Synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazine derivatives by palladium-catalyzed cross-coupling reactions

Article abstract of DOI:10.1055/s-2006-958963

8-Substituted pyrazolo[1,5-a]-1,3,5-triazine derivatives 6 were prepared from the corresponding 8-iodopyrazolo[1,5-a]-1,3,5-triazines 5 through palladium-catalyzed cross-coupling reactions. Several bioisosteres of hypoxanthine drugs 2 were then prepared b

Full text of DOI:10.1055/s-2006-958963

PAPER
367
Synthesis of 8-Substituted Pyrazolo[1,5-a]-1,3,5-triazine Derivatives by
Palladium-Catalyzed Cross-Coupling Reactions
Synthesis of
8
l
o
tuted Pyrazo
r
a
]
e
-1,3,5-triaz
n
ines ce Popowycz,a Philippe Bernard,b Pierre Raboisson,b Benoît Joseph*a
a
Laboratoire de Chimie Organique 1, UMR-CNRS 5181, Université Claude Bernard – Lyon 1, CPE – Bâtiment 308,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France
Fax +33(4)72431214; E-mail: benoit.joseph@univ-lyon1.fr
Greenpharma SA, 3 Allée du Titane, 45100 Orléans, France
b
Received 5 September 2006; revised 26 October 2006
N
N
N
N
N
Abstract: 8-Substituted pyrazolo[1,5-a]-1,3,5-triazine derivatives
6 were prepared from the corresponding 8-iodopyrazolo[1,5-a]-
1,3,5-triazines 5 through palladium-catalyzed cross-coupling reac-
tions. Several bioisosteres of hypoxanthine drugs 2 were then pre-
pared by final nucleophilic aromatic substitution.
N
H
N
N
Purine
Pyrazolo[1,5-a]-1,3,5-triazine
O
O
N
N
N
HN
HN
N
Key words: purine, bioisosteres, pyrazolo[1,5-a]-1,3,5-triazine,
palladium
N
N
1
2
NH
R
NH
R
Pyrazolo[1,5-a]-1,3,5-triazines are purine ‘carba-bioiso-
steres’ exhibiting pharmaceutical properties such as phos-
phodiesterase inhibitors,1 corticotropin-releasing factor
antagonists,2 cyclooxygenase-2 (COX-2) inhibitors,3 cy-
clin-dependent kinase (CDK) inhibitors4 and DNA gyrase
inhibitors.5 Because of their wide range of biological
properties, pyrazolo[1,5-a]-1,3,5-triazines have attracted
considerable interest from the medicinal chemistry com-
munity over the past few years, and have prompted the de-
velopment of novel efficient procedures for the synthesis
of functionalized pyrazolo[1,5-a]-1,3,5-triazines.
O
O
R =
N
OH
YO2C
O
OH
1c, 2c
1a Y = K , 2a Y = Na
1b, 2b
Figure 1 Hypoxanthine derivatives 1 and bioisosteres 2
With the aim to overcome some liabilities [e.g. poor drug
metabolism and pharmacokinetic (DMPK) properties] of
the parent drugs 1, we synthesized and biologically eval-
uated novel 8-substituted pyrazolo[1,5-a]-1,3,5-triazin-
4(1H)-one derivatives 2, as ring equivalent bioisosteres of
hypoxanthine-containing drugs 1, which have been devel-
oped for the treatment of neurodegenerative diseases
(Figure 1).6
mentia. Finally, compound 1c (AIT-203) is a dopamine
agonist, which was under preclinical investigation for the
treatment of Parkinson’s disease.11
We report here an efficient synthetic access to 8-substitut-
ed pyrazolo[1,5-a]-1,3,5-triazines through a panel of pal-
ladium-catalyzed coupling reactions (i.e. Stille, Suzuki,
Heck and Sonogashira reactions) as depicted in retrosyn-
thetic Scheme 1. Palladium-mediated cross-coupling re-
actions with similar substrates have been already reported
in the literature.12,13 In our research project, N-methyl-
Indeed, compound 1a (AIT-082, Leteprinim potassium,
NeotrofinTM) causes the production of multiple nerve
growth neurotrophic factors, thus it stimulates neuritoge-
nesis, or the sprouting of nerve cells.7 In animal model,
AIT-082 has been used to treat injuries to the central ner-
vous system,8 and clinical safety and efficacy studies have
been performed on patients with Alzheimer’s disease.9
Recently, the therapeutic potential of Neotrofin has been
extended to the peripheral nervous system.10 Compound
1b (AIT-034) enhances memory and reverses memory
deficits in severely impaired animal models providing
complementary therapy for Alzheimer’s disease. This
compound may have applications in treating severe de-
Ph
N
Ph
N
N
N
N
N
O
N
N
N
N
N
R1
R1
R2
I
O
4
N
N
HN
N
HN
R1
N
8
R1
N
2
SYNTHESIS 2007, No. 3, pp 0367–0374
x
x
.
x
x
.2
0
0
7
R2
Advanced online publication: 21.12.2006
DOI: 10.1055/s-2006-958963; Art ID: T13506SS
Scheme 1 Retrosynthetic strategy
© Georg Thieme Verlag Stuttgart · New York

368
F. Popowycz et al.
PAPER
Ph
N
Ph
N
Ph
N
N
N
N
N
O
N
N
N
N
N
i
ii
iii
N
N
N
HN
N
N
R1
R1
R1
3 R1 = H, Pr, SMe
N
R1
R2
I
4
5
6
for R2 see Table 2
Scheme 2 Reagents and conditions: i. a) POCl3, DMAP, reflux, 2 h; b) N-methylaniline, Et3N, CH2Cl2, r.t., overnight; ii. NIS, CHCl3, reflux,
30 min; iii. Method A: tributyl(1-ethoxyvinyl)tin, Pd(PPh3)4, LiCl, DMF, 90 °C, 12 h. Method B: phenylboronic acid, Pd(PPh3)4, NaHCO3,
EtOH, toluene, reflux, 12 h. Method C: pent-1-yne, PdCl2(PPh3)2, CuI, Et3N, DMF, 40 °C, 12 h. Method D: tert-butyl acrylate, Pd(OAc)2, PPh3,
Et3N, DMF, 90 °C, 12 h; for yields see Tables 1 and 2.
aniline activating group was introduced on position C-4 in Table 2 Compounds 6a–l Prepared
order to increase the solubility of derivatives and allow
Method R1
6
Yield (%)
further introduction of nucleophiles (e.g., amines, thiols)
under mild conditions.13 As example, displacement of this
group by hydroxide anion was performed, opening up the
access to 2.
A
A
A
H
SMe
Pr
6a
6b
6c
96
84
93
Ph
N
N
N
N
N
N
The readily available pyrazolo[1,5-a]-1,3,5-triazin-
4(1H)-ones 314 were first treated with 4-dimethylamino-
pyridine in refluxing phosphorus oxychloride followed by
addition of N-methylaniline to afford N-methylaniline de-
rivatives 4 in good yields (Scheme 2, Table 1). As already
described in the literature for this series, the N-methyl-N-
phenylamino group in position C-4 is a good candidate for
nucleophilic addition-elimination displacement.13,15 Re-
gioselective iodination on position C-8 of 4 was carried
out in the presence of N-iodosuccinimide to give 8-iodo-
pyrazolo[1,5-a]-1,3,5-triazines 5 in 82–93% yields
(Scheme 2, Table 1).12c,13
R1
R1
R1
N
N
COMe
B
B
B
H
SMe
Pr
6d
6e
6f
85
70
89
Ph
N
N
N
N
Ph
C
C
C
H
SMe
Pr
6g
6h
6i
81
67
70
Ph
N
N
N
Table 1 Compounds 4 and 5 Prepared
R1
4
Yield (%)
5
Yield (%)
H
4a
4b
4c
87
88
92
5a
5b
5c
82
93
87
D
D
D
H
SMe
Pr
6j
6k
6l
87
68
78
Ph
N
SMe
Pr
N
N
N
N
R1
Substituents at position C-8 were introduced in good to
excellent yields (Scheme 2 and Table 2) by palladium-
catalyzed cross-coupling reactions (Stille reaction: com-
pounds 6a–c; Suzuki reaction: compounds 6d–f; Sono-
gashira reaction: compounds 6g–i and Heck reaction:
compounds 6j–l) allowing a large diversity of functional-
ization. Several catalytic palladium systems [Pd(PPh3)4,
PdCl2(PPh3)2 or Pd(OAc)2] were used to perform these re-
actions. As anticipated, the thiomethyl derivative 5b gave
the lowest yield of coupling product.
