Synthesis of substituted 4(6)-amino-1,3,5-triazin-2-ones and -1,3,5-triazin-2-thiones

Full text of DOI:10.1021/jo010416a

J . Org. Chem. 2001, 66, 6797-6799
6797
Notes
presence of phosphorus oxychloride;4f (ii) cyclizations of
N-acyl-N′-cyanoguanidines;4f,g (iii) cyclizations of iso-
biurets with ethyl orthoformate;4h,j (iv) reactions of
guanylureas with dimethylformamide dimethylacetal;4j
(v) sequential displacements of two chlorine atoms fol-
lowed by hydrolysis of the third chlorine in 2,4,6-
trichloro-1,3,5-triazine (cyanuric chloride);5a-d and (vi)
reactions of biguanides with diethyl azodicarboxylate.6
4(6)-Amino-1,3,5-triazin-2-thiones were obtained by the
reaction of dicyandiamide with thiocarboxylic acids.7
Recently, we published an efficient synthetic procedure
for the preparation of 3-amino-1,2,4-triazoles starting
from N-acyl-1H-benzotriazole-1-carboximidamides 1.8a
We now report the application of compounds 1 in a new
synthetic route to 4(6)-amino-1,6(4)-substituted-1,3,5-
triazin-2-ones.
Syn th esis of Su bstitu ted
4(6)-Am in o-1,3,5-tr ia zin -2-on es a n d
-1,3,5-tr ia zin -2-th ion es
Alan R. Katritzky,*,‡ Boris V. Rogovoy,‡
Vladimir Y. Vvedensky,‡ Normand Hebert,§ and
Behrouz Forood§
Center for Heterocyclic Compounds, Department of
Chemistry, University of Florida, Gainesville, Florida
32611-7200, and Exploratory Chemistry, LION bioscience,
Inc., 9880 Campus Point Drive, San Diego, California 92121
katritzky@chem.ufl.edu
Received April 23, 2001
In tr od u ction
Resu lts a n d Discu ssion
1,3,5-Triazin-2-one derivatives include well-known an-
ticancer drugs.1a-c 5-Azacytidine (4-amino-1-â-D-ribofura-
nosyl-1,3,5-triazin-2(1H)-one), a synthetic analogue of the
natural pyrimidine nucleoside cytidine, has strong anti-
leukemic activity.2a-c When used in cancer chemotherapy,
5-azacytidine is phosphorylated in the cell, and after its
incorporation into the DNA, it inhibits the methyltrans-
ferase, causing a block in the cytosine methylation in
newly replicated DNA. Selective modulation of DNA
methylation may, therefore, have important clinical
implications for the prevention and treatment of cancer.1c,2b
Other derivatives of the 5-azacytidine, decitabine and
gemcitabine, were found active in the treatment of lung,
pancreas, bladder, and breast cancer.3a-c
N-Acyl-1H-benzotriazole-1-carboximidamides 1 can be
obtained from reactions of di(benzotriazol-1-yl)metha-
nimine with various primary and secondary amines
followed by acylation.8a-b We have used known deriva-
tives 1b-d ,g as well as novel compounds 1a ,e,f,h . The
construction of the 1,3,5-triazin-2-one ring from 1 in-
volves the displacement of the benzotriazolyl moiety with
urea or thiourea in the presence of potassium tert-
butoxide, followed by cyclocondensation into triazines 2
and 3.
Independent of the nature of the substituent R1 in the
starting N-acyl carboximidamides 1, reactions of 1 with
nonsubstituted urea and thiourea or with their N-
monoalkyl derivatives in the presence of 3 equiv of
potassium tert-butoxide proceed smoothly in THF at room
temperature to give the desired 4(6)-substituted-6(4)-
amino-1,3,5-triazin-2-ones 2a -f and 4(6)-substituted-
6(4)-amino-1,3,5-triazin-2-thiones 3a -c directly (Scheme
1, Table 1). In contrast, reactions of N-acyl carboximi-
damides 1 with phenylurea lead to noncyclic intermedi-
ates 4a -d (Scheme 1, Table 1), with the exception of the
reaction of the derivative 1c with phenylurea from which
the desired 1,3,5-triazin-2-one 6 was isolated exclusively
(Scheme 1).
