Direct access to pyrimidines through organocatalytic inverse-electron-demand Diels-Alder reaction of ketones with 1,3,5-triazine

Article abstract of DOI:10.1039/c5ra16995j

An organocatalytic inverse-electron-demand Diels-Alder reaction of ketones with 1,3,5-triazine through enamine catalysis has been developed. This method could furnish 4,5-disubstituted pyrimidines in good yields and high levels of regioselectivities.

Full text of DOI:10.1039/c5ra16995j

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Direct access to pyrimidines through
organocatalytic inverse-electron-demand Diels–
Alder reaction of ketones with 1,3,5-triazine†
Cite this: RSC Adv., 2015, 5, 76759
a
a
a
a
ab
Received 22nd August 2015
Accepted 4th September 2015
*
*
Gongming Yang, Qianfa Jia, Lei Chen, Zhiyun Du and Jian Wang
DOI: 10.1039/c5ra16995j
www.rsc.org/advances
An organocatalytic inverse-electron-demand Diels–Alder reaction of highly selective method for the synthesis of 4,5-disubstituted
ketones with 1,3,5-triazine through enamine catalysis has been pyrimidine skeleton has rarely been investigated. One of the
developed. This method could furnish 4,5-disubstituted pyrimidines in most efficient strategies for making such a structure is mainly
good yields and high levels of regioselectivities.
focused on the basis of N–C–N condensations. For examples,
condensation of an amidine with a 1,3-diketone or derivative is
one of major methods for the direct preparation of the six-
membered-ring pyrimidine (Scheme 1a).8 Notably, easily prep-
aration of the prerequisite diketones or dicarbonyl derivatives
makes this a more attractive strategy for synthesis of substituted
pyrimidines. Condensation of an amidine with a nitrile deriv-
ative, a common N–C source, is another versatile approach.
Despite these advances, due to the signicance of pyrimidines
in drug discovery, preparations of diversely substituted pyrim-
idines are still in high demand.9 Therefore, developing new
efficient method for the constructuion of various substituted
pyrimidines would be of high interest.
Pyrimidines are ubiquitous heterocyclic moieties present in
natural products, drugs and functional materials.1 A number of
pyrimidines exhibit biologically important activities.2 As shown
in Fig. 1, sulfadiazine is a sulfonamide antibiotic that contains a
5-aminopyrimidine.3 Trimethoprim is a bacteriostatic antibiotic
known as dihydrofolate reductase inhibitor, mainly used in the
prevention and treatment of urinary tract infections.4 Bosentan
is a drug for treating cardiovascular pathology.5
Although a number of approaches for the preparation of
pyrimidine frameworks have been developed,6,7 a general and
In 1975, Neunhoeffer and Bachmann demonstrated that
1,3,5-triazine could undergo a rapidly regiospecic cycloaddi-
tion reaction with ynamines, followed with a subsequent loss of
hydrogen cyanide, to efficiently form pyrimidines.10 In 1982, the
Boger group reported a regiospecic pyrimidine synthesis via a
thermal cycloaddition of 1,3,5-triazine with enamines.11
Fig. 1 Examples of important pyrimidines.
aAllan H. Conney Laboratory for Anticancer Research, Guangdong University of
Technology, Guang Dong, 510006, China
bDepartment of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543. E-mail: wangjian1999@hotmail.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra16995j
Scheme 1 Strategies in preparation of pyrimidines.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 76759–76763 | 76759

View Article Online
RSC Advances
Communication
Surprisingly, to the best of our knowledge, such a catalytic parameters revealed that solvent was another crucial factor.
example of 1,3,5-triazine reacted with in situ generated When reaction carried out in DMSO, reactivity was positively
enamines to assemble pyrimidines has not yet been reported. inuenced, leading to the desired product 3a in 81% yield.
As a part of our continuing interests in this area,12 especially in Other solvents, such as toluene, MeCN, CHCl3, THF, MeOH,
expanding enamine chemistry13 to generate heterocycles, DMA, and DMF, caused a signicant decrease in chemical
herein, we report our new progress regarding an enamine- yields (Table 1, 18–65%, entries 10–16). Lowering the reaction
catalyzed inverse-electron-demand14 Diels–Alder of ketones temperature to 60 ꢀC resulted in a poor chemical yield (entry 17,
with 1,3,5-triazine, which provided an efficient and comple- 41%, 32 h). Changing the catalyst loading of I from 20 mol% to
mentary route for pyrimidine synthesis (Scheme 1b).
