A tandem decarboxylation/Diels-Alder reaction of 5-amino-1-phenyl-4-pyrazolecarboxylic acid with 1,3,5-triazines

Article abstract of DOI:10.1016/S0040-4039(01)01822-6

A tandem decarboxylation/Diels-Alder reaction of 5-amino-1-phenyl-4-pyrazolecarboxylic acid with various 1,3,5-triazines was reported. The dienophile, 5-amino-1-phenylpyrazole, was generated in situ via decarboxylation and immediately trapped by 1,3,5-triazines leading to 4,6-disubstituted 1-phenylpyrazolo[3,4-d]pyrimidines in one step.

Full text of DOI:10.1016/S0040-4039(01)01822-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8419–8422
A tandem decarboxylation/Diels–Alder reaction of
5-amino-1-phenyl-4-pyrazolecarboxylic acid with 1,3,5-triazines
Qun Dang,* Yan Liu and Zhili Sun
Department of Medicinal Chemistry, Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, San Diego, CA 92121, USA
Received 4 August 2001; revised 26 September 2001; accepted 28 September 2001
Abstract—A tandem decarboxylation/Diels–Alder reaction of 5-amino-1-phenyl-4-pyrazolecarboxylic acid with various 1,3,5-tri-
azines was reported. The dienophile, 5-amino-1-phenylpyrazole, was generated in situ via decarboxylation and immediately
trapped by 1,3,5-triazines leading to 4,6-disubstituted 1-phenylpyrazolo[3,4-d]pyrimidines in one step. © 2001 Elsevier Science
Ltd. All rights reserved.
Many drug discovery efforts have been directed at the
regulation of purine metabolic pathways and functions
of purinergic receptors. Consequently, purine analogues
are extensively exploited as potential therapeutics.1
Since pyrazolo[3,4-d]pyrimidine is isomeric with purine,
its analogues are often synthesized and studied for their
biological activities related to purine metabolic path-
ways and purinergic receptors. For example, GP515 is a
potent adenosine kinase inhibitor (IC50=4.6 nM),2 and
2%-(4-amino-1-phenylpyrazolo[3,4-d]pyrimidin-6-ylthio)-
(N-ethyl)ethanamide (1)3 is a potent ligand at the A1
receptor (Ki=12 nM) (Fig. 1).
for the one-step synthesis of pyrazolo[3,4-d]pyrimi-
dines,5 and recently a tandem decarboxylation/Diels–
Alder (TDDA) reaction of various 5-amino-4-imida-
zolecarboxylic acids with 1,3,5-triazines for the one-step
synthesis of purine analogues.6 We envisioned that the
TDDA reaction can be extended to 5-amino-4-pyra-
zolecarboxylic acids, which should allow those other-
wise unreactive pyrazoles to serve as productive
dienophiles. Herein, we report the TDDA reaction of
5-amino-1-phenyl-4-pyrazolecarboxylate (2)7 with vari-
ous 1,3,5-triazines (3a–h)8 under both mild thermal and
Lewis acid conditions. This method is useful for the
one-step synthesis of various 4,6-disubstituted 1-phenyl-
pyrazolo[3,4-d]pyrimidines.
Our interest in adenosine regulating agents directed us
to study efficient synthetic methodologies for various
purine analogues.4 Such efforts led to the introduction
of 5-aminopyrazoles as dienophiles in the Diels–Alder
reaction with 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine
Previously, 1,3,5-triazine 3a was shown to be a reactive
diene with 5-aminopyrazoles as the dienophiles, and it
was proven to participate in the TDDA reaction of
Figure 1.