CO2t-Bu
peptide coupling conditions, methyl 4-aminobenzoate,
N-(3-aminopropyl)-2-pyrrolidinone or 2,2-diphenyl-1,3-
benzodioxole-5-propanamine16 were reacted with acid 8
to give the corresponding amides 9 in nearly quantitative
yield (Scheme 3, Table 3). The coupling reaction between
8 and dopamine afforded the corresponding amide in 40%
yield (not described in experimental part).
Moreover, the target pyrazolo[1,5-a]-1,3,5-triazin-4(1H)-
ones 2a–c were prepared in four to five steps from starting
material 6j as depicted in Scheme 3. Catalytic hydrogena-
tion of the exocyclic double bond of compound 6j in the
presence of 10% palladium on charcoal afforded com-
pound 7 in 95% yield. Subsequent hydrolysis of ester 7
was carried out in acidic medium (TFA, toluene) provid-
ing the key intermediate 8 in 87% yield. Using classical
To our satisfaction, the displacement of N-methyl-N-phe-
nyl group of 9 was achieved under mild conditions (5 N
aq NaOH at room temperature). Eventually, the target
compounds 2a, 2b and 10 were obtained in good yield as
reported in Table 4. The deprotection of the acetal group
of 10 was subsequently performed under acidic condi-
tions, to afford the final product 2c (Table 4).
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Substituted Pyrazolo[1,5-a]-1,3,5-triazines
369
Ph
O
Ph
N
Ph
N
N
N
N
N
N
N
N
HN
N
N
N
N
N
N
N
i
ii
iii
iv
6j
N
N
NHR
NHR
CO2t-Bu
CO2H
O
O
7
8
9
2, 10
for R see Tables 3 and 4
Scheme 3 Reagents and conditions: i. H2, 10% Pd/C, 10 bar, THF–EtOAc, r.t., 6 h, 95%; ii. TFA–toluene 1:1, r.t., 4 h, 87%; iii. EDCI, DMAP,
RNH2, CH2Cl2, Et3N, 0 °C to r.t., 24 h; iv. 5 N NaOH, EtOH, 60 °C, 5 h for 9a; r.t., 5 h for 9b; r.t., overnight for 9c; for yields see Tables 3 and 4.
Melting points were obtained with a Büchi capillary apparatus and
are uncorrected. IR spectra were recorded on a PerkinElmer 681 IR
Table 3 Compounds 9 Prepared
1
spectrophotometer. H and 13C NMR spectra were recorded on a
Amine
9
Yield (%)
95
Bruker Avance 300 MHz spectrometer. Chemical shifts are report-
ed in ppm (d) relative to tetramethylsilane (TMS) as an internal
standard. Mass spectra were recorded with a PerkinElmer SCIEX
API spectrometer. Elemental analyses were performed on a Ther-
moquest Flash 1112 series EA analyzer. TLC analyses were con-
ducted on silica gel Merck 60F254 coated on aluminum sheets. The
spots were visualized using an ultraviolet light. Flash chromatogra-
phy was carried out on silica gel 60 (40–63 mm, Merck) using the
indicated solvents [petroleum ether (PE): boiling range 40–60 °C].
All reactions requiring anhydrous conditions were conducted in
flame-dried apparatus. All commercially available reagents were
used without further purification.
9a
H2N
CO2Me
9b
9c
93
95
O
H2N
H2N
N
Ph
O
O
Ph
Compounds 4a–c; General Procedure
A solution of 3 (11.5 mmol), DMAP (40.1 mmol, 3.5 equiv) and
POCl3 (20 mL) was stirred at reflux for 2 h. After warming up the
solution to r.t., the excess of POCl3 was removed in vacuo. The oily
residue was dried in vacuum pump for 2 h and dissolved in CH2Cl2
(60 mL). N-Methylaniline (8 mL) and Et3N (10 mL) were added
dropwise under stirring at 0 °C under argon. After 10 min, the mix-
ture was allowed to warm up to r.t. and stirred overnight. The mix-
ture was washed with H2O (30 mL) and the organic layer was dried
(MgSO4) and concentrated in vacuo. After evaporation of the sol-
vent, the residue was purified by flash chromatography (eluent is in-
dicated below) to afford 4.
Table 4 Compounds 2 and 10 Prepared
R
2, 10
Yield (%)
2a
82
CO2Na
2b
10
66
O
N
87
Ph
O
O
4-(N-Methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazine
(4a)
Ph
Chromatography eluent: Et2O–PE (1:1); yield: 87%; solid; mp 141–
142 °C (purified by washing with cyclohexane).
2c
79a
OH
IR (KBr): 1605, 1555, 1460, 1415 cm–1.
OH
1H NMR (300 MHz, CDCl3): d = 3.84 (s, 3 H, CH3), 6.42 (d, J = 2.2
Hz, 1 H, H-8), 7.21 (d, J = 7.1 Hz, 2 H, ArH), 7.37–7.45 (m, 3 H,
ArH), 7.79 (d, J = 2.2 Hz, 1 H, H-7), 8.23 (s, 1 H, H-2).
a Reagents and conditions: 10, AcOH–H2O (8:2), reflux, 6 h
13C NMR (75 MHz, CDCl3): d = 42.3 (CH3), 95.6 (CH), 126.2 (2
CH), 127.4 (CH), 129.2 (2 CH), 144.7 (C), 144.8 (CH), 150.2 (C),
151.1 (C), 152.7 (CH).
In conclusion, we have disclosed a practical and efficient
synthesis of 8-substituted pyrazolo[1,5-a]-1,3,5-triazines
from readily available starting materials, which can be
used for parallel and large-scale applications. This reliable
and convenient method opens up the synthesis of numer-
MS (ESI): m/z = 226 (M + H)+.
Anal. Calcd for C12H11N5: C, 63.99; H, 4.92; N, 31.09. Found: C,
64.24; H, 5.17; N, 30.91.
ous
2,8-disubstituted
pyrazolo[1,5-a]-1,3,5-triazin-
4-(N-Methyl-N-phenylamino)-2-methylsulfanylpyrazolo[1,5-
a]-1,3,5-triazine (4b)
Chromatography eluent: Et2O–PE (1:1); yield: 88%; solid; mp 106–
108 °C (EtOAc–PE).
IR (KBr): 1605, 1550 cm–1.
4(1H)-one derivatives with potential CNS properties.17
The biological evaluation of these novel hypoxanthine
drug bioisosteres will be reported in due course.
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York

370
F. Popowycz et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 2.54 (s, 3 H, CH3), 3.73 (s, 3 H,
CH3), 6.16 (d, J = 2.1 Hz, 1 H, H-8), 7.18 (d, J = 7.1 Hz, 2 H, ArH),
7.31–7.42 (m, 3 H, ArH), 7.65 (d, J = 2.1 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.2 (CH3), 42.3 (CH3), 93.3 (CH),
126.2 (2 CH), 127.2 (CH), 129.1 (2 CH), 144.7 (C), 145.0 (CH),
148.3 (C), 151.5 (C), 166.8 (C).