10 mol% caused a decrease in chemical yield (Table 1, entry 18,
Initial experiments were conducted by using cyclohexanone 71%). Notably, addition of 10 mol% TEA further promoted the
1a and 1,3,5-triazine 2 in the presence of 10 mol% loading of reaction (entry 19, 91%). Finally, the best combination was
amine catalysts, such as secondary amines (I–VII) and tertiary achieved when the reaction was performed in the presence of
amines (VIII and IX). Among the catalysts tested (Table 1), we 10 mol% of prolinamide I as catalyst and 10 mol% of TEA as
found that secondary amines are generally more effective than additive.
tertiary amines (Table 1, 9). Tertiary amines exhibited low
With the optimized reaction conditions in hand, we then
catalytic activities (entries 8 and 9, <5% and 18%, respectively). investigated a variety of ketones 1 with 2. The results are
Pleasingly, secondary amine prolinamide I showed higher summarized in Table 2. Interestingly, among the various
reactivity than other catalysts (entry 1, 81%). Surprisingly, the examined ketones, cyclic ketones (e.g. ve-, six-, seven-, eight-
similar derivative proline VI only provided a moderate chemical and twelve-membered rings), all gave high to excellent yields
yield (entry 6, 28%). Finally, prolinamide I was identied as the under standard conditions (Table 2, 3a–3p, 80–95%). The best
most effective catalyst. Further optimization of other reaction yield was obtained with cyclooctanone, which afforded the
corresponding pyrimidine 3d in 95% isolated yield (Table 2, 3d).
It is worth noting that phenyl ring fused cyclohexanone 1o also
worked with 1,3,5-triazine 2 and afforded the corresponding
Table 1 Optimization of the reaction conditionsa
product 3o in 83%. To further indicate the generality and
Table 2 Scope of cyclic ketonesa
Entry
Cat.
Solvent
Yieldb/%
Entry
1
2
3
4
5
6
7
8
I
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
81
54
36
61
32
28
24
<5
18
65
53
41
35
62
42
43
41
71
91
63
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17c
18d
19e
20f
II
III
IV
V
VI
VII
VIII
IX
I
I
I
I
I
I
I
I
I
I
I
9
10
11
12
13
14
15
16
17c
18d
19e
20f
DMA
Toluene
MeOH
THF
CH3CN
CHCl3
DMSO
DMSO
DMSO
DMSO
a
Reaction conditions: a mixture of 1a (0.20 mmol), 2 (0.10 mmol) and
catalyst (20 mol%) in the solvent (0.25 mL) was stirred at 90 ꢀC for
b
c
24 h. Isolated yield. The reaction was conducted at 60 ꢀC for 32 h.
d
e
10 mol% catalyst I used. 10 mol% catalyst I and 10 mol% Et3N as
additive. f 10 mol% catalyst I and 10 mol% AcOH as additive.
a
Conditions see Table 1.
76760 | RSC Adv., 2015, 5, 76759–76763
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
potential of our approach, we turned our attention to examine
other types of ketones (e.g. acyclic ketones). Acetophenone 4a
was employed to react with triazine 2 in the presence of catalyst
prolinamide I. However, only 54% yield was achieved aer 72 h.
In order to improve reaction efficiency, a further reaction opti-
mization was conducted (see ESI†). Finally, amine V was found
to be the most efficient catalyst for this type of ketones (Table 2,
87%, 72 h). As indicated in Table 2, aryl methyl ketones 4b–i
gave good to excellent yields (5b–i, 84–92%). Pleasingly, heter-
oaryl methyl ketones 4j–l also afforded the corresponding
pyrimidine products in high yields (5j–l). Propiophenones and
butanophenone were also well tolerated (5n–p). Other alkyl
ketones (e.g. symmetric and dissymmetric alkyl ketones) were
also investigated and the desired products was obtained in
moderate chemical yields (5q and 5r, 56% and 62%, respec-
tively). Notably, all above reactions provided excellent levels of
regioselectivity. This phenomenon can be explained by the
Diels–Alder reaction occurring with most stabilized enamine
(Table 3).
Scheme 2 Proposed mechanism.
Our postulated reaction pathway is summarized in Scheme
2. While the reaction mechanism is unclear at this stage, it is
still believed that the sequence is triggered by the generation of
iminium 6 via the condensation of 4a and catalyst V. Iminium 6
rapidly converts to intermediate enamine 7 via a tautomeriza-
tion. Enamine 7 continuously reacts with 1,3,5-triazine 2 via an
inverse-electron-demand Diels–Alder reaction to access the
intermediate 8. Notably, this cycloaddition process demon-
strates a high regioselectivity, which leading to directly intro-
duce a diverse set of substituents to pyrimidine scaffold.
