Efficient synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines by regioselective acylation

Article abstract of DOI:10.1016/S0040-4039(02)02456-5

An efficient two-step synthesis of 8-acylated pyrazolo[1,5-a]-1,3,5-triazines has been accomplished. The key strategic elements of this novel synthetic approach involve the use of the N-methyl-N-phenylamino activating group, which was easily obtained in high yield by treatment of the pyrazolotriazin-4-one with phosphorus oxychloride and dimethylaniline through high pressure reaction coupled with a regioselective acylation at position 8 followed by the subsequent displacement of the N-methyl-N-phenylamino group upon treatment with various amines.

Full text of DOI:10.1016/S0040-4039(02)02456-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 9501–9503
Efficient synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines
by regioselective acylation
Pierre Raboisson,a,* Dominique Schultz,a Claire Lugnierb and Jean-Jacques Bourguignona
aLaboratoire de Pharmacochimie de la Communication Cellulaire (CNRS, UMR 7081), Faculte´ de Pharmacie, 74 route du Rhin,
BP24, 67401 Illkirch Cedex, France
bLaboratoire de Pharmacologie et de Physico-Chimie des Interactions Cellulaires et Mole´culaires (CNRS, UMR 7034),
Faculte´ de Pharmacie, 74 route du Rhin, BP24, 67401 Illkirch Cedex, France
Received 25 October 2002; accepted 30 October 2002
Abstract—An efficient two-step synthesis of 8-acylated pyrazolo[1,5-a]-1,3,5-triazines has been accomplished. The key strategic
elements of this novel synthetic approach involve the use of the N-methyl-N-phenylamino activating group, which was easily
obtained in high yield by treatment of the pyrazolotriazin-4-one with phosphorus oxychloride and dimethylaniline through high
pressure reaction coupled with a regioselective acylation at position 8 followed by the subsequent displacement of the
N-methyl-N-phenylamino group upon treatment with various amines. © 2002 Elsevier Science Ltd. All rights reserved.
Adenine derivatives substituted in position 9 (1, Fig. 1)
were found in several biologically active molecules and
have potent phosphodiesterase inhibition properties
with high selectivity toward PDE4.1 In our continuing
search on the synthesis and pharmacological evaluation
of a variety of structurally related compounds, our
attention was focused on 8-substituted pyrazolo[1,5-a]-
1,3,5-triazines (2, Fig. 1)2a–c as bioisosteres of 1. Thus,
regioselective acylation represent one of the most direct
methods to introduce substitutions and functionaliza-
tions at position 8.
Although electrophilic substitutions at position 8 of
pyrazolotriazine (3) are well documented,2a–c attempts
to acylate this bicycle using acyl chlorides or anhy-
drides under Friedel–Crafts general conditions failed to
produce the desired products.2a Thus, the development
of a generally applicable methodology to introduce acyl
substituents in position 8 still represent a nice challenge
in heterocyclic chemistry and merited further
investigation.
In this communication, we report the first general
method for the synthesis of 8-acylated pyrazolo[1,5-a]-
1,3,5-triazine using Tin(IV) chloride without solvent.
The nature of the substituent at position 4 appeared to
be a crucial element in electrophilic substitution reac-
tions on pyrazolo[1,5-a]-1,3,5-triazine because it can
modify the electron density at position 8 and thus,
regulate the rates of reactions. In addition, the optimal
substituent would possess a sufficient stability under
acylating conditions to avoid side products formations.
Not surprisingly, attempts to acylate iminoether (3a)
and iminochloride (3b) under Friedel–Crafts general
conditions failed to undergo the desired adducts and
led to a mixture of unseparable products. Similar
results were obtained with the poorly soluble and 8-
deactivated pyrazolotriazinones 4 (Scheme 1). There-
fore, it was of great interest to develop a new activating
group which would corroborate the low stability under
acylating conditions of those previously reported.2
Figure 1.
Keywords: pyrazolo[1,5-a]-1,3,5-triazine; activating group; adenine;
acylation; amidine.
* Corresponding author. Present address: Department of Chemistry,
3-Dimensional Pharmaceuticals, Inc., 665 Stockton Drive, Exton,
PA 19341, USA. E-mail: pierreraboisson@aol.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02456-5

