A novel synthesis of substituted 4H-pyrazolo[3,4-d]pyrimidin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2007.04.043

A novel synthesis of 4H-pyrazolo-[3,4-d]pyrimidin-4-ones is described. This approach utilizes an in situ generated iminochloride as a key precursor for amidine formation, with subsequent base-catalyzed ring closure. This method represents a mild and effic

Full text of DOI:10.1016/j.tetlet.2007.04.043

Tetrahedron Letters 48 (2007) 3983–3986
A novel synthesis of substituted 4H-pyrazolo[3,4-d]pyrimidin-4-ones
Nicholas D. Adams,* Stanley J. Schmidt, Steven D. Knight and Dashyant Dhanak
GlaxoSmithKline, Department of Medicinal Chemistry, Microbial, Musculoskeletal, and Proliferative Diseases Centre
for Excellence in Drug Discovery, 1250 South Collegeville Road, PO Box 5089, Collegeville, PA 19426-0989, United States
Received 11 January 2007; revised 6 April 2007; accepted 10 April 2007
Available online 19 April 2007
Abstract—A novel synthesis of 4H-pyrazolo-[3,4-d]pyrimidin-4-ones is described. This approach utilizes an in situ generated imino-
chloride as a key precursor for amidine formation, with subsequent base-catalyzed ring closure. This method represents a mild and
efficient entry into this ring system which is amenable to diversification of the core template.
Ó 2007 Elsevier Ltd. All rights reserved.
Several reports have demonstrated the utility of 4H-pyr-
azolo-[3,4-d]pyrimidin-4-ones as inhibitor templates of
various biological targets.1 Along those lines, we have
become interested in the design and synthesis of such
scaffolds, seeking an approach that would allow diversi-
fication of the pyrimidinone three-position in the pres-
ence of a 2-aminomethyl moiety was of particular
interest. We found several literature accounts detailing
the synthesis of these or related 6,5-fused heterocycles
with the desired substitution pattern.1–4 Our initial
approach was envisaged to proceed through an oxazi-
none intermediate (3), generated from 5-(acetylamino)-
carboxylate precursor 2 (Fig. 1).2 Subsequent opening
of the oxazinone with an amine,3 and base induced cycli-
zation4 was predicted to furnish the desired pyrazolo-
pyrimidinone ring system 5.
R2
R2
CO2Et
O
CO2Et
NH2
N
N
R3
N
N
N
H
R1
R1
NPG
1
2
O
O
N
3
R2
R2
CONHR4
O
N
N
R3
R3
N
N
N
H
R1
NPG
R1
NPG
4
O
R2
3
N
R4
N
R3
NH2
N
2
N
R1
5
Our synthetic efforts commenced with acylation of com-
mercially available ethyl 5-amino-1-methyl-1H-pyra-
zole-4-carboxylate (6) by racemic N-phthalyl valine
acid chloride 75 under thermal conditions (Scheme 1).
Several solvents (CH2Cl2, 1,2-dichloroethane, DMF,
PhH, toluene) and bases (TEA, i-Pr2NEt, pyridine,
1,5-diazabicyclo[4.3.0]non-5-ene) were employed ini-
tially, however portionwise addition of acid chloride 7
(1.0 equiv) to amine 6 (1.0 equiv) in refluxing toluene
in the presence of i-Pr2NEt (2.0 equiv) was found to
be optimal, providing amide 8 in high yield. We sur-
Figure 1.
mized that these somewhat forcing acylation conditions
were required due to the 5-amino group being a viny-
logous amide with the potential to internally hydrogen
bond to the ethyl ester. At this stage, intramolecular
cyclization of ester–amide 8 to the oxazinone was
investigated. Accordingly, treatment of amide 8 with
hexachloroethane and triphenylphosphine in refluxing
1,2-dichloroethane in the presence of i-Pr2NEt furnished
crude oxazinone 9 as a white solid after concentration of
the reaction mixture.2 Opening of the oxazinone ring
was then attempted in order to provide the requisite
pyrimidinone precursor. Unfortunately, treatment of
oxazinone 9 with benzylamine under thermal conditions
*
Corresponding author. Tel.: +1 610 917 6018; fax: +1 610 917
4171; e-mail: Nicholas.D.Adams@gsk.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.043