MS (ESI): m/z = 398 (M + H)+.
Anal. Calcd for C13H12IN5S: C, 39.31; H, 3.04; N, 17.63. Found: C,
38.98; H, 2.86; N, 17.65.
8-Iodo-4-(N-methyl-N-phenylamino)-2-propylpyrazolo[1,5-a]-
1,3,5-triazine (5c)
Chromatography eluent: EtOAc–PE (2:8); yield: 87%; solid; mp
100–102 °C (MeOH).
IR (KBr): 1590, 1535, 1440 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (t, J = 7.3 Hz, 3 H, CH3),
1.81–1.93 (m, 2 H, CH2), 2.80 (t, J = 7.3 Hz, 2 H, CH2), 3.73 (s, 3
H, CH3), 7.13–7.17 (m, 2 H, ArH), 7.30–7.41 (m, 3 H, ArH), 7.67
(s, 1 H, H-7).
MS (ESI): m/z = 272 (M + H)+.
Anal. Calcd for C13H13N5S: C, 57.54; H, 4.83; N, 25.81. Found: C,
57.33; H, 4.72; N, 25.99.
4-(N-Methyl-N-phenylamino)-2-propylpyrazolo[1,5-a]-1,3,5-
triazine (4c)
Chromatography eluent: Et2O–PE (1:4); yield: 92%; oil.
IR (film): 1590, 1535, 1440, 1405 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 21.3 (CH2), 40.9
(CH2), 42.2 (CH3), 47.1 (C), 126.0 (2 CH), 127.1 (CH), 128.9 (2
CH), 144.5 (C), 148.4 (CH), 149.2 (C), 150.9 (C), 167.2 (C).
1H NMR (300 MHz, CDCl3): d = 1.07 (t, J = 7.4 Hz, 3 H, CH3),
1.92 (m, 2 H, CH2), 2.81 (t, J = 7.4 Hz, 2 H, CH2), 3.79 (s, 3 H,
CH3), 6.31 (d, J = 2.1 Hz, 1 H, H-8), 7.21 (d, J = 7.1 Hz, 2 H, ArH),
7.32–7.45 (m, 3 H, ArH), 7.74 (d, J = 2.1 Hz, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 21.4 (CH3), 40.9
(CH2), 42.1 (CH3), 94.3 (CH), 126.1 (2 CH), 126.9 (CH), 129.0 (2
CH), 144.8 (CH), 144.9 (C), 149.4 (C), 151.6 (C), 165.7 (C).
MS (ESI): m/z = 394 (M + H)+.
Anal. Calcd for C15H16IN5: C, 45.82; H, 4.10; N, 17.81. Found: C,
45.66; H, 3.99; N, 17.67.
Stille Reaction with Compounds 5; General Procedure (Method
A)
MS (ESI): m/z = 268 (M + H)+.
To a stirred mixture of 5 (0.33 mmol), freshly prepared Pd(PPh3)4
(30 mg, 0.03 mmol, 0.08 equiv) and LiCl (35 mg, 0.82 mmol, 2.5
equiv) in anhyd DMF (3 mL) was added tributyl(1-ethoxyvinyl)tin
(160 mL, 0.49 mmol, 1.5 equiv). The mixture was stirred at 90 °C
for 12 h and then the solvent was evaporated in vacuo. The crude
residue was purified by flash chromatography (eluent indicated be-
low) to give 6a–c.
Anal. Calcd for C15H17N5: C, 67.39; H, 6.41; N, 26.20. Found: C,
67.55; H, 6.31; N, 26.03.
Iodination of Compounds 4a–c; General Procedure
A solution of 4 (11.0 mmol) and NIS (3.46 g, 15.4 mmol, 1.4 equiv)
in anhyd CHCl3 (90 mL) was stirred at reflux for 30 min. The sol-
vent was evaporated in vacuo. The residue was dissolved in CH2Cl2
(100 mL) and washed with a sat. aq solution of Na2S2O3 (3 × 20
mL). The organic layer was dried (MgSO4) and concentrated in vac-
uo. The crude product was purified by flash chromatography (eluent
is indicated below) to afford derivatives 5.
8-Acetyl-4-(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-
triazine (6a)
Chromatography eluent: PE, then EtOAc–PE (1:9, then 2:8); yield:
96%; solid; mp 120–121 °C (MeOH).
IR (KBr): 1655, 1590, 1545 cm–1.
8-Iodo-4-(N-methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-tri-
azine (5a)
Chromatography eluent: EtOAc–PE (2:8); yield: 82%; solid; mp
191–192 °C (EtOH).
1H NMR (300 MHz, CDCl3): d = 2.69 (s, 3 H, CH3), 3.84 (s, 3 H,
CH3), 7.18–7.21 (m, 2 H, ArH), 7.38–7.43 (m, 3 H, ArH), 8.20 (s, 1
H, H-7), 8.38 (s, 1 H, H-2).
IR (KBr): 1590, 1555, 1445, 1405 cm–1.
13C NMR (75 MHz, CDCl3): d = 29.3 (CH3), 42.8 (CH3), 111.3 (C),
126.3 (2 CH), 128.0 (CH), 129.5 (2 CH), 144.3 (C), 145.8 (CH),
150.3 (C), 151.6 (C), 155.5 (CH), 192.3 (C=O).
1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3 H, CH3), 7.18–7.20 (m,
2 H, ArH), 7.34–7.44 (m, 3 H, ArH), 7.76 (s, 1 H, H-7), 8.31 (s, 1
H, H-2).
MS (ESI): m/z = 268 (M + H)+.
13C NMR (75 MHz, CDCl3): d = 42.6 (CH3), 48.8 (C), 126.2 (2
CH), 127.7 (CH), 129.2 (2 CH), 144.3 (C), 148.5 (CH), 150.0 (C),
150.6 (C), 153.9 (CH).
Anal. Calcd for C14H13N5O: C, 62.91; H, 4.90; N, 26.20. Found: C,
62.73; H, 4.87; N, 26.03.
8-Acetyl-4-(N-methyl-N-phenylamino)-2-methylsulfanylpyra-
zolo[1,5-a]-1,3,5-triazine (6b)
Chromatography eluent: PE, then CH2Cl2–PE–EtOAc (5:6:1);
yield: 84%; solid; mp 223–225 °C (MeOH).
MS (ESI): m/z = 352 (M + H)+.
Anal. Calcd for C12H10IN5: C, 41.05; H, 2.87; N, 19.94. Found: C,
40.85, H, 2.94; N; 20.07.
IR (KBr): 1670, 1560 cm–1.
8-Iodo-4-(N-methyl-N-phenylamino)-2-methylsulfanylpyrazo-
lo[1,5-a]-1,3,5-triazine (5b)
Chromatography eluent: Et2O–PE (1:9); yield: 93%: solid; mp 162–
163 °C (Et2O–PE).
1H NMR (300 MHz, CDCl3): d = 2.59 (s, 3 H, CH3), 2.70 (s, 3 H,
CH3), 3.75 (s, 3 H, CH3), 7.16–7.19 (m, 2 H, ArH), 7.38–7.45 (m, 3
H, ArH), 8.08 (s, 1 H, H-7).
IR (KBr): 1605, 1585 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.4 (CH3), 29.2 (CH3), 42.5
(CH3), 109.4 (C), 126.1 (2 CH), 127.6 (CH), 129.2 (2 CH), 144.1
(C), 145.4 (CH), 148.2 (C), 151.5 (C), 170.9 (C), 192.1 (C=O).
1H NMR (300 MHz, CDCl3): d = 2.59 (s, 3 H, CH3), 3.71 (s, 3 H,
CH3), 7.16 (br d, J = 7.1 Hz, 2 H, ArH), 7.36–7.39 (m, 3 H, ArH),
7.61 (s, 1 H, H-7).
