Convenient one-pot synthesis of multisubstituted tetrahydropyrimidines via catalyst-free multicomponent reactions

Article abstract of DOI:10.1021/ol701592h

A novel and convenient one-pot synthesis of multisubstituted pyrimidine analogues via multicomponent reactions is disclosed. This catalyst-free domino reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, a simple experimental workup procedure, and no toxic byproduct. In addition, the obtained products in our experiments are interesting nitrogen heterocyclic molecules containing α- and β-amino acid blocks.

Full text of DOI:10.1021/ol701592h

ORGANIC
LETTERS
2
007
Vol. 9, No. 21
111-4113
Convenient One-Pot Synthesis of
Multisubstituted Tetrahydropyrimidines
via Catalyst-Free Multicomponent
Reactions
4
Min Zhang, Huanfeng Jiang,* Hailing Liu, and Qiuhua Zhu
The College of Chemistry, South China UniVersity of Technology,
Guangzhou 510640, PRC
jianghf@scut.edu.cn
Received May 31, 2007
ABSTRACT
A novel and convenient one-pot synthesis of multisubstituted pyrimidine analogues via multicomponent reactions is disclosed. This catalyst-
free domino reaction proceeded smoothly in good to excellent yields and offered several other advantages including short reaction time, a
simple experimental workup procedure, and no toxic byproduct. In addition, the obtained products in our experiments are interesting nitrogen
heterocyclic molecules containing
r- and â-amino acid blocks.
Pyrimidines and their analogues represent an important class
of nitrogen heterocycles, which is found in both various
biologically active natural compounds and designed medici-
ship (SAR) studies of the tetrahydropyrimidine derivatives
showed that the substituent groups on the rings are all critical
for the activity. However, to our knowledge, rare methods
6
1
nal agents. Specifically, tetrahydropyrimidines containing
were developed to construct multiply substituted tetra-
7
an amino acid unit have attracted much attention due to their
interesting and unique properties such as muscarinic agonist
hydropyrimidine rings. Moreover, some of these protocols
have not been entirely satisfactory because of such drawbacks
as low yields, long reaction time, and cumbersome experi-
mental processes. Recently, one-pot multicomponent reac-
tions (MCRs) have emerged as a powerful tool in synthetic
organic chemistry because of their significant advantages.8
The convergent synthesis of these multisubstituted pyrimidine
analogues from readily available starting materials along this
line has also remained to be developed. In this context, we
explore a novel multicomponent coupling strategy to syn-
thesize multisubstituted tetrahydropyrimidines containing R-
and â-amino acid units. Our approach could comprise the
2
3
activity, protein-nucleic acids interaction, antiviral activ-
4
5
ity, and inflammatory activity. Structure-activity relation-
-11
(1) (a) Looper, R. E.; Runnegar, M. T. C.; Williams, R. M. Angew. Chem.
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2
774. (e) Dunbar, P. G.; Durant, G. J.; Fang, Z.; Abuh, Y. F.; El-Assadi,
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(
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920.
1
0.1021/ol701592h CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/22/2007

