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Chinese Science Bulletin 2004 Vol. 49 No. 2 127ü130
Cyclotrimerization of nitriles
catalyzed by Li3N
affording 2,4,6-substituted s-triazines or amino-pyrimidi
nes in high yields. To the best of our knowledge, it is the
first time that lithium nitride has been found to be a highly
active catalyst for the cyclotrimerization of nitriles.
DENG Zhaoxiang, QIU Wenfeng, LI Weijia
& LI Yadong
Department of Chemistry and Key Laboratory of Atomic & Molecular
Nanosciences (Ministry of Education, China) Tsinghua University, Beijing 100084, China
Correspondence should be addressed to Li Yadong (e-mail: ydli@
tsinghua.edu.cn)
Abstract Nitriles were unexpectedly trimerized into
s-triazines or amino-pyrimidines in high yields in the presence of catalytic amount of Li3N, resulting in a simple, solvent-free and easy-to-scale-up one-pot way to synthesize
s-triazines and 4-amino-pyrimidines with high yield.
Keyworks: Li3N, nitrile, cyclotrimerization, catalyze, triazine and
pyrimidine.
DOI: 10.1360/03wb0128
Cyclotrimerization of nitriles into s-triazines or
amino-pyrimidines is important in many applications. For
example, s-triazines or amino-pyrimidines are core parts
of many biologically and therapeutically significant
ü
molecules[1 4]. In addition, s-triazines and amino-pyrimidines can also act as important herbicides and insecticides[5,6]. Recently, compounds containing a s-triazine unit
have gathered much attention due to their liquid- crystalü
line and nonlinear optical properties[7 11].
s-Triazines can be synthesized via different routes,
among which the direct trimerization of nitriles is simple
and efficient. Cairns et al. found that extremely high pressure ((50008000) × 105 Pa) could be beneficial for the
cyclotrimerization of nitriles into s-triazines or pyrimidines in the presence of alcohols and amines[12,13]. It was
also found that alcohols and amines were not needed if the
pressure was increased to the range of tens of thousands of
bars[14,15]. Forsberg et al. during their research on the reactions between amines and nitriles, found that amidines
could readily trimerize with nitriles into s-triazines[16],
thus rare earth compounds have been found to be efficient
for the cyclotrimerization of nitriles with amines as
ü
co-catalyst[17 19]. Other research has also revealed that a
combined catalytic system such as PCl5/HCl or AlCl3/HCl
also exhibited enhanced catalytic activities in trimerizing
nitiriles into s-triazines[20,21].
During our attempts to synthesize inorganic nitride
solids with lithium nitride as nitriding reagent and acetonitrile as solvent, the solvent was unexpectedly solidified after heating. Further research revealed that lithium
nitride, a common laboratory chemical, could serve as a
very efficient catalyst for the cyclotrimerization of nitriles,
In this paper, as shown in Fig. 1, we chose acetonitrile (1), butyronitrile (3) and benzonitrile (5) as three initial examples to demonstrate the catalytic action of lithium
nitride on the self-cyclotrimerization of nitriles.
Co-trimerizations between different nitriles were also investigated by the reaction between acetonitrile and benzonitrile.
Typical procedure for the reactions: In a typical synthesis, 20 mL of nitriles was put into a Teflon-lined autoclave with 30 mL capacity. lithium nitride (0.01 equiv)
was then mixed with the reactant and then the autoclave
was sealed and heated at 180 for 324 h. Sublimation
followed by recrystallization in chloroform gives pure
products.
Synthesis of 2, 4, 6: In a typical synthesis, after the
reaction, sublimation followed by recrystallization in
chloroform gives pure products of 4-amino-2,6-bimethyl-pyrimidine (2, 91% isolated yield), 1H NMR
(CDCl3, 300 MHz) δ 6.13 (s, 1 H), 4.77 (br s, 2 H), 2.49 (s,
3 H), 2.33 ppm (s, 3 H), 1H NMR (D2O, 200 MHz) δ 6.21
(s, 1 H), 2.25 (s, 3 H), 2.14 ppm (s, 3 H), ESI-MS m/z
(M++H): 124; 4-amino-2,6-bipropyl-5-ethylpyrimidine (4,
85% isolated yield), 1H NMR (CDCl3, 300 MHz) δ 4.78
(br s, 2 H), 2.65 (t, J = 7.8 Hz, 2 H), 2.62 (t, J = 7.8 Hz, 2
H), 2.46 (q, J = 7.7 Hz, 2 H), 1.651.80 (m, 4 H), 1.16 (t,
Chinese Science Bulletin Vol. 49 No. 2 January 2004
127
Fig. 1. Synthetic route and reagents.