MS (ESI): m/z = 314 (M + H)+.
13C NMR (75 MHz, CDCl3): d = 14.4 (CH3), 42.5 (CH3), 46.2 (C),
126.2 (2 CH), 127.5 (CH), 129.1 (2 CH), 144.4 (C), 148.1 (C),
148.6 (CH), 150.8 (C), 166.5 (C).
Anal. Calcd for C15H15N5OS: C, 57.49; H, 4.82; N, 22.35. Found:
C, 57.32; H, 4.73; N, 22.55.
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Substituted Pyrazolo[1,5-a]-1,3,5-triazines
371
8-Acetyl-4-(N-methyl-N-phenylamino)-2-propylpyrazolo[1,5-
a]-1,3,5-triazine (6c)
Anal. Calcd for C19H17N5S: C, 65.68; H, 4.93; N, 20.16. Found: C,
65.39; H, 5.00; N, 19.99.
Chromatography eluent: PE, then Et2O–PE (1:9), then EtOAc–PE
(1:9); yield: 93%; solid; mp 122–123 °C (MeOH).
IR (KBr): 1650, 1590, 1475 cm–1.
4-(N-Methyl-N-phenylamino)-8-phenyl-2-propylpyrazolo[1,5-
a]-1,3,5-triazine (6f)
Chromatography eluent: Et2O–PE (1:9); yield: 89%; solid; mp 100–
101 °C (MeOH).
IR (KBr): 1595, 1535, 1410 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.10 (t, J = 7.3 Hz, 3 H, CH3),
1.93–2.00 (m, 2 H, CH2), 2.87 (t, J = 7.3 Hz, 2 H, CH2), 3.77 (s, 3
H, CH3), 7.20–7.26 (m, 3 H, ArH), 7.35–7.45 (m, 5 H, ArH), 8.00
(d, J = 7.5 Hz, 2 H, ArH), 8.05 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 21.2 (CH2), 41.0
(CH2), 42.1 (CH3), 108.0 (C), 126.0 (CH), 126.1 (2 CH), 126.2 (2
CH), 126.9 (CH), 128.8 (2 CH), 129.0 (2 CH), 132.1 (C), 142.9
(CH), 145.0 (C), 147.8 (C), 149.5 (C), 166.0 (C).
1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.5 Hz, 3 H, CH3),
1.85–1.93 (m, 2 H, CH2), 2.71 (s, 3 H, CH3), 2.82 (t, J = 7.5 Hz, 2
H, CH2), 3.75 (s, 3 H, CH3), 7.16 (br d, J = 6.8 Hz, 2 H, ArH), 7.35–
7.42 (m, 3 H, ArH), 8.13 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 21.0 (CH2), 29.2
(CH3), 41.0 (CH2), 42.4 (CH3), 110.4 (C), 126.2 (2 CH), 127.5
(CH), 129.3 (2 CH), 144.5 (C), 145.7 (CH), 149.6 (C), 152.2 (C),
169.1 (C), 192.6 (C=O).
MS (ESI): m/z = 310 (M + H)+.
Anal. Calcd for C17H19N5O: C, 66.00; H, 6.19; N, 22.64. Found: C,
66.40; H, 6.27; N, 22.45.
MS (ESI): m/z = 344 (M + H)+.
Suzuki Reaction with Compounds 5; General Procedure (Meth-
od B)
Anal. Calcd for C21H21N5: C, 73.44; H, 6.16; N, 20.39. Found: C,
73.05; H, 6.18; N, 20.19.
To a stirred solution of 5 (0.19 mmol) in anhyd toluene (1.5 mL)
was added freshly prepared Pd(PPh3)4 (33 mg, 0.028 mmol, 0.15
equiv). The mixture was stirred for 30 min at r.t. Phenylboronic acid
(35 mg, 0.28 mmol, 1.5 equiv) diluted in EtOH (1 mL) was then
added, followed immediately by a sat. aq NaHCO3 solution (1 mL).
The heterogeneous solution was stirred at reflux for 12 h. The Pd
catalyst was removed by filtration. Brine (2 mL) was then added,
the layers were separated and the aqueous phase was extracted with
EtOAc (3 × 5 mL). The combined organic extracts were dried
(MgSO4) and evaporated in vacuo. The crude residue was purified
by flash chromatography (eluent indicated below) to afford the 8-
phenyl derivatives 6d–f.
Sonogashira Reaction with Compounds 5; General Procedure
(Method C)
To a stirred solution of 5 (0.27 mmol), PdCl2(PPh3)2 (28 mg, 0.04
mmol, 0.15 equiv) and CuI (7.7 mg, 0.04 mmol, 0.15 equiv) in an-
hyd DMF (2 mL) were added successively Et3N (160 mL, 1.13
mmol, 4.2 equiv) and pent-1-yne (132 mL, 1.35 mmol, 5 equiv). The
solution was stirred at 40 °C for 12 h. After cooling, the solvent was
evaporated in vacuo. The crude residue was purified by flash chro-
matography (eluent indicated below) to afford the 8-pentynyl deriv-
atives 6g–i.
4-(N-Methyl-N-phenylamino)-8-(pentyn-1-yl)pyrazolo[1,5-a]-
1,3,5-triazine (6g)
Chromatography eluent: EtOAc–PE (1:2); yield: 81%; solid; mp
>250 °C (MeOH).
4-(N-Methyl-N-phenylamino)-8-phenylpyrazolo[1,5-a]-1,3,5-
triazine (6d)
Chromatography eluent: Et2O–PE (1:9); yield: 85%; solid; mp 147–
148 °C (MeOH).
IR (KBr): 1615, 1565, 1485 cm–1.
IR (KBr): 1595, 1540, 1490 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (t, J = 7.3 Hz, 3 H, CH3),
1.59–1.66 (m, 2 H, CH2), 2.43 (t, J = 7.1 Hz, 2 H, CH2), 3.80 (s, 3
H, CH3), 7.16–7.19 (m, 2 H, ArH), 7.35–7.43 (m, 3 H, ArH), 7.78
(s, 1 H, H-7), 8.26 (s, 1 H, H-2).
1H NMR (300 MHz, CDCl3): d = 3.84 (s, 3 H, CH3), 7.22–7.28 (m,
3 H, ArH), 7.38–7.46 (m, 5 H, ArH), 7.94 (d, J = 7.2 Hz, 2 H, ArH),
8.11 (s, 1 H, H-7), 8.34 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 42.5 (CH3), 109.5 (C), 126.2 (2
CH), 126.5 (2 CH), 127.4 (CH), 128.9 (2 CH), 129.3 (2 CH), 129.6
(CH), 131.6 (C), 143.0 (CH), 144.7 (C), 147.1 (C), 150.3 (C), 152.9
(CH).
13C NMR (75 MHz, CDCl3): d = 13.7 (CH3), 21.8 (CH2), 22.3
(CH2), 42.5 (CH3), 69.3 (C), 93.6 (C), 94.4 (C), 126.1 (2 CH), 127.5
(CH), 129.2 (2 CH), 144.4 (C), 146.5 (CH), 150.1 (C), 151.4 (C),
153.4 (C).
MS (ESI): m/z = 302 (M + H)+.
MS (ESI): m/z = 292 (M + H)+.
Anal. Calcd for C18H15N5: C, 71.74; H, 5.02; N, 23.24. Found: C,
71.69; H, 4.90; N, 22.94.
Anal. Calcd for C17H17N5: C, 70.08; H, 5.88; N, 24.04. Found: C,
69.99; H, 5.98; N, 23.93.