Intermediate 8 then transfers to intermediate 9 aer an elimi-
nation of HCN. Last, a liberation of catalyst V leads to the
formation of nal product 5a.
Table 3 Scope of acyclic ketonesa
In summary, an organocatalytic inverse-electron-demand
Diels–Alder reaction between various ketones and 1,3,5-
triazine has been developed. The reaction is catalyzed by second
amines to generate 4,5-disubstituted- or 5-monosubstituted
pyrimidines with high levels of regioselectivity. It is noteworthy
that this Diels–Alder reaction proceeds efficiently with a simple
and inexpensive amine catalyst. Considering the large variety
and ready availability of the starting materials and the opera-
tional simplicity, a convenient, practical and highly modular
pyrimidine synthesis has been developed. We believe that this
work will arouse more research interest in organocatalytic
synthesis of other biologically active heterocycles. Such studies
are actively under way in this laboratory, and more results will
be reported in due course.
Acknowledgements
The authors acknowledge the nancial support from National
Natural Science Foundation of China (NSFC 21272043), the
Science and Technology Planning Project of Guangdong Prov-
ince (2007A020300007-10, 2011B090400573) and Guangdong
Natural Science Foundation (S2011010004967).
Notes and references
1 For selected examples, see: (a) D. J. Brown, in Comprehensive
Heterocyclic Chemistry, ed., A. R. Katritzky, C. W. Rees and E.
F. V. Scrieven, Pergamon, Oxford, 1984, vol. 3, ch 2.13, pp.
142–155; (b) P. Callery and P. Gannett, in Foye's Principles
a
Reaction conditions: a mixture of 4 (0.20 mmol), 2 (0.10 mmol) and
catalyst V (20 mol%), TEA (10 mol%) in MeOH (0.50 mL) was stirred
at 90 ꢀC for 72 h.
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 76759–76763 | 76761

View Article Online
RSC Advances
Communication
of Medicinal Chemistry, ed. D. A. Williams and T. L. Lemke,
Lippincott Williams and Wilkins, Philadelphia, 2002, pp.
934–935; (c) K. S. Jain, T. S. Chitre, P. B. Miniyar,
M. K. Kathiravan, V. S. Bendre, V. S. Veer, S. R. Shahane
and C. J. Shishoo, Curr. Sci., 2006, 90, 793; (d) S. von
Angerer, Science of Synthesis, ed. Y. Yamamoto, Thieme,
Stuttgart, 2003, vol. 16, pp. 379À572; (e) A. S. Karpov and
A. Deagostino, C. Prandi, C. Zavattaro and P. Venturello,
Chem. Commun., 2008, 1689; (e) H. Kakiya, K. Yagi,
H. Shinokubo and K. Oshima, J. Am. Chem. Soc., 2002, 124,
9032; (f) M. M. Heravi, S. Sadjadi, H. A. Oskooie,
R. H. Shoar and F. F. Bamoharram, Tetrahedron Lett., 2009,
50, 662; (g) M. D. Hill and M. Movassaghi, Synthesis, 2008,
823; (h) F. Xie, S. Li, D. Bai, L. Lou and Y. Hu, J. Comb.
Chem., 2007, 9, 12; (i) J. M. Kremsner, A. Stadler and
C. O. Kappe, J. Comb. Chem., 2007, 9, 285; (j) A. S. Kiselyov,
Tetrahedron Lett., 2005, 46, 1663; (k) A. S. Karpov and
T. J. J. Mueller, Org. Lett., 2003, 5, 3451; (l) T. J. J. Mueller,
R. Braun and M. Ansorge, Org. Lett., 2000, 2, 1967.
8 For reviews, see: (a) K. Undheim and T. Benneche, in
Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky,
C. W. Rees, E. F. V. Scriven and A. McKillop, Pergamon,
Oxford (UK), 1996, vol. 6, pp. 93–231; (b) I. M. Lagoja,
Chem. Biodiversity, 2005, 2, 1; (c) J. P. Michael, Nat. Prod.