* Corresponding author. E-mail: dang@mbasis.com
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01822-6

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Q. Dang et al. / Tetrahedron Letters 42 (2001) 8419–8422
current TDDA reaction of 3a and 2 was done quickly
(in 2 h). This suggests that current TDDA reaction
conditions appeared to accelerate the decarboxylation
of 2 possibly via trapping of the in situ generated
5-amino-1-phenylpyrazole by 3a. A reaction mechanism
analogous to our previous observations is envisioned
(Scheme 1).11 Decarboxylation of 2 gave 5-amino-1-
phenylpyrazole that was subsequently trapped by 3a
through a [4+2] cycloaddition reaction, and then the
resulting cycloadduct underwent a retro Diels–Alder
reaction with the loss of ethyl cyanoformate followed
by final aromatization with loss of ammonia to regiose-
lectively produce 4a. Other 1,3,5-triazines (3b–d) with
electron-withdrawing substituents generated the corre-
sponding pyrazolo[3,4-d]pyrimidines (4b–d) in high
yields as well (Table 1, entries 3–5). The parent 1,3,5-
pyrazole 2 as well. Thus, heating a mixture of 2 and 3a
(90°C, DMF–AcOH) generated 4,6-bis(ethoxycar-
bonyl)-1-phenylpyrazolo[3,4-d]pyrimidine (4a) in high
yield (83%).9 This TDDA reaction appears to be acid-
mediated, since no 4a was detected with only starting
materials being recovered when the sodium salt of 2
was used in the absence of an acid (Table 1, entry 2).10
Such observation suggests that the decarboxylation of 2
precedes the [4+2] cycloaddition reaction and 2 itself is
not reactive enough to participate in the [4+2] cycload-
dition reaction with 3a. This result is consistent with
our observations from the TDDA reaction of 5-amino-
4-imidazolecarboxylic acids with 1,3,5-triazines. It is
surprising that under the same reaction conditions, 2
was only slowly converted to 5-amino-1-phenylpyrazole
(60%, DMF–AcOH, 95°C, 56 h), even though the
Table 1. Tandem decarboxylation/Diels–Alder reactions of pyrazole 2 with 1,3,5-triazines 3a–h
Entry
Diene
X=
Conditionsa
Product
Yield (%)
1
2
3
4
5
6
7
8
3a
3a
3b
3c
3d
3e
3f
CO2Et
CO2Et
CO2Me
CF3
CF2Cl
PO(OEt)2
H
H
Ph
Ph
SMe
SMe
DMF–AcOH, 90°C, 2 h
DMF, 90°C, 48 h
4a
4a
4b
4c
4d
4e
4f
83
0b,c
87
78
70
10d
0c
DMF–AcOH, 95°C, 3.5 h
DMF–AcOH, 90°C, 2 h
DMF–AcOH, 95°C, 4.5 h
DMF–AcOH, 95°C, 3 h
DMF–AcOH, 100°C, 48 h
DMSO, BF3·OEt2, 100°C, 3 h
DMF–AcOH, 100°C, 48 h
DMSO, BF3·OEt2, 100°C, 48 h
DMF–AcOH, 100°C, 48 h
DMSO, BF3·OEt2, 100°C, 48 h
3f
4f
64
9
3g
3g
3h
3h
4g
4g
4h
4h
0c
10
11
12
0c
0c
0c
a Reactions were conducted using sodium salt of 2 (2 equiv) and 3a–h.
b DMF was the sole solvent.
c Unreacted 1,3,5-triazine was recovered.
d No unreacted 1,3,5-triazine was detected.
Scheme 1. X groups: (a) EtO2C; (b) MeO2C; (c) F3C; (d) ClF2C; (e) (EtO)2OP; (f) H; (g) Ph; (h) MeS.

Q. Dang et al. / Tetrahedron Letters 42 (2001) 8419–8422
8421
triazine (3f) and those 1,3,5-triazines (3g and 3h) with
electron-donating substituents, however, did not give
the corresponding pyrazolo[3,4-d]pyrimidines (4f–h)
under thermal conditions (Table 1, entries 7, 9 and 11).