1
Experiment
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J = 7.7 Hz, 3 H), 1.00 (t, J = 7.2 Hz, 3 H), 0.98 ppm (t, J =
7.2 Hz, 3 H); and 2,4,6-triphenyl-s-triazine (6, 83% isolated yield), 1H NMR (CDCl3, 300 MHz) δ 8.788.80 (d,
J = 7.8 Hz, 6 H), 7.61 (s, 6 H), 7.59 ppm (s, 3 H). ESI-MS
m/z (M++H): 310.
Synthesis of 7: A mixture of the acetonitrile (1.5
equiv), benzonitrile (1 equiv) and Li3N (0.01 equiv) was
sealed into the autoclave and heated at 180 for 1224
h, affording a viscous brown product insoluble in water.
Purification was conducted by adding a large amount of
water as precipitant into the alcohol (99%) solution of the
initial product followed by recrystallization of the precipitate in chloroform, affording white powdery product of
4-amino-2,6-biphenyl-pyrimidine (7, isolated yield 87%
based on benzonitrile), 1H NMR (CDCl3, 200 MHz) δ
8.488.51 (br, 2 H), 8.118.14 (br, 2 H), 7.47 (br, 6 H),
6.77 (s, 1 H), 4.98 ppm (br s, 2 H). ESI-MS m/z (M++H):
248.1.
2
Results and discussion
For acetonitrile and butyronitrile bearing more than
one H, the final products are not s-triazines, but
4-amino-2,6-bimethyl-pyrimidine (2) and 4-amino-2,6bipropyl-5-ethyl-pyrimidine (4). This kind of rearrangeü
ment has been observed previously[12 18]. In the case of
benzonitrile, the product was 2,4,6-triphenyl-s-triazine
(6)[22], as expected for a nitrile reactant with α-H. In reactions (1) and (2), it is well accepted that the s-triazines are
the intermediate, which will rearrange into pyrimidines at
ü
high temperatures or under high pressures[12 18]. Investigations were also performed with much lower reaction
temperatures (100) or much shorter reaction periods
(0.5 h) with the attempt to obtain the corresponding
s-triazine products. However, the results indicated that no
s-triazines existed in the products. The factor causing the
rearrangement of s-triazines into amino-pyrimidines is
worthy of a detailed research in the future.
The reaction kinetics of the cyclotrimerization of
acetonitrile was also investigated. Fig. 2 shows the typical
evolution of reaction yield with prolonged reaction time. It
could be seen that at 180 the reaction was 96% completed after 24 h. However, an 80% yield could be reached
only after less than 5 h reaction at 180. For a temperature as low as 100, the reaction could still progress to
50% completion after hearing for 24 h.
Different from most of other catalysts used for the
cyclotrimerization of nitriles, Li3N should be a heterogeneous catalyst rather than a homogeneous one since it is
rather insoluble in all the nitriles we used. The crystal
structure of lithium nitride contains layered Li2N- sheets
(Fig. 3) and interlayer Li+[22]. Therefore the naked and
negatively charged Li2N- sheets could be accessible to
nitriles at the surface of the catalyst particles. The catalytic
activity could then be attributed to the high nucleophilicity
of the nitride anions in the Li2N- sheets. The slightly positively charged carbon atom (Cδ+) in the CN group would
ü
then be attacked by N3− to form a reaction complex[16 18].
Since the N-Li distance is larger than the bond length of
CN, the Li+ could electrostatically interact with Nδ − along
with the interaction between N3− and Cδ +. This finally
activates the CN bond, resulting in a strong charge separation in the CN triple bond. The activated nitrile molecule
could then react with another two nitrile molecules in series to finalize the cyclotrimerization to s-triazine.