Known syntheses of 4(6)-amino-1,3,5-triazin-2-ones4a-b
include (i) reactions of cyanoguanidines with carboxylic
acids,4c-d acid anhydrides,4e or carboxylic acids in the
‡ University of Florida.
§ LION bioscience, Inc.
(1) (a) Steuber, C. P.; Krischer, J .; Holbrook, T.; Camitta, B.; Land,
V.; Sexauer, C.; Mahoney, D.; Weinstein, H. J . Clin. Oncol. 1996, 14,
1521. (b) Kantarjian, H. M.; Talpaz, M.; O’Brien, S.; Kurzrock, R.;
Gutterman, J .; Keating, M. J .; McCredie, K. B.; Freireich, E. J . Clin.
Cancer Res. 1997, 3, 2723. (c) Momparler, R. L.; Bovenzi, V. J . Cell
Physiol. 2000, 183, 145.
(2) (a) Marin, D.; Teijeiro, C.; Pina, J . J . J . Electroanal. Chem. 1996,
407, 189. (b) Singal, R.; Ginder, G. D. Blood 1999, 93, 4059. (c) Smith,
R. D.; Li, J .; Noguchi, C. T.; Schechter, A. N. Blood 2000, 95, 863.
(3) (a) Gregoire, V.; Hittelman, W. N.; Rosier, J . F.; Milas, L. Oncol.
Rep. 1999, 6, 949. (b) Sacchi, S.; Kantarjian, H. M.; O’Brien, S.; Cortes,
J .; Rios, M. B.; Giles, F. J .; Beran, M.; Koller, C. A.; Keating, M. J .;
Talpaz, M. Cancer 1999, 86, 2632. (c) Poplin, E.; Roberts, J .; Tombs,
M.; Grant, S.; Rubin, E. Invest. New Drugs 1999, 17, 57.
(4) (a) Quirke, J . M. E. In Comprehensive Heterocyclic Chemistry;
Boulton, A. J ., McKillop, A., Eds.; Pergamon Press: Oxford, 1984; Vol.
3, p 457 and references herein. (b) Bartholomew, D. In Comprehensive
Heterocyclic Chemistry II; Boulton, A. J ., Ed.; Pergamon Press: Oxford,
The mode of the addition of the base is important: 1
equiv does not lead to complete reaction. Adding 2 equiv
of potassium tert-butoxide in one portion gives the desired
(5) (a) Thurston, J . T.; Dudley, J . R.; Kaiser, D. W.; Hechenbleikner,
I.; Schaefer, F. C.; Holm-Hansen, D. J . Am. Chem. Soc. 1951, 73, 2981.
(b) Dudley, J . R.; Thurston, J . T.; Schaefer, F. C.; Holm-Hansen, D.;
Hull, C. J .; Adams, P. J . Am. Chem. Soc. 1951, 73, 2986. (c) Schaefer,
F. C.; Dudley, J . R.; Thurston, J . T. J . Am. Chem. Soc. 1951, 73, 2996.
(d) Schaefer, F. C.; Dudley, J . R.; Thurston, J . T. J . Am. Chem. Soc.
1951, 73, 3004.
(6) Kihara, Y.; Kabashima, S.; Yamasaki, T.; Ohkawara, T.; Furu-
kawa, M. J . Heterocycl. Chem. 1990, 27, 1213.
(7) Russel, P. B.; Hitchings, G. H.; Chase, B. H.; Walker, J . J . Am.
Chem. Soc. 1952, 74, 5403.
1996; Vol. 6,
p 575 and references herein. (c) Grundmann, C.;
Schwennicke, L.; Beyer, E. Chem. Ber. 1954, 87, 19. (d) Davydov, A.