It is somewhat surprising that the reaction between 2
and 3e gave the corresponding pyrazolo[3,4-
d]pyrimidines (4e) only in low yield despite the presence
of electron-withdrawing substituents (-P(O)(OEt)2) on
the 1,3,5-triazine. The fact that no 3e was detected
suggested that either 3e and/or 4e were not stable under
the reaction conditions or the conversion of the initial
[4+2] cycloadduct to 4e was not complete under current
conditions.
2. (a) Wiesner, J.; Ugarkar, B. G.; Castellino, A. J.;
Barankiewicz, J.; Dumas, D. P.; Gruber, H. E.; Foster,
A. C.; Erion, M. D. J. Pharmacol. Exp. Ther. 1999, 289,
1669; (b) Rosengren, S.; Firestein, G. S. In Purinergic
Approaches in Experimental Therapeutics; Jacobson, K.
A.; Jarvis, M. F., Eds.; Wiley: New York, 1997; (c)
Rosengren, S.; Bong, G. W.; Firestein, G. S. J. Immunol.
1995, 154, 5444; (d) Firestein, G. S.; Bullough, D. A.;
Erion, M. D.; Jimenez, R.; Ramirez-Weinhouse, M.;
Barankiewicz, J.; Smith, C. W.; Gruber, H. E.; Mullane,
K. M. J. Immunol. 1995, 154, 326; (e) Firestein, G. S.;
Boyle, D.; Bullough, D. A.; Gruber, H. E.; Sajjadi, F. G.;
Montag, A.; Sambol, B.; Mullane, K. M. J. Immunol.
1994, 152, 5853.
Although mineral acids have been shown to facilitate
inverse electron-demand Diels–Alder reactions,12 the
presence of acetic acid under the current reaction condi-
tions was not enough to promote reactions for 1,3,5-tri-
azine 3f–h. We decided to investigate the effect of Lewis
acids on the current TDDA reactions, and when the
reaction between 2 and 3f was conducted in the pres-
ence of BF3·OEt2, the desired TDDA product 4f was
isolated in good yield (64%, Table 1, entry 8).13 How-
ever, preliminary studies showed that, even in the pres-
ence of BF3·OEt2, 1,3,5-triazines 3g and 3h were not
reactive enough to participate in the current TDDA
reactions (Table 1, entries 10 and 12).
3. Poulsen, S.; Quinn, R. J. Bioorg. Med. Chem. Lett. 1996,
6, 357 and references cited therein.
4. Dang, Q.; Brown, B. S.; Erion, M. D. Tetrahedron Lett.
2000, 41, 6559.
5. (a) Dang, Q.; Brown, B. S.; Erion, M. D. J. Org. Chem.
1996, 61, 5204. For examples of inverse electron-demand
Diels–Alder reaction between pyrazoles and 1,2,4,5-tetra-
zines, see: (b) Seitz, G.; Hoferichter, R.; Mohr, R. Arch.
Pharm. (Weinheim) 1989, 322, 415; (c) Seitz, G.; Mohr,
R.; Hoferichter, R. Chem. Ztg. 1988, 112, 17.
6. Dang, Q.; Liu, Y.; Erion, M. D. J. Am. Chem. Soc. 1999,
121, 5833.
7. Garin, J.; Loscertales, M. P.; Melendez, E.; Merchan, F.
L.; Rodriguez, R.; Tejero, T. Heterocycles 1987, 26, 1303.
8. (a) Compounds 3a, 3b and 3h were prepared according
Boger’s procedure. See: Boger, D. L.; Dang, Q. Tetra-
hedron 1988, 44, 3379; (b) Compound 3e was prepared
according to Morrison’s procedure. See: Morrison, D. C.
J. Org. Chem. 1957, 22, 444; (c) Compounds 3c, 3f, and
3g were purchased from Aldrich, and 3d was purchased
from Lancaster.