Fig. 3. The Li2N− sheet existing in solid state Li3N. White and black
balls represent nitride and lithium ions respectively.
Fig. 2. Variation of the yield of 2 before isolation with reaction period
at different reaction temperatures.
128
In all the three cases, the final products after isolation were colorless needles. Among these, the product
from trimerization of acetonitrile was suitable for a single
crystal structure determination. 2: C6N3H9, M = 123.16,
Monoclinic, space group P21/n, a = 7.4140(15), b =
7.7110(15), c = 11.663(2) Å, V = 658.5(2) Å3 , T = 293 K,
Z = 4, β = 99.044(8)º, µ (Mo-Kα) = 0.081 mm−1, R/Rw2[I
> 2.0σ (I)] = 0.0497/0.0372; (CCDC Number: 189588
refcode: FAGSUB). The thermal ellipsoid plot and the
crystal packing diagram of 2 are depicted in Figs. 4 and 5
respectively, from which the hydrogen boning and π-π
interactions between the molecules of 2 are found to be
two major factors determining the molecular packing
Chinese Science Bulletin Vol. 49 No. 2 January 2004
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process. The hydrogen bonding appears as N(1)H1D···N(2) and N(1)-H1E···N(3), and the distance between the two N atoms is around 3.0 Å, close to those
found in the DNA base-pairs with Watson-Crick complementarity[23].
in the presence of catalytic amount of Li3N, a common
inorganic chemical. The procedure based on this catalytic
cyclotrimerization is one-pot and solvent-free, and it is
very convenient, simple and easy to scale up reaction,
which makes the utilization of extremely high reaction
pressure no longer necessary, and avoids the use of large
amounts of co-catalysts such as amines, alcohols or acids.
This finding should contribute significantly to the current
efforts in search of new functional molecules containing
triazine or pyrimidine units. Further studies on the catalytic action of lithium nitride, as well as other alkali or
alkali-earth metal nitrides, on a variety of nitriles including dinitriles are ongoing, and the results will be reported
later.
Acknowledgements This work was supported by the National Natural
Science Foundation of China (Grant No. 20025102).
References
1. El-Gendy, Z., Morsy, J. M., Allimony, H. A. et al., Synthesis of heterobicyclic nitrogen systems bearing the 1,2,4-triazine moiety as
Fig. 4. ORTEP plot of the molecule of 2 at 50% probability.
anti-HIV and anticancer drugs, Pharmazie, 2001, 56, 376383.
2. Klenke, B., Stewart, M., Barrett, M. P. et al., Synthesis and biological evaluation of s-triazine substituted polyamines as potential
new anti-trypanosomal drugs, J. Med. Chem, 2001, 44, 3440
3452.
3. Lee, J. Y., Brune, M. E., Warner, R. B. et al., Characterization of
antihypertensive activity of abbott-81988, a nonpeptide angiotensin-II antagonist in the renal hypertensive rat, J Pharm. and Exper. Therap. 1994, 268(1), 427433.
4. Okada, M., Yoden, T., Kawaminami, E. et al., Studies on aromatase
inhibitors. IV. Synthesis and biological evaluation of N ,N
-disubstituted-5-aminopyrimidine derivatives, Chem. Pharm. Bull,
1997, 45, 12931299.
5. Baker, D. R., Fenyes, J. G., Basarad, G. S. et al., Synthesis and insecticidal activity of N-(4-pyridinyl and pyrimidinyl)phenylacetamides, ACS Symposium Series 686, American Chemical Society: Washington, DC, 1998, 136146.
Fig. 5. Molecular packing of 2 in solid state.
6. Ballantine, L. G., McFarland, J. E., Hackett, D. S., The metabolism
of atrazine and related 2-chloro-4,6-bis(alkylamino)-s-trizaines in
Co-trimerizations between different nitriles were also
investigated. Reaction between acetonitrile and benzonitrile afforded 4-amino-2,6-biphenyl-pyrimidine (7, isolated yield 87% based on benzonitrile). The co-trimerization of two or even three kinds of nitriles provides a
way for synthesizing triazines or pyrimidines bearing different substituent groups. Further investigation on the copolymerization reactions is being carried out in our laboratory.
