.; Samarai, L. I. Ukr. Khim. Z. 1991, 57, 431–432; (e)
Guillot, N.; Janousek, M. B.; Viehe, H. G. Synth.
Commun. 1989, 19, 2825.
13. Vorbruggen, H. Adv. Heterocycl. Chem. 1990, 49, 117.
14. Experimental procedure: 5.5 mmol of VieheÕs salt
(Aldrich) was added to a vigorously stirred solution of
5 mmol of lactam in dry degassed toluene (70 mL) at room
temperature under Ar. The heterogeneous dark yellow
mixture was slowly warmed up to 80 ꢁC (30 min), and the
resulting mixture was stirred at this temperature for an
additional 1.5 h. The dark-red mixture was quickly filtered
under argon blanket, and a solution of 7 mmol of amidine
hydrochloride in 20 mL of dry DMF followed by 25 mmol
of HunigÕs base were introduced. The resulting mixture
was brought to 80 ꢁC, stirred for 12 h at this temperature,
cooled down to room temperature, diluted with 100 mL of
EtOAc and washed with 3 · 50 mL of saturated NaHCO3.
The organic phase was dried over Na2SO4, concentrated,
and the resulting residue was recrystallized twice from
EtOH to afford the analytically pure pyrimidines in 48–
67% isolated yields. A representative example: 3e: 56%
9. Maliverney, C.; Merenyi, R.; Viehe, H. G. Bull. Soc. Chim.
Belg. 1990, 99, 941–949.
10. (a) Van Vyve, T.; Viehe, H. G. Angew. Chem., Int. Ed.
Engl. 1974, 13, 79; (b) De Voghel, G. J.; Eggerichs, T. L.;
Janousek, Z.; Viehe, H. G. J. Org. Chem. 1974, 39, 1233;
(c) Van Vyve, T.; Viehe, H. G. Angew. Chem. 1974, 86, 45;
(d) Hervens, F.; Viehe, H. G. Angew. Chem., Int. Ed. Engl.
1973, 12, 405.
11. For the synthesis of fused heterocycles using VieheÕs salt,
see: (a) Quintela, J. M.; Moreira, M. J.; Peinador, C.
Tetrahedron 1996, 52, 3037–3048; (b) Quntela, J. M.;
Veiga, M. C.; Peinador, C.; Gonzalez, L. Heterocycles
1997, 1733–1743; (c) Peinador, C.; Quintela, J. M.;
Moreira, M. J. Tetrahedron 1997, 53, 8269–8272; (d)
1
yield, mp 176 ꢁC. H NMR (400 MHz, DMSO-d6): d 2.98
(s, 6H, NMe2), 3.18 (t, J = 8.0 Hz, 2H, CH2), 3.54 (m, 4H,
morpholino), 3.62 (m, 4H, morpholino), 3.86 (t,
J = 8.0 Hz, 2H, CH2), 6.92 (m, 1H, Ph), 7.23 (m, 2H,
Ph), 7.68 (m, 2H, Ph). ESI MS: (M+1) 326, (MÀ1) 324;
HR ESI MS: exact mass calcd for C18H23N5O 325.1903,
found: 325.1907. Elemental analysis, calcd for
C18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C,
66.21; H, 7.32; N, 21.47.