In summary, we have demonstrated that TDDA reac-
tions of 5-amino-1-phenyl-4-pyrazolecarboxylic acid
with various electron-deficient 1,3,5-triazines (3a–e)
under mild thermal conditions allow the one-step syn-
theses of highly substituted pyrazolo[3,4-d]pyrimidines
in excellent yields. Moreover, in a preliminary study a
Lewis acid (BF3·OEt2) was shown, for the first time, to
facilitate inverse electron-demand Diels–Alder reaction
of 1,3,5-triazine (3f). In addition, four new 1,3,5-triazi-
nes 3b–e were introduced as productive heteroaromatic
dienes for inverse electron-demand Diels–Alder reac-
tions. It is anticipated that TDDA reactions could
introduce a new set of productive dienophiles, which
normally are deactivated (by the presence of an elec-
tron-withdrawing group (-CO2R)) towards inverse
electron-demand Diels–Alder reactions, for the 1,3,5-
triazine Diels–Alder reactions. Moreover, the current
TDDA reaction may be more useful in the case of a
thermally unstable dienophile since it will be generated
in situ and immediately trapped by 1,3,5-triazines.
9. Representative procedures for the thermal TDDA reac-
tion: A mixture of 2 (225 mg, 1 mmol) and 3a (150 mg,
0.5 mmol) in anhydrous DMF–AcOH (1:1) was heated at
90°C under nitrogen for 2 h. The cooled reaction mixture
was evaporated to dryness, and the residue was purified
by flash chromatography (SiO2, 2×15 cm, 30% EtOAc–
hexane) to give 4,6-bis(ethoxycarbonyl)-1-phenylpyra-
zolo[3,4-d]pyrimidine (4a) as a sticky solid (170 mg,
1
83%); H NMR (200 MHz, CDCl3): l 8.80 (1H, s), 8.28
(2H, m), 7.57 (2H, m), 7.39 (1H, m), 4.62 (2H, q, J=7.4
Hz), 4.57 (2H, q, J=7.4 Hz), 1.54 (3H, t, J=7.4 Hz),
1.49 (3H, t, J=7.4 Hz); 13C NMR (50 MHz, CDCl3): l
163.38, 163.30, 154.21, 154.09, 150.48, 138.16, 135.37,
129.51, 127.57, 121.55, 114.76, 63.24, 63.01, 14.13; MS
calcd for C17H16N4O4+H+: 341, found 341. Anal. calcd
for C17H16N4O4·0.25H2O: C, 59.21; H, 4.82; N, 16.25.
Found: C, 59.29; H, 4.72; N, 16.19%.
References
4,6-Bis(methoxycarbonyl)-1-phenylpyrazolo[3,4-d]pyrimi-
dine (4b). Flash chromatography (SiO2, 2×15 cm, 30%
EtOAc–hexane) gave 4b as a sticky solid (160 mg, 87%);
1H NMR (200 MHz, CDCl3): l 8.83 (1H, s), 8.29 (2H,
m), 7.60 (2H, m), 7.41 (1H, m), 4.19 (3H, s), 4.15 (3H, s);
MS calcd for C15H12N4O4+H+: 313, found 313. Anal.
calcd for C15H12N4O4·0.11EtOAc: C, 57.60; H, 4.03; N,
17.40. Found: C, 57.53; H, 3.73; N, 17.02%.
1. (a) Appleman, J. R.; Erion, M. D. Exp. Opin. Invest.
Drugs 1998, 7, 225; (b) Purinergic Approaches in Experi-
mental Therapeutics; Jacobson, K. A.; Jarvis, M. F., Eds.;
Wiley: New York, 1997; (c) Nucleosides and Nucleotides
as Antitumor and Antiviral Agents; Chu, C. K.; Baker, D.
C., Eds.; Plenum: New York, 1993; (d) Bonnet, P. A.;
Robins, R. K. J. Med. Chem. 1993, 36, 635; (e) Huryn,
D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745; (f) Jacob-
son, K. A.; van Galen, P. J. M.; Williams, M. J. Med.
Chem. 1992, 35, 407.