V.; Finkel’shtein, A. I.; Shcherbakov, E. K.; Fokin, A. V.; Roginskaya,
Ts. N. J . Gen. Chem. USSR (Engl. Transl.) 1968, 38, 2415. (e)
Andreasch, R. Monatsh. Chem. 1927, 48, 149. (f) Klosa, J . Arch.
Pharm.(Weinheim, Ger.) 1955, 228, 139. (g) Adams, P.; Kaiser, D. W.;
Nagy, D. E.; Peters, G. A.; Sperry, R. L.; Thurston, J . T. J . Org. Chem.
1952, 17, 1162. (h) Piskala, A.; Sorm, F. Collect. Czech. Chem.
Commun. 1964, 29, 2060. (j) Piskala, A. Collect. Czech. Chem. Com-
mun. 1967, 32, 3966.
(8) (a) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V.; Kovalenko,
K.; Steel, P. J . Markov, V. I. Synthesis 2001, 897. (b) Katritzky, A. R.;
Rogovoy, B. V.; Chassaing, C.; Vvedensky, V. J . Org. Chem. 2000, 65,
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10.1021/jo010416a CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/08/2001

6798 J . Org. Chem., Vol. 66, No. 20, 2001
Ta ble 1. P r ep a r a tion of Sta r tin g Ma ter ia ls 1, In ter m ed ia tes 4, a n d F in a l P r od u cts 2, 3, a n d 5
Notes
yield, % (R3)
entry
R1
R2
1
2
3
4
5
6
1
2
(CH2)2O(CH2)2
(CH2)2O(CH2)2
4-CH3-C6H4
Ph
a : 86
b: 93
a : 89 (H)
b: 85 (H)
c: 79 (CH3)
a : 68
a : 95
3
(CH2)2O(CH2)2
ethyl
c: 91
a : 88 (H)
b: 44 (Et)
94
4
5
6
7
8
(CH2)2O(CH2)2
(CH2)2O(CH2)2
ethyl, ethyl
ethyl, ethyl
allyl, allyl
thiophen-2-yl
4-F-C6H4
4-CH3-C6H4
tert-butyl
d : 64
e: 98
f: 86
g: 88
h : 72
d : 76 (CH3)
e: 91 (CH3)
f: 87 (H)
c: 63 (H)
b: 82
c: 89
d : 61
b: 96
c: 51
d : 88
4-CH3-C6H4
Sch em e 1
Con clu sion
In summary, we have developed a new, efficient
procedure for the preparation of 4(6)-amino-1,6(4)-disub-
stituted-1,3,5-triazin-2-ones 2a -f, 5a -d , and 6, and 4(6)-
amino-1,6(4)-disubstituted-1,3,5-triazin-2-thiones 3a -c.