4-(N-Methyl-N-phenylamino)-2-methylsulfanyl-8-phenylpyra-
zolo[1,5-a]-1,3,5-triazine (6e)
Chromatography eluent: Et2O–PE (1:9), yield: 70%; solid; mp 128–
4-(N-Methyl-N-phenylamino)-2-methylsulfanyl-8-(pentyn-1-
yl)pyrazolo[1,5-a]-1,3,5-triazine (6h)
Chromatography eluent: Et2O–PE (1:9); yield: 67%; solid; mp 104–
129 °C (MeOH).
105 °C (MeOH).
IR (KBr): 1610, 1530, 1455 cm–1.
IR (KBr): 1610, 1535, 1505 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.64 (s, 3 H, CH3), 3.73 (s, 3 H,
CH3), 7.18–7.21 (m, 3 H, ArH), 7.34–7.43 (m, 5 H, ArH), 7.95 (d,
J = 7.5 Hz, 2 H, ArH), 7.98 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.5 (CH3), 42.3 (CH3), 107.2 (C),
126.0 (2 CH), 126.1 (CH), 126.2 (2 CH), 127.3 (CH), 128.8 (2 CH),
129.2 (2 CH), 131.9 (C), 143.1 (CH), 144.8 (C), 147.4 (C), 148.4
(C), 167.2 (C).
1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H, CH3),
1.59–1.66 (m, 2 H, CH2), 2.41 (t, J = 7.1 Hz, 2 H, CH2), 2.57 (s, 3
H, CH3), 3.70 (s, 3 H, CH3), 7.13–7.16 (m, 2 H, ArH), 7.34–7.38 (m,
3 H, ArH), 7.64 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 13.6 (CH3), 14.3 (CH3), 21.9
(CH2), 22.3 (CH2), 42.3 (CH3), 69.9 (C), 91.2 (C), 93.7 (C), 126.1
(2 CH), 127.3 (CH), 129.1 (2 CH), 144.5 (C), 146.8 (CH), 148.2
(C), 151.7 (C), 168.0 (C).
MS (ESI): m/z = 348 (M + H)+.
MS (ESI): m/z = 338 (M + H)+.
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York

372
F. Popowycz et al.
PAPER
Anal. Calcd for C18H19N5S: C, 64.07; H, 5.68; N, 20.75. Found: C,
63.88; H, 5.65; N, 20.60.
MS (ESI): m/z = 398 (M + H)+.
Anal. Calcd for C20H23N5O2S: C, 60.43; H, 5.83; N, 17.62. Found:
C, 60.65; H, 5.91; N, 17.49.
4-(N-Methyl-N-phenylamino)-8-(pentyn-1-yl)-2-propylpyrazo-
lo[1,5-a]-1,3,5-triazine (6i)
Chromatography eluent: EtOAc–PE (2:8); yield: 70%; solid; mp
92–93 °C (MeOH).
IR (KBr): 1605, 1540, 1480, 1405 cm–1.
tert-Butyl 3-[4-(N-Methyl-N-phenylamino)-2-propylpyrazo-
lo[1,5-a]-1,3,5-triazin-8-yl]prop-2-enoate (6l)
Chromatography eluent: Et2O–PE (1:4); yield: 78%; solid, mp 149–
150 °C (MeOH).
1H NMR (300 MHz, CDCl3): d = 1.01 (t, J = 7.3 Hz, 3 H, CH3),
1.02 (t, J = 7.3 Hz, 3 H, CH3), 1.57–1.69 (m, 2 H, CH2), 1.80–1.93
(m, 2 H, CH2), 2.42 (t, J = 7.1 Hz, 2 H, CH2), 2.79 (dd, J = 7.1 Hz,
2 H, CH2), 3.72 (s, 3 H, CH3), 7.12–7.15 (m, 2 H, ArH), 7.31–7.39
(m, 3 H, ArH), 7.70 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 13.7 (CH3), 14.1 (CH3), 21.4
(CH2), 22.0 (CH2), 22.3 (CH2), 40.9 (CH3), 42.1 (CH3), 69.9 (C),
92.1 (C), 93.8 (C), 126.1 (2 CH), 127.1 (CH), 129.0 (2 CH), 144.6
(C), 146.8 (CH), 149.3 (C), 151.7 (C), 166.8 (C).
IR (KBr): 1695, 1635, 1550, 1415 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.04 (t, J = 7.3 Hz, 3 H, CH3),
1.52 (s, 9 H, 3 CH3), 1.82–1.93 (m, 2 H, CH2), 2.80 (t, J = 7.3 Hz, 2
H, CH2), 3.73 (s, 3 H, CH3), 6.52 (d, J = 15.8 Hz, 1 H, CH=), 7.15–
7.20 (m, 2 H, ArH), 7.34–7.42 (m, 3 H, ArH), 7.67 (d, J = 15.9 Hz,
1 H, CH=), 7.80 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 21.2 (CH2), 28.4 (3
CH3), 41.0 (CH2), 42.2 (CH3), 80.0 (C), 104.9 (C), 117.9 (CH),
126.2 (2 CH), 127.3 (CH), 129.1 (2 CH), 132.7 (CH), 144.5 (CH),
144.7 (C), 149.3 (C), 150.0 (C), 167.2 (C), 167.7 (C=O).
MS (ESI): m/z = 334 (M + H)+.
Anal. Calcd for C20H23N5: C, 72.04; H, 6.95; N, 21.00. Found: C,
71.88; H, 7.06; N, 20.75.
MS (ESI): m/z = 394 (M + H)+.
Anal. Calcd for C22H27N5O2: C, 67.15; H, 6.92; N, 17.80. Found: C,
66.80; H, 6.81; N, 17.60.
Heck Reaction with Compounds 5; General Procedure (Method
D)
tert-Butyl 3-[4-(N-Methyl-N-phenylamino)pyrazolo[1,5-a]-
1,3,5-triazin-8-yl]propanoate (7)
To a solution of 5 (0.26 mmol), PPh3 (8.2 mg, 0.031 mmol, 0.12
equiv) and Pd(OAc)2 (4.7 mg, 0.021 mmol, 0.08 equiv) in anhyd
DMF (2 mL), were added successively Et3N (62 mL, 0.44 mmol, 1.7
equiv) and tert-butyl acrylate (190 mL, 1.30 mmol, 5 equiv). The re-
sulting mixture was stirred at 90 °C for 12 h. After cooling, the sol-
vent was evaporated in vacuo. The crude residue was purified by
flash chromatography (eluent indicated below) to afford alkenes 6j–
l.
A suspension of 6j (1.50 g, 4.27 mmol) and 10% Pd/C (500 mg) in
THF–EtOAc (30 mL, 1:1) was stirred in a stainless steel reactor un-
der 10 bar of H2 for 6 h at r.t. The catalyst was removed by filtration
over Celite and the filtrate was concentrated in vacuo. The crude
solid was recrystallized from EtOH to give 7 (1.43 g, 95%); solid;
mp 84–85 °C (EtOH).
IR (KBr): 1695, 1635, 1555, 1485 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 9 H, CH3), 2.57 (t, J = 7.5
Hz, 2 H, CH2), 2.97 (t, J = 7.5 Hz, 2 H, CH2), 3.81 (s, 3 H, CH3),
7.17–7.20 (m, 2 H, ArH), 7.32–7.43 (m, 3 H, ArH), 7.68 (s, 1 H, H-
7), 8.19 (s, 1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 18.4 (CH2), 28.2 (3 CH3), 35.9
(CH2), 42.3 (CH3), 80.3 (C), 107.9 (C), 126.1 (2 CH), 127.3 (CH),
129.2 (2 CH), 144.7 (C), 144.8 (CH), 147.9 (C), 150.1 (C), 151.6
(CH), 172.2 (C=O).
tert-Butyl 3-[4-(N-Methyl-N-phenylamino)pyrazolo[1,5-a]-
1,3,5-triazin-8-yl]prop-2-enoate (6j)
Chromatography eluent: Et2O–PE (3:5); yield: 87%; solid; mp 152–
153 °C (EtOAc–PE).