Rep., 2005, 22, 627; (d) J. A. Joule and K. Mills, in
Heterocyclic Chemistry, Blackwell Science, Cambridge (MA),
4th edn, 2000, pp. 194–232; (e) A. W. Erian, Chem. Rev.,
1993, 93, 1991; (f) M. D. Hill and M. Movassaghi, Chem.–
Eur. J., 2008, 14, 6836.
9 For selected papers on the functional group transformation
to 4,5-disubstituted pyrimidines, see: (a) H. Sard,
M. D. Gonzalez, A. Mahadevan and J. McKew, J. Org.
Chem., 2000, 65, 9261; (b) N. Boudet, S. R. Dubbaka and
P. Knochel, Org. Lett., 2008, 10, 1715; (c) M. Schlosser,
O. Lefebvre and L. Ondi, Eur. J. Org. Chem., 2006, 1593; (d)
H. Togo, S. Ishigami, M. Fujii, T. Ikuma and M. Yokoyama,
J. Chem. Soc., Perkin Trans. 1, 1994, 2931; (e) R. J. Mattson
and C. P. Sloan, J. Org. Chem., 1990, 55, 3410; (f)
H. Yamanaka, T. Sakamoto, S. Nishimura and M. Sagi,
Chem. Pharm. Bull., 1987, 35, 3119; (g) T. J. Kress, J. Org.
Chem., 1985, 50, 3073; (h) T. J. Kress, J. Org. Chem., 1979,
44, 2081.
¨
T. J. J. Muller, Synthesis, 2003, 2815; (f) K. S. Atwal,
S. V. O'Neil, S. Ahmad, L. Doweyko, M. Kirby, C. R. Dorso,
G. Chandrasena, B.-C. Chen, R. Zhao and R. Zahler, Bioorg.
Med. Chem. Lett., 2006, 16, 4796; (g) M. Alvarado,
M. Barcelo, L. Carro, C. F. Masaguer and E. Ravina, Chem.
Biodiversity, 2006, 3, 106; (h) E. T. Buurman, A. E. Blodgett,
K. G. Hull and D. Carcanague, Antimicrob. Agents
Chemother., 2004, 48, 313.
2 For selected examples, see: (a) M. S. Puar, A. K. Ganguly,
A. Afonso, R. Brambilla, P. Mangiaracina, O. Sarre and
R. D. MacFarlane, J. Am. Chem. Soc., 1981, 103, 5231; (b)
S. Ananthan, H. S. Kezzar III, R. L. Carter, S. K. Saini,
K. C. Rice, J. L. Wells, P. Davis, H. Xu, C. M. Dersch,
E. J. Bilsky, F. Porreca and R. B. Rothman, J. Med. Chem.,
1999, 42, 3527; (c) N. Oku, S. Matsunaga and N. Fusetani,
J. Am. Chem. Soc., 2003, 125, 2044; (d) S. A. Raw,
C. D. Wilfred and R. J. K. Taylor, Chem. Commun., 2003,
2286; (e) J. C. McManus, J. S. Carey and R. J. K. Taylor,
Synlett, 2003, 365; (f) J. C. McManus, T. Genski, J. S. Carey
and R. J. K. Taylor, Synlett, 2003, 369; (g) M. Botta,
F. Corelli, G. Maga, F. Manetti, M. Renzulli and S. Spadari,
Tetrahedron, 2001, 57, 8357; (h) R. Garg, S. P. Gupta,
H. Gao, M. S. Babu, A. K. Debnath and C. Hansch, Chem.
Rev., 1999, 99, 3525; (i) M. Botta, F. Occhionero,
R. Nicoletti, P. Mastromarino, C. Conti, M. Magrini and
R. Saladino, Bioorg. Med. Chem., 1999, 7, 1925; (j) D. Hurst,
in An Introduction to Chemistry
&
Biochemistry of
Pyrimidines, Purines & Pteridines, Wiley, Chichester, 1988;
(k) D. J. Brown, in The Pyrimidines, Interscience Publishers, 10 H. Neunhoeffer and M. Bachmann, Chem. Ber., 1975, 108,
New York, 1994. 3877.
3 M. Finland, E. Strauss and O. L. Peterson, JAMA, J. Am. Med. 11 D. L. Boger, J. Schumacher, M. D. Mullican, M. Patel and
Assoc., 1984, 251, 1467. J. S. Panek, J. Org. Chem., 1982, 47, 2673.
4 S. Hess, M. Dolker, D. Haferburg, H. P. Kertscher, 12 (a) W. J. Li, Q. F. Jia, Z. Y. Du and J. Wang, Chem. Commun.,
F.-M. Matysik, J. Ortwein, U. Teubert, W. Zimmermann
and K. Eger, Pharmazie, 2001, 56, 306.