3984
N. D. Adams et al. / Tetrahedron Letters 48 (2007) 3983–3986
Table 1.
O
O
CO2Et
Et
CO2Et
Cl
NHEt
N
CO2Et
NH2
O
N
N
7
NPhth
-Pr2NEt, toluene
reflux, 1 h (89%)
N
N
N
N
N
N
N
N
N
H
i
NPhth
NPhth
13
14
NPhth
6
8
Entry
Basea
Solvent (T, °C)
Time (h)
Yield (%)
O
1
2
3
4
5
No base
NaOMe
NaOH
K2CO3
K2CO3
Toluene (110)
MeOH (60)
Aq MeOH (65)
DMF (60)
24
16
24
1
0
0
0
Cl3CCCl3, PPh3
O
N
ClCH2CH2Cl,
80 ˚C, 26 h
(74%)
i-Pr2NEt,
N
N
Trace
65b
NPhth
9
DMF (100)
3
a 1.2 equiv of base employed except entry 3 (0.05 equiv).
b Isolated yield after silica gel chromatography.
CONHR
O
BnNH
2
N
N
CHCl , reflux
N
H
3
NPhth
10
ture. Encouragingly, the chloride displacement took
place at room temperature to provide amidine 13 in
71% yield after silica gel chromatography.8
Scheme 1.
With amidine 13 in hand, intramolecular cyclization to
form the pyrimidinone ring was explored. Thermal cycli-
zation in refluxing toluene resulted in recovered starting
material, while base-mediated cyclization with sodium
methoxide or aqueous sodium hydroxide in methanol
resulted in the formation of the corresponding methyl
ester and carboxylic acid, respectively, with no cyclized
product (Table 1).9 Although reasons for the resistance
of amidine 13 to cyclize utilizing sodium methoxide or
sodium hydroxide remain unclear, we ultimately found
that treatment with 1.2 equiv of potassium carbonate
in DMF at 100 °C resulted in clean conversion to pyri-
midinone 14 in good yield.10 It should be noted that
high temperature was required for a reasonable reaction
time (3 h).
led to an intractable mixture of products, and was
thought to be a result of incompatibility of the nucleo-
phile with the phthalimide group. Use of a tert-butoxy-
carbonyl (Boc) or a benzyloxycarbonyl (Cbz) as an
alternative protecting group was not pursued since
N-(oxycarbonyl)amino acid chlorides have the propen-
sity to undergo facile intramolecular cyclization to the
corresponding Leuch anhydrides.6 Furthermore, even
if opening the oxazinone with amines proved feasible,
the typical strongly basic conditions (excess NaOH, eth-
ylene glycol, reflux) required for the dehydrative cycliza-
tion may have also proved incompatible with the
phthalimide group.4,7 For these reasons, an alternate
approach was pursued.
During the course of these investigations, we observed
that treatment of amide 8 with hexachloroethane and
triphenylphosphine in dichloromethane at room temper-
ature, instead of refluxing dichloroethane (83 °C),
resulted in clean conversion to iminochloride intermedi-
ate 12, with no detectable amounts of oxazinone 9 by
LCMS and 1H NMR (Scheme 2), indicating that higher
temperature was required for oxazinone formation in
this system. We reasoned that in situ displacement of
the iminochloride with amines should provide an inter-
mediate amidine which could undergo facile cyclization
to the desired pyrimidinone ring system. In order to test
this hypothesis, iminochloride 12, generated in situ from
amide 8, was treated with ethylamine at room tempera-
To test further the scope of this sequence, as well as to
investigate diversification of the pyrimidinone three-
position, reaction of iminochloride 12 with other amines
was examined (Table 2). Accordingly, the reaction to
prepare the amidine intermediates appears to be fairly
general with comparable yields across different types
of amines, including aliphatic, propargylic and benz-
ylic. Cyclization of the resultant amidines with potas-
sium carbonate in DMF provided the desired
pyrazolopyrimidinones in yields ranging from 63% to
72%.
In summary, a synthesis of 4H-pyrazolo-[3,4-d]pyrimi-
din-4-ones has been developed. This novel approach to
the core template utilizes an in situ generated iminochlo-
ride as a key intermediate for amidine formation, with
subsequent base-catalyzed ring closure. The method
provides a mild and efficient entry into these ring sys-
tems, which is amenable to diversification of the pyri-
midinone three-position. Furthermore, elimination of a
later stage sequence to incorporate the 2-aminomethyl
functionality represents an advantage over the previ-
ously reported methods.4 Although not described here-
in, this method can be applied to the preparation of
related heterofused systems, such as oxazolo- and thiaz-
olopyrimidinones, and these findings will be reported in
due course.
CO2Et
O
CO2Et
Cl
Cl3CCCl3, PPh3
CH2Cl2, -Pr2NEt,
RT, 4 h; then EtNH2 (11)
(71%)
N
N
i
N
N
H
N
N
NPhth
NPhth
12
8
CO2Et
NHEt
N
N
N
NPhth
13
Scheme 2.