IR (KBr): 1700, 1635, 1595, 1555, 1485 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (s, 9 H, 3 CH3), 3.81 (s, 3 H,
CH3), 6.55 (d, J = 15.9 Hz, 1 H, CH=), 7.19–7.22 (m, 2 H, ArH),
7.38–7.45 (m, 3 H, ArH), 7.66 (d, J = 15.9 Hz, 1 H, CH=), 7.88 (s,
1 H, H-7), 8.31 (s, 1 H, H-2).
MS (ESI): m/z = 354 (M + H)+.
13C NMR (75 MHz, CDCl3): d = 28.3 (3 CH3), 42.6 (CH3), 80.1 (C),
106.0 (C), 118.9 (CH), 126.3 (2 CH), 127.7 (CH), 129.3 (2 CH),
132.0 (CH), 144.4 (CH + C), 149.3 (C), 150.0 (C), 154.0 (CH),
166.9 (C=O).
Anal. Calcd for C19H23N5O2: C, 64.57; H, 6.56; N, 19.82. Found: C,
64.92; H, 6.68; N, 20.00.
3-[4-(N-Methyl-N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazin-
8-yl]propionic Acid (8)
MS (ESI): m/z = 352 (M + H)+.
A solution of 7 (1.00 g, 2.83 mmol) in TFA–anhyd toluene (22 mL,
1:10) was stirred for 4 h at r.t. The solvent was evaporated in vacuo.
The crude residue was purified by flash chromatography (EtOAc)
to give 8 (732 mg, 87%); solid; mp 161–163 °C (MeOH).
1H NMR (300 MHz, DMSO-d6): d = 2.56 (t, J = 7.5 Hz, 2 H, CH2),
2.81 (t, J = 7.5 Hz, 2 H, CH2), 3.72 (s, 3 H, CH3), 7.27–7.41 (m, 5
H, ArH), 7.82 (s, 1 H, H-7), 8.16 (s, 1 H, H-2), 12.13 (s, 1 H, OH).
Anal. Calcd for C19H21N5O2: C, 64.94; H, 6.02; N, 19.93. Found: C,
65.23; H, 5.98; N, 20.12.
tert-Butyl 3-[4-(N-Methyl-N-phenylamino)-2-methylsulfanyl-
pyrazolo[1,5-a]-1,3,5-triazin-8-yl]prop-2-enoate (6k)
Chromatography eluent: Et2O–PE (1:9, then 1:4); yield: 68%; solid;
mp 192–193 °C (MeOH).
13C NMR (75 MHz, DMSO-d6): d = 17.9 (CH2), 33.9 (CH2), 41.9
(CH3), 107.1 (C), 126.2 (2 CH), 126.8 (CH), 128.8 (2 CH), 144.3
(CH), 144.7 (C), 147.5 (C), 149.5 (C), 151.4 (CH), 173.8 (C=O).
IR (KBr): 1695, 1625, 1595 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (s, 9 H, 3 CH3), 2.59 (s, 3 H,
CH3), 3.71 (s, 3 H, CH3), 6.48 (d, J = 16.0 Hz, 1 H, CH=), 7.15–7.19
(m, 2 H, ArH), 7.34–7.42 (m, 3 H, ArH), 7.63 (d, J = 16.0 Hz, 1 H,
CH=), 7.74 (s, 1 H, H-7).
13C NMR (75 MHz, CDCl3): d = 14.4 (CH3), 28.4 (3 CH3), 42.4
(CH3), 80.0 (C), 104.1 (C), 117.7 (CH), 126.3 (2 CH), 127.6 (CH),
129.2 (2 CH), 132.6 (CH), 144.4 (C), 144.5 (CH), 148.1 (C), 149.6
(C), 167.2 (C), 169.2 (C=O).
MS (ESI): m/z = 298 (M + H)+.
Anal. Calcd for C15H15N5O2: C, 60.60; H, 5.09; N, 23.55. Found: C,
60.45; H, 4.93; N, 23.56.
Coupling Reaction of 8, General Procedure
To a solution of the appropriate amine (11 mmol, 1.1 equiv,
Table 3) in anhyd CH2Cl2 (100 mL), were successively added at
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York

PAPER
Synthesis of 8-Substituted Pyrazolo[1,5-a]-1,3,5-triazines
373
0 °C, a catalytic amount of DMAP, 8 (2.87 g, 10 mmol) and EDCI
(2.10 g, 11 mmol, 1.1 equiv). The mixture was stirred for 24 h at r.t.
and the solvent was evaporated. The residue was taken up in EtOAc
(50 mL) and 10% HCl (20 mL), and stirred for 10 min. The two
phases were separated, the aqueous phase was extracted with
EtOAc (2 × 20 mL) and the combined organic layers were succes-
sively washed with 1 M NaOH (25 mL) and brine (25 mL). After
drying (MgSO4), the organic phase was evaporated in vacuo. The
crude residue was purified by flash chromatography (eluent indicat-
ed below) to give 9.
13C NMR (75 MHz, CDCl3): d = 18.8 (CH2), 35.4 (CH2), 36.6
(CH2), 40.8 (CH2), 42.2 (CH3), 107.6 (C), 108.3 (CH), 109.0 (CH),
116.6 (C), 121.5 (CH), 126.1 (2 CH), 126.2 (4 CH), 127.2 (CH),
128.2 (4 CH), 129.0 (2 CH), 129.1 (2 CH), 132.7 (C), 140.3 (2 C),
144.5 (C), 144.9 (CH), 145.7 (C), 147.3 (C), 147.8 (C), 149.9 (C),
151.5 (CH), 172.0 (C=O).
MS (ESI): m/z = 597 (M + H)+.
Anal. Calcd for C36H32N6O3: C, 72.47; H, 5.41; N, 14.08. Found: C,
72.40; H, 5.33; N, 13.97.
Sodium 4-{[3-(1,4-Dihydro-4-oxopyrazolo[1,5-a]-1,3,5-triazin-
8-yl)-1-oxopropyl]amino}benzoate (2a)
To a solution of 9a (120 mg, 0.28 mmol) in EtOH (10 mL) was add-
ed a 5 N aq solution of NaOH (0.28 mL) at 0 °C. The mixture was
stirred at 60 °C for 5 h. After cooling, the precipitate obtained was
filtered and washed with cold EtOH to afford 2a (80 mg, 82%); sol-
id; mp >210 °C (MeOH).
N¢-(4-Ethoxycarbonylphenyl)-3¢-[4-(N-methyl-N-phenylami-
no)pyrazolo[1,5-a]-1,3,5-triazin-8-yl]propionamide (9a)
Amine used: methyl 4-aminobenzoate; chromatography eluent:
PE–EtOAc (1:1); yield: 95%; solid; mp 184–186 °C (MeOH).
IR (KBr): 3310, 1715, 1665, 1615, 1530, 1480 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.81 (t, J = 7.0 Hz, 2 H, CH2),
3.12 (t, J = 7.0 Hz, 2 H, CH2), 3.84 (s, 3 H, CH3), 3.89 (s, 3 H, CH3),
7.17–7.21 (m, 2 H, ArH), 7.37–7.45 (m, 3 H, ArH), 7.61 (d, J = 8.7
Hz, 2 H, ArH), 7.71 (s, 1 H, H-7), 7.97 (d, J = 8.7 Hz, 2 H, ArH),
8.22 (s, 1 H, H-2), 8.40 (s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 19.1 (CH2), 37.7 (CH2), 42.5
(CH3), 52.1 (CH3), 107.3 (C), 118.8 (2 CH), 125.3 (C), 126.3 (2
CH), 127.6 (CH), 129.3 (2 CH), 130.8 (2 CH), 142.5 (C), 144.5 (C),
145.2 (CH), 147.6 (C), 150.1 (C), 151.7 (CH), 166.8 (C=O), 171.1
(C=O).