Our method allows the introduction of a variety of amino
group substituents which is not possible by direct reac-
tions with cyanoguanidines4a,b,d,e or is limited by the
availability of N,N-disubstituted formamide diacetals.4g
Use of acyl cyanoguanidines could give a diversity in the
4(6)-position, but once again, it does not allow the
introduction of a substituent in the amino group at the
same time. The proposed protocol does not need rigorous
control of the reaction conditions in comparison to the
protocol for the condensation of cyanuric chloride with
amines.5a The option of introducing the thione group
increases the usefulness of the reported protocol. Each
step of the reaction sequence gave the desired final
products 2a -f, 3a -c, and 6 or intermediates 4a -d in
high yields with good purity.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined using a
capillary melting point apparatus equipped with
a digital
thermometer and are uncorrected. 1H and 13C NMR spectra were
recorded on a 300 MHz NMR spectrometer (300 and 75 MHz,
respectively) using CDCl3 or DMSO-d6 as solvent, with tetra-
methylsilane as an internal standard. Tetrahydrofuran (THF)
was distilled under nitrogen from sodium/benzophenone im-
mediately before use. Column chromatography was conducted
with silica gel grade 230-400 mesh. All other reagents were of
reagent grade and were used without purification.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acyl Der iva -
tives of 1H-Ben zotr ia zol-1-ca r boxim id a m id es 1a -h . An
appropriate 1H-benzotriazol-1-carboximidamide (1 equiv) was
dissolved in chloroform, and an acyl chloride (1 equiv) was added,
followed by the addition of triethylamine (1 equiv). The mixture
was allowed to react for 2-4 h at ambient temperature. The
completion of the reaction was monitored by TLC. Then the
chloroform solution was washed with water to remove triethyl-
amine hydrochloride. The chloroform layer was separated, dried,
and concentrated under reduced pressure. The preparation and
characterization of compounds 1b-d ,g were described previously
in our earlier work.8a-b
N-(1H -Ben zot r ia zol-1-yl(m or p h olin o)m et h ylid en e)-4-
m eth ylben za m id e (1a ). White needles (ethyl acetate), mp
294-295 °C. 1H NMR: δ 2.36 (s, 3H), 3.56-3.60 (m, 4H), 3.80-
3.84 (m, 4H), 7.26 (d, J ) 7.9 Hz, 2H), 7.49 (t, J ) 7.3 Hz, 1H),
7.58-7.69 (m, 2H), 7.84 (d, J ) 7.9 Hz, 2H), 8.17 (t, J ) 8.2 Hz,
1H). 13C NMR: δ 21.1, 47.2, 65.6, 110.9, 119.9, 125.3, 128.9,
129.3, 129.6, 132.3, 132.6, 142.7, 144.6, 146.1, 174.0. Anal. Calcd
for C19H19N5O2: C, 65.31; H, 5.48; N, 20.04. Found: C, 65.08;
H, 5.53; N, 20.16.
products 2a -f, 3a -c, or intermediates 4a -d along with
unidentified side products. The optimal conditions were
found to be the portionwise addition of 3 equiv of
potassium tert-butoxide for 1 h, which gave the interme-
diates 4a -d or final products 2a -f and 3a -c in high
yields. Replacement of potassium tert-butoxide by sodium
methoxide in the reaction of 1b with phenylurea de-
creases the yield of the desired compound 4a . Attempts
to synthesize the compound 4a in the presence of DBU
failed.
In search of a general method for the cyclization of
compounds 4 into triazinones 5, we refluxed compound
4a (a) in toluene in the presence of p-toluenesulfonic acid
and (b) in TFA. Derivative 4b was treated with an EtOH/
KOH mixture under reflux. Although all these attempts
were unsuccessful, it was found that compounds 4 can
be easily cyclized into triazinones 5 using HMDS as a
dehydrating agent under reflux (Scheme 1, Table 1).
P r oced u r e for th e P r ep a r a tion of Com p ou n d s 2, 3, 4 a n d
6. N-Acyl benzotriazole-1-carboximidamide 1 (1 mmol) and urea
(thiourea) (1 mmol) were mixed in THF (10 mL). Potassium tert-

Notes
J . Org. Chem., Vol. 66, No. 20, 2001 6799
butoxide (3 mmol) was added portionwise by 1 equiv in 15 min.
The reaction mixture was allowed to react for 6-8 h. Then water
(15 mL) was added to give a clear solution. Water solution was
extracted with ethyl acetate (3 × 30 mL). Sodium bicarbonate
was added to a water layer, and the water layer was additionally
extracted with chloroform (2 × 30 mL). Extracts were combined,
dried over MgSO4, and evaporated under reduced pressure. The
residue obtained was recrystallized from an appropriate solvent
to give 2, 3, 4, and 6.
P r oced u r e for th e P r ep a r a tion of Com p ou n d s 5a -d
Sta r tin g fr om 4a -d . Noncyclic products 4a -d (1 mmol) were
refluxed in HMDS (30 mL) for 1-3 d (TLC control). Then HMDS
was evaporated under reduced pressure, and the residues
obtained were recrystallized from an appropriate solvent to give
the desired compounds 5a -d .