3
plants, ACS Symposium Series 683, American Chemical Society:
Washington, DC, 1998, 60~81.
7. Lee, C. H., Yamamoto, T., Synthesis and characterization of a new
class of liquid-crystalline, highly luminescent molecules containing
a 2,4,6-triphenyl-1,3,5-triazine unit, Tetrahedron. Lett, 2001, 42:
39933996.
8. Janietz, D, Structure formation of functional sheet-shaped
mesogens, J. Mater. Chem., 1998, 8: 265274.
9. Goldmann, D., Janietz, D., Wendorff, J. H. et al., Induction of la-
Conclusion
In conclusion, a new method for the synthesis of
s-triazine and amino-pyrimidine has been established on
the basis of highly efficient cyclotrimerization of nitriles
10. Cherioux, F., Maillotte, H., Zyss, J. et al., Synthesis and charac-
Chinese Science Bulletin Vol. 49 No. 2 January 2004
129
mellar
mesomorphic
structures
in
columnar-phase-forming
1,3,5-triazines through charge-transfer interactions with electron
acceptors. Angew, Chem. Int. Ed., 2000, 39: 18511854.
ARTICLES
11.
12.
13.
14.
15.
16.
130
terisation of an octupolar polymer and new molecular octupoles
17. Forsberg, J. H., Spaziano, V. T., Sanders, K. M. et al., Lanthanide
with off-resonant third order optical nonlinearities, Chem. Com-
ion catalyzed reaction of Ammonia and nitriles: synthesis of
mun. Chem. Commun., 1999, 20832084.
Brasselet, S., Cherioux, F., Zyss, J. et al., New octupolar
star-shaped strucures for quadratic nonlinear optics, Chem. Mater,
1999, 11: 19151920.
Cairns, T. L, Larchar, A. W., McKusick, B. C., The trimerization of
nitriles at high pressures, J. Am. Chem. Soc., 1952, 74: 5633
5636.
Koppes, W. M., Adolph, H. G., Pressure-induced cyclotrimerization
of electron-deficient nitriles, Catalysis by acidic alcohols and phenols, J. Org. Chem., 1981, 46: 406412.
Bengelsdorf, I. S., High pressure-high temperature reactions, I. The
trimerization of aromatic nitriles, J. Am. Chem. Soc., 1958, 80:
14421444.
Bengelsdorf, I. S., High pressure-high temperature reactions. II.
The reaction of aliphatic nitriles and amides, J. Org. Chem., 1963,
28: 13691373.
Forsberg, J. H., Spaziano, V. T., Miller, J. L. et al., Use of lanthanide ions as catalysts for the reactions of amines with nitriles, J.
Org. Chem., 1987, 52: 10171021.
2,4,6-trisubstituted-s-triazine, J. Hetercycl. Chem., 1988, 25: 767
770.
18. Xu, F., Sun, J. H., Shen, Q. et al., Cyclotrimerization of nitriles
catalyzed by SmI2/amines: synthesis of 2,4,6-trisubstituted-striazines, Synth. Commun., 2000, 30: 10171022.
19. Xu, F., Sun, J. H., Shen Q., Samarium diiodide promoted synthesis
of N,N
-disubstituted amidines, Tetrahedron. Lett., 2002, 43(10):
1867.
20. Sandner, J., Fierce, W. L., U.S. Patent 3071586, 1963.
21. Yanagida, S, Yokoe, M, Komori, S et al., Studies on nitrile salts. IV.
Trimerization of nitriles to 1,3,5-triazines by the combined catalyst
PCl5-HCl, Bull. Chem. Soc. Jpn., 1973, 46: 306310.
22. Wyckoff, R. W. G., Crystal Structures, 2nd ed., Interscience: New
York, 1973, Vol. 2, 111.
23. Lehninger, A. L., Nelson, D. L., Cox, M. M., Principles of Biochemistry, 2nd ed., Worth publishers: New York, 1993, 331.
(Received July 17, 2003; accepted November 14, 2003)
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