IR (KBr): 3460, 1670, 1605, 1530, 1470 cm–1.
NMR (300 MHz, D2O): d = 2.70 (t, J = 7.0 Hz, 2 H, CH2), 3.01 (t,
J = 7.0 Hz, 2 H, CH2), 7.31 (d, J = 8.5 Hz, 2 H, ArH), 7.79 (d,
J = 8.5 Hz, 2 H, ArH), 7.84 (s, 1 H, H-7), 7.88 (s, 1 H, H-2).
13C NMR (75 MHz, D2O): d = 19.4 (CH2), 37.9 (CH2), 107.3 (C),
121.3 (2 CH), 130.4 (2 CH), 133.3 (C), 139.9 (C), 144.5 (CH),
148.3 (C), 155.0 (C), 156.0 (CH), 175.1 (C=O), 175.6 (C=O).
MS (ESI): m/z = 328 (M + H)+.
HRMS (LSIMS): m/z (M + H)+ calcd for C15H14N5O4: 328.1046;
MS (ESI): m/z = 431 (M + H)+.
found: 328.1044.
Anal. Calcd for C23H22N6O3: C, 64.17; H, 5.15; N, 19.52. Found: C,
64.33; H, 5.09; N, 19.44.
N-[3-(2-Oxo-1-pyrrolidinyl)propyl]-4-{[1-oxo-3-(4-oxopyrazo-
lo[1,5-a]-1,3,5-triazin-8-yl)propyl]amino}propionamide (2b)
To a solution of 9b (120 mg, 0.28 mmol) in EtOH (10 mL) was add-
ed a 5 N aq solution of NaOH (0.28 mL) at 0 °C. The mixture was
stirred for 5 h at r.t. The solvent was evaporated in vacuo and the
residue was partitioned between CH2Cl2 (10 mL) and 10% HCl (un-
til pH 7–8). The two phases were separated and the aqueous phase
was extracted with CH2Cl2 (2 × 5 mL). The combined organic lay-
ers were dried (MgSO4) and evaporated in vacuo. The crude residue
was purified by flash chromatography (eluent: CH2Cl2–MeOH,
85:15) to afford 2b (62 mg, 66%); solid; mp 180–181 °C (MeOH).
N¢-[3-(2-Oxopyrrolidin-1-yl)propyl]-4-({1-oxo-3-[4-(N-methyl-
N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazin-8-yl]propyl}ami-
no)propionamide (9b)
Amine used: N-(3-aminopropyl)-2-pyrrolidinone; chromatography
eluent: CH2Cl2–MeOH (98:2); yield: 93%; oil.
IR (film): 3310, 1670, 1615, 1545, 1480 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.58–1.67 (m, 2 H, CH2), 1.97–
2.07 (m, 2 H, CH2), 2.38 (t, J = 7.9 Hz, 2 H,CH2), 2.54 (t, J = 7.9
Hz, 2 H, CH2), 3.01 (t, J = 7.5 Hz, 2 H, CH2), 3.15 (br q, J = 6.3 Hz,
2 H, CH2), 3.26 (t, J = 6.3 Hz, 2 H, CH2), 3.36 (t, J = 7.1 Hz, 2 H,
CH2), 3.79 (s, 3 H, CH3), 6.73 (br t, J = 6.3 Hz, 1 H, NH), 7.16–7.19
(m, 2 H, ArH), 7.30–7.41 (m, 3 H, ArH), 7.67 (s, 1 H, H-7), 8.16 (s,
1 H, H-2).
13C NMR (75 MHz, CDCl3): d = 17.7 (CH2), 18.8 (CH2), 26.4
(CH2), 30.7 (CH2), 35.6 (CH2), 36.7 (CH2), 39.4 (CH2), 42.1 (CH3),
47.1 (CH2), 107.7 (C), 126.0 (2 CH), 127.0 (CH), 128.9 (2 CH),
144.5 (C), 144.6 (CH), 147.7 (C), 149.9 (C), 151.4 (CH), 172.1
(C=O), 175.5 (C=O).
IR (KBr): 3265, 1760, 1725, 1655, 1620, 1560, 1460 cm–1.
1H NMR (300 MHz, DMSO-d6 + D2O): d = 1.44–1.53 (m, 2 H,
CH2), 1.82–1.92 (m, 2 H, CH2), 2.20 (t, J = 8.0 Hz, 2 H, CH2), 2.38
(t, J = 7.4 Hz, 2 H, CH2), 2.77 (t, J = 7.4 Hz, 2 H, CH2), 2.95 (t,
J = 7.1 Hz, 2 H, CH2), 3.04 (t, J = 7.1 Hz, 2 H, CH2), 3.26 (t, J = 7.1
Hz, 2 H, CH2), 7.88 (s, 1 H, H-7), 7.89 (s, 1 H, H-2).
13C NMR (75 MHz, DMSO-d6): d = 17.5 (CH2), 18.5 (CH2), 26.9
(CH2), 30.4 (CH2), 35.7 (CH2), 36.2 (CH2), 39.5 (CH2), 46.3 (CH2),
111.3 (C), 145.1 (C), 145.9 (2 CH), 171.1 (2 C=O), 173.8 (C=O).
MS (ESI): m/z = 422 (M + H)+.
MS (ESI): m/z = 333 (M + H)+.
HRMS (LSIMS): m/z (M + H)+ calcd for C15H21N6O3: 333.1675;
Anal. Calcd for C22H27N7O2: C, 62.69; H, 6.46; N, 23.26. Found: C,
62.90; H, 6.58; N, 23.35.
found: 333.1676.
N-[2-(2,2-Diphenyl-1,3-benzodioxol-5-yl)ethyl]-3-[4-(N-methyl-
N-phenylamino)pyrazolo[1,5-a]-1,3,5-triazin-8-yl]propion-
amide (9c)
Amine used: 2,2-diphenyl-1,3-benzodioxole-5-propanamine; chro-
matography eluent: PE–EtOAc (8:2); yield: 95%; oil.
1H NMR (300 MHz, CDCl3): d = 2.49 (t, J = 7.4 Hz, 2 H, CH2),
2.63 (t, J = 6.9 Hz, 2 H, CH2), 2.99 (t, J = 7.3 Hz, 2 H, CH2), 3.40
(br q, J = 6.8 Hz, 2 H, CH2), 3.80 (s, 3 H, CH3), 6.53 (dd, J = 1.5,
7.9 Hz, 1 H, ArH), 6.66 (d, J = 1.5 Hz, 1 H, ArH), 6.76 (d, J = 7.9
Hz, 1 H, ArH), 7.16–7.19 (m, 2 H, ArH), 7.34–7.42 (m, 9 H, ArH),
7.55–7.58 (m, 4 H, ArH), 7.67 (s, 1 H, H-7), 8.14 (s, 1 H, H-2).
N-[2-(2,2-Diphenyl-1,3-benzodioxol-5-yl)ethyl]-3-(4-oxopyra-
zolo[1,5-a]-1,3,5-triazin-8-yl)propionamide (10)
To a solution of 9c (175 mg, 0.29 mmol) in EtOH (10 mL) was add-
ed a 5 N aq solution of NaOH (0.29 mL) at 0 °C. The mixture was
stirred overnight at r.t. The residue was partitioned between CH2Cl2
(10 mL) and 10% HCl (until pH 7–8). The two phases were separat-
ed and the aqueous phase was extracted with CH2Cl2 (2 × 5 mL).
The combined organic layers were dried (MgSO4) and evaporated
in vacuo. The solid obtained was taken up in Et2O and filtered to af-
ford 10 (130 mg, 87%); solid; mp 142–143 °C (purified by washing
with Et2O).