relay process of the following three domino sequences
a Mannich-type reaction with benzylamine 2b and formal-
dehyde 3 to give intermediate 6. The presence of formalde-
hyde promotes the amine-aldehyde dehydration-cyclization
process to afford the target compound 4ab. Significantly,
these reactions occurred in a catalyst-free fashion with high
selectivity and atom efficiency. To our knowledge, the use
of three different catalyst-free reactions, namely, hydro-
amination, Mannich-type reaction, and sequent dehydration-
cyclization, has not been reported previously.
(Scheme 1): (1) two-component hydroamination; (2) three-
Scheme 1
Screening of the reaction conditions established the
suitable solvents and the mole ratio of reactants for the
desired MCRs (Table 1). It was exciting that the chosen
Table 1. Optimization of Reaction Conditions for the
Multicomponent Reactionsa
component Mannich-type reaction; (3) two-component amine-
aldehyde dehydration-cyclization process.
But-2-ynedioic acid diethyl ester 1 reacts with aniline 2a,
formaldehyde 3, and benzylamine 2b to afford diethyl
1
:2a:3:2b
entry
solvent
[mole ratio]
t (h)
yield (%)b
1
2
3
4
5
6
7
8
9
dioxane
DMF
MeCN
toluene
DMSO
Et3N
none
DMF
DMF
DMF
1:1:6:2
1:1:6:2
1:1:6:2
1:1:6:2
1:1:6:2
1:1:6:2
1:1:6:2
1:1:6:1.2
1:1:6:1
1:1:6:1.1
1:1:3:1.1
1:1:4:1.1
5
1
3
3
3
3
3
1
1
1
1
1
72
92
86
83
85
1
-benzyl-3-phenyl-1,2,3,6-tetrahydropyrimidine-4,5-dicar-
boxylate 4ab, one of the tetrasubstituted tetrahydropyrim-
idines with R- and â-amino acid building blocks, in excellent
yield (Scheme 1, 92%).12 The hydroamination of but-2-
ynedioic acid diethyl ester 1 with aniline 2a could rapidly
63
13
complex
93
form the active intermediate 5, which would then undergo
84
92
78
92
(7) For some examples on the synthesis of substituted tetrahydro-
1
1
0
1
pyrimidines, see: (a) Kang, S. H.; Kang, S. Y.; Lee, H. S.; Buglass, A. J.
Chem. ReV. 2005, 105, 4537. (b) Adamo, M. F. A.; Baldwin, J. E.;
Adlington, R. M. J. Org. Chem. 2005, 70, 3307. (c) Prasad, B. A. B.; Bisai,
A.; Singh, V. K. Org. Lett. 2004, 6, 4829. (d) Clark, J. D.; Collin, J. T.;
Kleine, H. P.; Weisenburger, G. A.; Anderson, D. K. Org. Process Res.
DeV. 2004, 8, 571. (e) Adib, M.; Yavari, H.; Mollahosseini, M. Tetrahedron
Lett. 2004, 45, 1803. (f) Christian, D.; Jacqueline, C. S. W.; Mackay, D.
B.; Roch, M. A. L. Tetrahedron Lett. 2004, 45, 7197. (g) When, P. M.;
Bois, J. D. J. Am. Chem. Soc. 2002, 124, 12950. (h) Folkers, K.; Johnson,
T. B. J. Am. Chem. Soc. 2002, 124, 3784. (i) Cho, H.; Shima, K.;
Hayashimatsu, M.; Ohnaka, Y.; Mizuno, A.; Takeuchi, Y. J. Org. Chem.
DMF
DMF
12
a
All reactions were carried out in DMF (2 mL) at 100 °C using the
substrates according to the indicated ratio in the mmol scale. Isolated
yields.
b
solvents, such as dioxane, N,N-dimethylformamide (DMF),
acetonitrile (MeCN), toluene, dimethyl sulfoxide (DMSO),
3
N), were suitable for the MCRs (Table
, entries 1-6). DMF proved to be the best one among them
1
1
985, 50, 4227. (j) Zamri, A.; Sirockin, F.; Abdallah, M. A. Tetrahedron
999, 55, 5157. (k) Ohta, S.; Hinata, Y.; Yamashita, M.; Kawasaki, I.; Jinda,
and triethylamine (Et
Y.; Horie, S. Chem. Pharm. Bull. 1994, 42, 1730. (l) Carboni, B.; Toupet,
L.; Carrie, et R. Tetrahedron 1987, 43, 2293.
1
(
8) For recent examples on multicomponent reactions, see: (a) Ohno,
H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46, 2295.
b) Bonne, D.; Dekhane, M.; Zhu, J. P. Angew. Chem., Int. Ed. 2007, 46,
2
4
(Table 1, entry 2). Under solvent-free conditions, a complex
result was obtained (Table 1, entry 7). To modulate the ratio
of reactants and improve the yield, we examined various
ratios of but-2-ynedioic acid diethyl ester 1, aniline 2a,
formaldehyde 3, and benzylamine 2b by using DMF as the
solvent (Table 1, entries 8-12). The best result was obtained
when but-2-ynedioic acid diethyl ester 1/aniline 2a/formal-
dehyde 3/benzylamine 2b ) 1:1:4:1.1-1.2.
(
485. (c) Pinto, A.; Neuville, L.; Zhu, J. P. Angew. Chem., Int. Ed. 2007,
6, 3291 and references therein. (d) Komagawa, S.; Saito, S. Angew. Chem.,
Int. Ed. 2006, 45, 2446. (e) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai,
A. J. Am. Chem. Soc. 2006, 128, 11040. (f) Dondas, H. A.; Fishwick, C.
W. G.; Gai, X.; Grigg, R.; Kilner, C.; Dumrongchai, N.; Kongkathip, B.;
Kongkathip, N.; Polysuk, C.; Sridharan, V. Angew. Chem., Int. Ed. 2005,
4
4, 7570. (g) Pache, S.; Lautens, M. Org. Lett. 2003, 5, 4827.
9) For recent examples on domino reactions, see: (a) Miyamoto, H.;
Okawa, Y.; Nakazaki, A.; Kobayashi, S. Angew. Chem., Int. Ed. 2006, 45,
274. (b) Tietze, L. F.; Sommer, K. M.; Zinngrebe, J.; Stecker, F. Angew.
(
2
(12) For our early work on alkyne chemistry, see: (a) Huang, J.; Zhou,
L.; Jiang, H. Angew. Chem., Int. Ed. 2006, 45, 1945. (b) Jiang, H.; Tang,
J.; Wang, A.; Deng, G.; Yang, S. Synthesis 2006, 1155. (c) Wang, Y.; Jiang,
H.; Liu, H.; Liu, P. Tetrahedron Lett. 2005, 46, 3935. (d) Li, J.; Jiang, H.;
Chen, M. J. Org. Chem. 2001, 66, 3627. (e) Li, J.; Jiang, H. Chem. Commun.
1999, 2369. (f) Li, J.; Jiang, H.; Feng, A.; Jia, L. J. Org. Chem. 1999, 64,
5984.
Chem., Int. Ed. 2005, 44, 257. (c) Yamamoto, Y.; Hayashi, H.; Saigoku,
T.; Nishiyama, H. J. Am. Chem. Soc. 2005, 127, 10804. (d) Tietze, L. F.;
Ila, H.; Bell, H. P. Chem. ReV. 2004, 104, 3453.
(10) For a recent example on one-pot synthesis, see: Siamaki, A. R.;
Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128, 6050.
11) For recent books, see: (a) Multicomponent Reactions; Zhu, J.,
(
Bienaym e´ , H., Eds.; Wiley-VCH: Weinheim, 2005. (b) Domino Reactions
in Organic Synthesis; Tietze, L.F., Brasche, G., Gericke, K., Eds.; Wiley-
VCH: Weinheim, 2006.
(13) Intermediate 5 could be isolated as a pure compound and then react
with benzylamine and formaldehyde to form the same product 4ab. See
Supporting Information for the detailed characterization data of 5.
4112
Org. Lett., Vol. 9, No. 21, 2007