4,6-Bis(trifluoromethyl)-1-phenylpyrazolo[3,4-d]pyrimidine
(4c). Flash chromatography (SiO2, 2×15 cm, 10%

8422
Q. Dang et al. / Tetrahedron Letters 42 (2001) 8419–8422
EtOAc–hexane) gave 4c as a solid (181 mg, 78%). mp
104–105°C; H NMR (200 MHz, CDCl3): l 8.59 (1H, s),
gested by a referee, no [4+2] cycloaddition was observed
with only starting materials being recovered.
1
8.23 (2H, m), 7.61 (2H, m), 7.46 (1H, m); MS calcd for
C13H6N4F6+H+: 333, found 333. Anal. calcd for
C13H6F6N4: C, 47.00; H, 1.82; N, 16.87. Found: C, 47.22;
H, 1.74; N, 16.78%.
11. For a theoretical study on Diels–Alder reactions between
various five-membered aromatic heterocycles and 1,3,5-
triazine, see: Yu, Z.-X.; Dang, Q.; Wu, Y.-D. J. Org.
Chem. 2001, 66, 6029.
12. (a) Boger, D. L.; Dang, Q. Tetrahedron 1988, 44, 3379;
(b) Taylor, E. C.; Macor, J. E. Tetrahedron Lett. 1985,
26, 2415.
4,6-Bis(chlorodifluoromethyl)-1-phenylpyrazolo[3,4-d]pyri-
midine (4d). Flash chromatography (SiO2, 2×15 cm, 10%
EtOAc–hexane) gave 4d as a solid (67 mg, 70%). mp
1
104–106°C; H NMR (200 MHz, CDCl3): l 8.58 (1H, s),
13. General procedure for Lewis acid-promoted TDDA reac-
tions. A mixture of 2 (100 mg, 0.5 mmol), 3f (20 mg, 0.25
mmol) and BF3·OEt2 (42 mg, 0.3 mmol) in anhydrous
DMSO was heated at 100°C under nitrogen for 3 h. The
cooled reaction mixture was diluted with ethyl acetate (50
mL), washed with 0.1 M NaOH (2×30 mL), water (30
mL), brine (15 mL), dried (MgSO4) and evaporated to
dryness. The residue was purified by flash chromatogra-
phy (SiO2, 2×15 cm, 30% EtOAc–hexane) to give 1-
phenylpyrazolo[3,4-d]pyrimidine (4f) as a yellow solid (31
8.21 (2H, m), 7.80 (2H, m), 7.42 (1H, m); MS calcd for
C13H6N4Cl2F4+H+: 366, found 366. Anal. calcd for
C13H6Cl2F4N4: C, 42.77; H, 1.66; N, 15.34. Found: C,
42.80; H, 1.51; N, 15.26%.
4,6-Bis(diethylphosphono)-1-phenylpyrazolo[3,4-d]pyrimi-
dine (4e). Flash chromatography (SiO2, 2×15 cm, 70%
1
EtOAc–hexane) gave 4e as a hard gel (13 mg, 10%); H
NMR (200 MHz, CDCl3): l 8.78 (1H, s), 8.25 (2H, m),
7.58 (2H, m), 7.40 (1H, m); MS calcd for C19H26N4O6P2+
Na+: 491, found 491. Anal. calcd for C19H26N4O6P2: C,
48.72; H, 5.60; N, 11.96. Found: C, 48.72; H, 5.24; N,
12.15%.
1
mg, 64%); H NMR (200 MHz, CDCl3): l 9.27 (1H, s),
9.13 (1H, s), 8.33 (1H, s), 8.26–7.33 (5H, m), 7.39 (1H,
m). Anal. calcd for C11H8N4: C, 67.34; H, 4.11; N, 28.55.
Found: C, 67.24; H, 4.14; N, 28.44%.
10. When the ethyl ester of 2 was subjected to the current
TDDA conditions (DMF–AcOH, 90°C, 15 h), as sug-