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York

374
F. Popowycz et al.
PAPER
1H NMR (300 MHz, CD3OD + D2O): d = 2.44 (t, J = 7.3 Hz, 2 H,
CH2), 2.63 (t, J = 6.9 Hz, 2 H, CH2), 2.89 (t, J = 7.3 Hz, 2 H, CH2),
3.31 (t, J = 6.9 Hz, 2 H, CH2), 6.58 (dd, J = 1.3, 7.9 Hz, 1 H, ArH),
6.72 (d, J = 1.3 Hz, 1 H, ArH), 6.76 (d, J = 7.9 Hz, 1 H, ArH), 7.33–
7.37 (m, 6 H, ArH), 7.50–7.53 (m, 4 H, ArH), 7.80 (s, 1 H, H-7),
7.90 (s, 1 H, H-2).
Shelton, S.; Christ, D.; Trainor, G.; Hartig, P. J. Med. Chem.
2000, 43, 449.
(3) Almansa, C.; de Arriba, A. F.; Cavalcanti, F. L.; Gómez, L.
A.; Miralles, A.; Merlos, M.; García-Rafanell, J.; Forn, J. J.
Med. Chem. 2001, 44, 350.
(4) (a) Prevost, G.; Lonchampt, M.-O.; Kim, S.; Morgan, B.;
Ulibarri, G.; Thurieau, C. PCT Int. Appl. WO 2002050079,
Chem. Abstr. 2002, 137, 47234. (b) Guzi, T. J.; Paruch, K.
US Patent US 2005187219, Chem. Abstr. 2005, 143,
248417.
MS (ESI): m/z = 508 (M + H)+.
Anal. Calcd for C29H25N5O4: C, 68.63; H, 4.96; N, 13.80. Found: C,
68.45; H, 5.05; N, 13.90.
(5) Lübbers, T.; Angehrn, P.; Gmünder, H.; Herzig, S.;
Kulhanek, J. Bioorg. Med. Chem. Lett. 2000, 10, 821.
(6) Subramanyam, C.; Ault, B.; Sawutz, D.; Bacon, E. R.;
Singh, B.; Pennock, P. O.; Kelly, M. D.; Kraynak, M.;
Krafte, D.; Treasurywala, A. J. Med. Chem. 1995, 38, 587.
(7) Glasky, A. J.; Glasky, M. S.; Ritzmann, R. F.; Rathbone, M.
P. Exp. Opin. Invest. Drugs 1997, 6, 1413.
(8) Rathbone, M. P.; Middlemiss, P. J.; Crocker, C. E.; Glasky,
M. S.; Juurlink, B. H. J.; Ramirez, J. J.; Cicarelli, R.; Di Ioro,
P.; Caciagli, F. Exp. Opin. Invest. Drugs 1999, 8, 1255.
(9) Grundman, M.; Caparelli, E.; Kim, H. T.; Morris, J. C.;
Farlow, M.; Rubin, E. H.; Heidebrink, J.; Hake, A.; Ho, G.;
Schultz, A. N.; Schafer, K.; Houston, W.; Thomas, R.; Thal,
L. J. Life Sci. 2003, 73, 539.
(10) Holmes, M.; Maysinger, D.; Foerster, D.; Pertens, E.; Barlas,
C.; Diamond, J. Mol. Cell. Neurosci. 2003, 24, 568.
(11) Glasky, A. J. PCT Int. Appl. WO 9957119, Chem. Abstr.
1999, 131, 322486.
(12) (a) Zhang, H.-C.; Brakta, M.; Daves, G. D. Jr. Tetrahedron
Lett. 1993, 34, 1571. (b) Zhang, H.-C.; Daves, G. D. Jr.
Organometallics 1993, 12, 1499. (c) Zhang, H.-C.; Brakta,
M.; Daves, G. D. Jr. Nucleosides Nucleotides 1995, 14, 105.
(13) Raboisson, P.; Baurand, A.; Cazenave, J.-P.; Gachet, C.;
Schultz, D.; Spiess, B.; Bourguignon, J.-J. J. Org. Chem.
2002, 67, 8063.
N-[2-(3,4-Dihydroxyphenyl)ethyl]3-(4-oxopyrazolo[1,5-a]-
1,3,5-triazin-8-yl)propionamide (2c)
Compound 10 (130 mg, 0.26 mmol) was placed in a mixture of
AcOH–H2O (10 mL, 4:1). The mixture was heated at reflux for 6 h.
Then, EtOAc (15 mL) and a sat aq NaHCO3 solution (until pH 7–8)
were added. The organic phase was separated and washed with a sat
aq NaHCO3 solution (10 mL). The combined organic extracts were
dried (MgSO4) and evaporated in vacuo. The solid obtained was
taken up in Et2O (2 × 10 mL) and filtered to afford 2c (70 mg, 79%);
solid; mp 236–238 °C (purified by washing Et2O).
IR (KBr): 3400–2500, 3282, 1770, 1620 cm–1.
1H NMR (300 MHz, CD3OD + D2O): d = 2.50 (t, J = 7.4 Hz, 2 H,
CH2), 2.57 (t, J = 7.4 Hz, 2 H, CH2), 2.93 (t, J = 7.4 Hz, 2 H, CH2),
3.30 (t, J = 7.4 Hz, 2 H, CH2), 6.45 (dd, J = 1.7, 7.9 Hz, 1 H, ArH),
6.60 (d, J = 1.7 Hz, 1 H, ArH), 6.65 (d, J = 7.9 Hz, 1 H, ArH), 7.85
(s, 1 H, H-7), 7.91 (s, 1 H, H-2).
13C NMR (75 MHz, CD3OD): d = 19.9 (CH2), 35.7 (CH2), 37.3
(CH2), 42.1 (CH2), 112.2 (C), 116.4 (CH), 116.9 (CH), 121.1 (CH),
132.1 (C), 144.5 (C), 146.0 (C), 146.4 (CH), 147.5 (C), 148.0 (CH),
175.1 (2 C=O).
MS (ESI): m/z = 342 (M – H)–.
HRMS (LSIMS): m/z (M – H)– calcd for C16H16N5O4: 342.1202;
found: 342.1208.
(14) (a) Kobe, J.; Robins, R. K.; O’Brien, D. E. J. Heterocycl.
Chem. 1974, 199. (b) Tam, S. Y.-K.; Klein, R. S.; Wempen,
I.; Fox, J. J. J. Org. Chem. 1979, 44, 4547. (c) Vogel, A.;
Troxler, F. Helv. Chim. Acta 1975, 58, 761.
References
(15) (a) Raboisson, P.; Schultz, D.; Lugnier, C.; Bourguignon,
J.-J. Tetrahedron Lett. 2002, 43, 9501. (b) Raboisson, P.;
Schultz, D.; Lugnier, C.; Mathieu, R.; Bourguignon, J.-J.
Tetrahedron Lett. 2003, 44, 703.
(16) Liu, Y.; Li, K. Macromol. Rapid Commun. 2002, 23, 739.
(17) Bernard, P.; Raboisson, P.; Joseph, B. PCT Int. Appl. WO
2004011464, Chem. Abstr. 2004, 140, 146171.
(1) Senga, K.; O’Brien, D. E.; Scholten, M. B.; Novinson, T.;
Miller, J. P.; Robins, R. K. J. Med. Chem. 1982, 25, 243.
(2) (a) Gilligan, P. J.; Folmer, B. K.; Hartz, R. A.; Koch, S.;
Nanda, K. K.; Andreuski, S.; Fitzgerald, L.; Miller, K.;
Marshall, W. J. Bioorg. Med. Chem. 2003, 11, 4093.
(b) He, L.; Gilligan, P. J.; Zaczek, R.; Fitzgerald, L. W.;
McElroy, J.; Shen, H.-S. L.; Saye, J. A.; Kalin, N. H.;
Synthesis 2007, No. 3, 367–374 © Thieme Stuttgart · New York