4-(4-Met h ylp h en yl)-6-m or p h olin o-1,3,5-t r ia zin -2(3H )-
on e (2a ). White needles (ethanol/water), mp 301-302 °C. 1H
NMR: δ 2.44 (s, 3H), 3.77 (br s, 4H), 3.98 (br s, 2H), 4.07 (br s,
2H), 7.35 (d, J ) 7.9 Hz, 2H), 8.21 (d, J ) 8.1 Hz, 2H), 12.93 (s,
1H). 13C NMR: δ 21.7, 44.1, 44.7, 66.7, 66.8, 127.8, 128.2, 129.8,
144.1, 159.4, 163.5, 164.4. Anal. Calcd for C14H16N4O2: C, 61.75;
H, 5.92; N, 20.57. Found: C, 61.85; H, 5.62; N, 20.63.
4-E t h yl-6-m or p h olin o-1,3,5-t r ia zin e-2(1H )-t h ion e (3a ).
White needles (benzene/hexanes), mp 252-253 °C. 1H NMR
(DMSO-d6): δ 1.22 (t, J ) 7.4 Hz, 3H), 2.54 (q, J ) 7.4 Hz, 2H),
3.65-3.69 (m, 4H), 3.89-3.95 (m, 4H), 12.91 (s, 1H). 13C NMR
(DMSO-d6): δ 10.0, 26.7, 43.5, 43.8, 56.8, 65.9, 158.9, 168.3,
182.7. Anal. Calcd for C9H14N4OS: C, 47.77; H, 6.24; N, 24.76.
Found: C, 48.02; H, 6.44; N, 24.90.
N -(An i li n o c a r b o n y l)a m i n o (m o r p h o li n o )m e t h y li -
d en eben za m id e (4a ). White prisms (ethanol/water), mp 136-
1
137 °C. H NMR: δ 3.66 (br s, 4H), 3.69-3.81 (m, 4H), 7.03 (t,
J ) 7.2 Hz, 1H), 7.19 (br s, 1H), 7.25-7.30 (m, 2H), 7.43-7.58
(m, 5H), 8.01 (d, J ) 7.7 Hz, 2H), 12.60 (s, 1H). 13C NMR: δ
40.7 (br s), 66.5, 119.1, 123.2, 128.1, 128.9, 128.9, 132.7 133.0,
138.6, 154.3, 162.1, 164.9. Anal. Calcd for C19H20N4O3: C, 64.76;
H, 5.72; N, 15.90. Found: C, 64.74; H, 5.77; N, 15.99.
4-(Dia llyla m in o)-6-(4-m eth ylp h en yl)-1-p h en yl-1,3,5-tr i-
a zin -2(1H)-on e (5d ). White prisms (benzene/hexanes), mp 123-
1
124 °C. H NMR: δ 2.28 (s, 3H), 4.31-4.35 (m, 4H), 5.20-5.24
(m, 4H), 5.83-5.93 (m, 2H), 6.99 (d, J ) 7.9 Hz, 2H), 7.14-7.20
(m, 4H), 7.24-7.32 (m, 3H). 13C NMR: δ 21.4, 48.7, 48.9, 117.3,
117.6, 128.2, 128.6, 128.8, 128.9, 129.3, 130.6, 132.6, 133.1, 137.7,
141.1, 155.7, 162.8, 165.4. Anal. Calcd for C22H22N4O: C, 73.72;
H, 6.19; N, 15.63. Found: C, 73.46; H, 6.47; N, 15.61.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and CHN analysis data for compounds 1e,f,h , 2b-f, 3b,c, 4b-
d , 5a -c, and 6 and 1H NMR and 13C NMR spectra for
compounds 2d , 4c,d , 5a -c, and 6. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O010416A