With the optimized conditions in hand, we examined the
scope of the multicomponent reactions (Table 2). We were
first resulting in product 4ab in 93% yield (Table 2, entry
6). On the contrary, 1-phenyl-3-benzyl-1,2,3,6-tetrahydro-
pyrimidine-4,5-dicarboxylic acid diethyl ester 4ba was
obtained in 86% yield when benzylamine 2b was added first
(
Table 2, entry 7). The structures of 4ab and 4ba were
Table 2. One-Pot Synthesis of Tetrasubstituted
Tetrahydropyrimidines via the MCRsa
distinguished via the HMBC spectra (Scheme 2). Obviously
Scheme 2
the correlation between the 1′-carbon in the benzene ring
and hydrogen of CH in the tetrahydropyrimidine ring is quite
2
different in 4ab and 4ba. The HMBC spectrum of 4ab
showed the correlation from C-1′ to H-2, while the correla-
tions from C-1′ to H-2 and H-6 are clearly observed in 4ba.
Similarly, other different amines were also successfully
employed to produce the 1,3-position differently substituted
cyclic products according to the addition order (Table 2,
entries 8-12). All the substituted aryl, alkyl, and benzyl
amines perform well, and the corresponding products were
obtained in good to excellent yields, although the steric
hindrance associated with the methyl group on the ortho-
position of the benzene ring resulted in a lower yield (Table
2
).
In conclusion, we have described a novel and convenient
one-pot synthesis of multisubstituted pyrimidine analogues
via multicomponent reactions. This catalyst-free domino
reaction proceeded smoothly in good to excellent yields and
offered several other advantages including short reaction
time, simple experimental workup procedure, and no toxic
byproduct. In addition, the obtained products in our experi-
ments are interesting nitrogen heterocyclic molecules con-
taining R- and â-amino acid blocks. Further studies and
applications on this domino reaction are ongoing in our
laboratory and will be published in due course.
a
All the reactions were carried out with 1 (1 mmol), amine 2 (2.1 mmol),
formaldehyde (4 mmol), and DMF (2 mL) at 100 °C for the desired time.
Isolated yields.
b
pleased to find that the reaction proceeded smoothly, and
the desired products were afforded in excellent yields.
Interestingly, although the reaction time of aliphatic primary
amines (Table 2, entries 2 and 3) was shorter than that of
aromatic primary amines (Table 2, entries 1, 4, and 5),
aliphatic primary amines gave higher yields. The results
indicated that the activity of aliphatic amines is higher.
Notably, the electronic effects of the substituents on the
aromatic ring, either the electron-donating methyl (Table 2,
entry 4) or electron-withdrawing fluorine group (Table 2,
entry 5), have no significant influence on the reaction.
Meaningfully, the substituted groups at the 1- or 3-position
on the tetrahydropyrimidine ring could be selectively induced
by changing the addition order of the two different amines
under the same employed conditions. Aniline 2a was dripped
Acknowledgment. We thank the National Natural Foun-
dation of China (NSFC Nos. 20332020, 20572027, and
2
0625205) for financial support.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for the reaction
products included in this paper. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL701592H
Org. Lett., Vol. 9, No. 21, 2007
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