9502
P. Raboisson et al. / Tetrahedron Letters 43 (2002) 9501–9503
Scheme 1. Reagents and conditions: (a) POCl3, dimethylaniline, CHCl3, 120°C, sealed tube; (b) R8COCl, SnCl4, 60°C; (c)
R4R4%NH, EtOH, 100°C, sealed tube.
Table 1.
through high-pressure reaction.3 Indeed, this N-methyl-
N-phenylamino group is readily displaced by various
amines to afford the target compound.3 Moreover, their
high stability, makes the N-methyl-N-phenylamino
derivatives 5 suitable candidates for acylating reactions.
Thus, different experimental conditions using different
Lewis acids and solvents in the presence of benzoyl
chloride as a typical acid chloride were also investi-
gated. Attempts to drive the reaction in presence of
carbon disulfide, toluene, benzene or dichlorobenzene
in presence of aluminum- or Tin(IV)-chloride at differ-
ent temperatures were found inefficient, highlighted the
poor nucleophilicity at the C-8 position. However, to
our satisfaction, when the reaction was performed with-
out solvent, in the presence of benzoyl- and Tin(IV)-
chlorides, the target acylated compound 6a was
obtained in 85% isolated yield (Table 1).4 Moreover,
this reaction was generalized to other pyrazolotriazines
5 and other acylating agents. Results are summarized in
Table 1. Although the reaction of 5 with various aro-
matic acyl chlorides afforded the expected 8-substituted
derivatives 6 in acceptable yield (36–85%),4 these condi-
tions were not successfully generalized to the aliphatic
Compda
R2
R8
Yieldsb (%)
6a
6b
6c
6d
6e
6f
6g
6h
6i
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Ph
85
76
78
64
81
52
49
47
63
36
41
43
n-Pr
n-Bu
CH3OCH2
2-Furyl
MeS
Me
Me
Me
Me
Me
4-(MeO)Ph
3-(CF3)Ph
2-ClPh
EtO
6j
6k
6l
(Et)2N
a Conditions: PhCOCl, SnCl4, 60°C.
b Unoptimized yields represent the result of a single experiment.
Recently, we have found that the 4-(N-methyl-N-
phenylamino) group represents an optimized activating
group, which was easily obtained in high yield by
treatment of corresponding pyrazolotriazin-4-one 4
with phosphorus oxychloride and dimethylaniline
Table 2.
Compd
R2
R4
R4%
R8
Yieldsa (%)
7a
7b
7c
7d
Me
Me
Me
Me
H
H
H
Me
H
Ph
Ph
Ph
Ph
67
95
Me
Me
Bn
63
53
7e
Me
Ph
7f
Me
Ph
78
7d
7e
7f
7g
7h
7i
7j
7k
7l
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
68
87
55
74
56
75
40
61
79
69
86
n-Pr
n-Bu
CH3OCH2
2-Furyl
MeS
Me
Me
Me
Me
Me
4-(MeO)Ph
3-(CF3)Ph
2-ClPh
EtO
7m
7n
(Et)2N
a Unoptimized yields represent the result of a single experiment.