5 W. Neidhart, V. Breu, K. Burri, M. Clozel, G. Hirth,
U. Klinkhammer, T. Giller and H. Ramuz, Bioorg. Med.
Chem. Lett., 1997, 7, 2223.
6 For selected reviews on the preparation of pyrimidine
derivatives, see: (a) M. D. Hill and M. Movassaghi, Chem.–
Eur. J., 2008, 14, 6836; (b) D. M. D'Souza and T. J. J. Mueller,
2013, 49, 10187; (b) D. K. J. Yeung, T. Gao, J. Y. Huang,
S. F. Sun, H. B. Guo and J. Wang, Green Chem., 2013, 15,
2384; (c) L. Wang, J. Y. Huang, X. J. Gong and J. Wang,
Chem.–Eur. J., 2013, 19, 7555; (d) W. Li and J. Wang,
Angew. Chem., Int. Ed., 2014, 53, 14186; (e) L. J. T. Danence,
Y. Gao, M. Li, Y. Huang and J. Wang, Chem.–Eur. J., 2011,
17, 3584; (f) L. Wang, S. Y. Peng, L. J. T. Danence, Y. Gao
and J. Wang, Chem.–Eur. J., 2012, 18, 6088.
Chem. Soc. Rev., 2007, 36, 1095; (c) I. M. Lagoja, Chem. 13 For reviews and books: see: (a) P. I. Dalko and L. Moisan,
Biodiversity, 2005, 2, 1; (d) S. von Angerer, Sci. Synth., 2004,
16, 379.
Angew. Chem., Int. Ed., 2001, 40, 3726; (b) M. Benaglia,
A. Puglisi and F. Cozzi, Chem. Rev., 2003, 103, 3401; (c)
A. Berkessel and H. GrMger, Metal-Free Organic Catalysts in
Asymmetric Synthesis, Wiley-VCH, Weinheim, 2004; (d)
K. N. Houk and B. List, Special Issue: Asymmetric
Organocatalysis, Acc. Chem. Res., 2004, 37, 487; (e)
P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43,
5138; (f) J. T. Mohr, M. R. Krout and B. M. Stoltz, Nature,
7 For selected recent examples on the preparation of
pyrimidine derivatives, see: (a) M. Movassaghi and
M. D. Hill, J. Am. Chem. Soc., 2006, 128, 14254; (b)
A. S. Karpov, E. Merkul, F. Rominger and T. J. J. Mueller,
Angew. Chem., Int. Ed., 2005, 44, 6951; (c) M. Matloobi and
C. O. Kappe, J. Comb. Chem., 2007, 9, 275; (d) M. Blangetti,
76762 | RSC Adv., 2015, 5, 76759–76763
This journal is © The Royal Society of Chemistry 2015

View Article Online
Communication
RSC Advances
2008, 455, 323; (g) D. W. C. MacMillan, Nature, 2008, 455,
304; (h) A. Berkessel and H. Groger, Asymmetric
Organocatalysis, Wiley, Weinheim, 2005; (i) P. I. Dalko,
Enantioselective Organocatalysis, Wiley, Weinheim, 2007; (j)
M. T. Reetz, B. List, S. Jaroch and H. Weinmann,
Organocatalysis, Springer, 2007; (k) B. List, Asymmetric
Organocatalysis, Springer, 2009; (l) B. List, Acc. Chem. Res.,
2004, 37, 548.
D. L. Boger, Chem. Rev., 1986, 86, 781; (c) L. Lee and
J. K. Snyder, Adv. Cycloaddit., 1999, 3, 119; (d)
K. A. Jorgensen, Angew. Chem., Int. Ed., 2000, 39, 3558; (e)
M. Behforouz and M. Ahmadian, Tetrahedron, 2000, 56,
5259; (f) P. Buonora, J. C. Olsen and T. Oh, Tetrahedron,
2001, 57, 6099; (g) H. Pellissier, Tetrahedron, 2009, 65,
2839; (h) J.-L. Li, T.-Y. Liu and Y.-C. Chen, Acc. Chem. Res.,
2012, 45, 1491.
14 For selected reviews of inverse-electron-demand Diels–Alder
reaction, see: (a) D. L. Boger, Tetrahedron, 1983, 39, 2869; (b)
This journal is © The Royal Society of Chemistry 2015
RSC Adv., 2015, 5, 76759–76763 | 76763