P. Raboisson et al. / Tetrahedron Letters 43 (2002) 9501–9503
9503
acyl chlorides or anhydrides. Interestingly, oxalyl
chloride permitted, after treatment at the end of the
reaction with ethanol or diethylamine, the access to
the 8-ethoxycarbonyl and diethylaminocarbonyl
derivatives (6k and 6l, respectively). Finally, the N-
methyl-N-phenylamino group was easily displaced
with various amines, leading to N4-substituted deriva-
tives 7.5 The final products are grouped in Table 2.
Novinson, T.; Miller, J. P.; Robins, R. K. J. Med.
Chem. 1982, 25, 243–249; (c) Zhang, H.-C.; Brakta, M.;
Davies, G. D., Jr. Nucleosides Nucleotides 1995, 14, 105–
116.
3. Raboisson, P.; Schultz, D.; Baurand, A.; Cazenave, J.-P.;
Gachet, C.; Spiess, B.; Bourguignon, J.-J. J. Org. Chem.
2002, 67, 8063–8071.
4. Typical procedure: 8-benzoyl-2-methyl-4-(N-methyl-N-
phenylamino)pyrazolo[1,5-a]-1,3,5-triazine 6a: To a solu-
tion of 2-methyl-4-(N-methyl-N-phenylamino) pyrazolo-
[1,5-a]-1,3,5-triazine 5a (227 mg, 1.0 mmol) in benzoyl
chloride (580 mL, 5.0 mmol) was slowly added Tin(IV)-
chloride (588 mL, 5 mmol) under an argon atmosphere.
The mixture was stirred at 60°C for 12 h, concentrated
under reduced pressure, then diluted with cold water (20
mL) and extracted three times with ethyl acetate (30
mL). Organic layers were subsequently dried (Na2SO4)
and concentrated to dryness under reduced pressure.
Chromatography on silica (AcOEt/hexane, 1:2) afforded
compounds 6a as a colorless solid (293 mg, 85%). 1H
NMR (200 MHz, CDCl3) l 2.68 (s, 3H, 2-CH3), 3.79 (s,
3H, NCH3), 7.20–7.60 (m, 8H, 8 ArH), 7.84–7.90 (m,
2H, 2 ArH), 8.05 (s, 1H, 7-H); 13C NMR (CDCl3, 50
MHz) l 26.6, 42.8, 108.8, 126.6, 127.9, 128.5, 129.6,
129.7, 132.3, 139.6, 144.8, 147.7, 149.6, 152.6, 167.3,
188.7. EIMS m/z 344 (M+H)+. Anal. calcd for
C20H17N5O: C, 69.96; H, 4.99; N, 20.39. Found: C,
70.01; H, 5.10; N, 20.52.
In summary, we have developed a rapid, practical
and regioselective acylation of pyrazolo[1,5-a]-1,3,5-
triazines as 9-substituted adenine bioisosteres. The
impetus for this work is the easy access to the 4-(N-
methyl-N-phenylamino) derivatives (5), obtained by
treatment of the corresponding pyrazolo[1,5-a]-1,3,5-
triazin-4-one (4) with phosphorus oxychloride and
dimethylaniline. Another main advantage of this
method is the regioselectivity of the acylation at posi-
tion 8 that eliminated the need for regioisomer sepa-
ration and thus, significantly enhances the
convenience and efficiency of this synthetic approach.
Finally, the displacement of the N-methyl-N-phenyl-
amino group at the end of the reaction represent a
concise and general method to introduce substitutions
and functionalities under position 4. However, this
methodology appeared to be limited to aromatic and
oxalyl chlorides. This novel series of compounds are
currently under biological evaluation for their phos-
phodiesterase inhibition properties.
5. A solution of 6a (300 mg, 0.87 mmol), methylamine (2
M, 2.0 mL, 4.0 mmol) in ethanol (10 mL) was stirring
at 80°C in a sealed tube for 6 h. After cooling the
solvent was evaporated under reduced pressure. The
crude reaction product was purified by column chro-
matography on silica gel (AcOEt/hexane, 1:1). Recrystal-
lization from ethanol and diethyl ether yielded
compound 7a (212 mg, 91%) as colorless crystals: mp:
198°C. 1H NMR (200 MHz, CDCl3) l 2.62 (s, 3H, 2-
CH3), 3.27 (d, J=3.34, 3H, NCH3), 6.64 (q, J=3.34,
1H, NH), 7.46–761 (m, 3H, 3 ArH), 7.90–7.93 (m, 2H, 2
ArH), 8.32 (s, 1H, 7-H). 13C NMR (CDCl3, 75 MHz) l
26.7, 27.9, 110.4, 128.6, 129.8, 132.6, 139.3, 148.4, 149.5,
149.6, 168.3, 188.7. EIMS m/z 268 (M+H)+. Anal. calcd
for C14H13N5O: C, 62.91; H, 4.90; N, 26.20. Found: C,
63.01; H, 5.07; N, 26.19.
Acknowledgements
Support from the Louis Pasteur University is grate-
fully acknowledged.
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