N. D. Adams et al. / Tetrahedron Letters 48 (2007) 3983–3986
3985
Table 2.
O
CO2Et
O
CO2Et
K CO
R
NHR
2
3
scheme 2
N
N
N
N
N
DMF, 100 ˚C
N
N
H
N
N
N
NPhth
NPhth
NPhth
A
B
8
Amine
Amidinea,b (A)
Yield,c % (A)
Pyrimidinoneb (B)
Yield, % (B)
O
Me
Me
CO2Et
NHEt
N
N
H2N
71
65
63
72
N
N
N
N
11
N
NPhth
13
NPhth
14
O
CO2Et
HN
N
N
79
84
N
N
N
N
H2N
N
N
N
N
N
N
15
NPhth
NPhth
16
NPhth
Ph
17
O
CO2Et
Ph
NHBn
H2N
N
N
18
19
NPhth
20
a Reaction conditions detailed in Scheme 2 were employed.
b All compounds were characterized by 1H NMR, LCMS and provided satisfactory elemental analyses.
c Isolated yield after silica gel chromatography.
phosphine (789 mg, 3.01 mmol), and hexachloroethane
(712 mg, 3.01 mmol), successively at rt. After stirring for
4 h under nitrogen, TLC indicated complete consumption
of the starting material. Ethylamine (1.9 mL of a 2.0 M
solution in THF, 3.77 mmol) was then added dropwise
over ꢀ3 min. After 2 h, an additional portion of ethyl-
amine (0.63 mL of a 2.0 M solution in THF, 1.26 mmol)
and N,N-diisopropylethyl amine (0.22 mL, 1.26 mmol)
was added. After stirring overnight under nitrogen, the
reaction mixture was quenched with saturated aqueous
NaHCO3 (10 mL). The organic layer was washed with
brine (10 mL) and the combined aqueous layers were
extracted with CH2Cl2 (20 mL). The extracts were dried
over Na2SO4 and decolorizing carbon, filtered through a
pad of celite, and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (3:2
hexanes/EtOAc) to give 763 mg (71%) of ethyl 5-{[(1Z)-2-
(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(ethylamino)-
3-methylbutylidene]amino}-1-methyl-1H-pyrazole-4-car-
boxylate (13) as a pale yellow solid. Rf 0.32 (1:1 EtOAc/
hexane); 1H NMR (400 MHz, CDCl3) displayed a com-
plex mixture of broadened peaks, presumably due to
rotamers; LCMS m/z 426.4 (M+1). Anal. Calcd for
C22H27N5O4: C, 62.10; H, 6.40; N, 16.46. Found: C,
61.97; H, 6.12; N, 16.39.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.04.043.
References and notes
1. For selected examples, see: (a) Ali, A.; Taylor, G. E.;
Ellsworth, K.; Harris, G.; Painter, R.; Silver, L. L.;
Young, K. J. Med. Chem. 2003, 46, 1824–1830; (b) Taylor,
E. C.; Patel, H. H. Tetrahedron 1992, 48, 8089–
8100.
2. Preparation of similar imidazooxazinones has been
reported: Wamhoff, H.; Berressem, R.; Hermann, S.
Synthesis 1993, 107–111.
3. Deck, L. M.; Turner, S. D.; Deck, J. A.; Papadopoulos, E.
P. J. Heterocyclic Chem. 2001, 343–347.
4. Fraley, M. E.; Hartman, G. D.; Hoffman, W. F. WO
03049572, 2003.
5. Acid chloride 7 was prepared in two steps from commer-
cially available DL-valine as previously reported: Camps,
P.; Perez, F.; Soldevilla, N.; Borrego, M. A. Tetrahedron:
Asymmetry 1999, 10, 493–510.
6. Konopinska, D.; Siemion, I. Z. Angew. Chem., Int. Ed.
Engl. 1967, 6, 288.
7. Greene, T. W.; Wutz, P. G. M. Protective Groups in
Organic Synthesis; John Wiley & Sons: New York, 1999.
8. General procedure for the synthesis of amidines: Ethyl 5-
{[(1Z)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(eth-
ylamino)-3-methylbutylidene]amino}-1-methyl-1H-pyra-
zole-4-carboxylate (13). To a solution of 5-[2-(1,3-dioxo-
1,3-dihydro-isoindol-2-yl)-3-methyl-butanoylamino]-1-
methyl-1H-pyrazole-4-carboxylic acid ethyl ester (8)
(1.0 g, 2.51 mmol) in CH2Cl2 (17 mL) was added N,N-
diisopropylethyl amine (0.52 mL, 3.01 mmol), triphenyl-
9. Pech, R.; Boehm, R. Pharmazie 1989, 44, 790–791.
10. General procedure for the synthesis of pyrazolopyrimidi-
nones: 2-[1-(5-Ethyl-1-methyl-4-oxo-4,5-dihydro-1H-pyr-
azolo[3,4-d]pyrimidin-6-yl)-2-methylpropyl]-1H-isoindole-
1,3(2H)-dione (14). To a solution of ethyl 5-{[(1Z)-2-
(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(ethylamino)-
3-methylbutylidene]amino}-1-methyl-1H-pyrazole-4-car-
boxylate (13) (0.50 g, 1.18 mmol) in DMF (6 mL) was
added anhydrous K2CO3 (326 mg, 2.36 mmol). The resul-
tant suspension was heated to 100 °C and stirred under
nitrogen. After 3 h, the reaction mixture was allowed to
cool to rt, then quenched by slow addition of water
(25 mL). The resultant suspension was cooled to 0 °C and

3986
N. D. Adams et al. / Tetrahedron Letters 48 (2007) 3983–3986
1
stirred vigorously for 15 min. The precipitated product
EtOAc/hexane); H NMR (400 MHz, DMSO-d6): d 8.07
(s, 1H), 7.91–7.86 (m, 4H), 5.14 (d, J = 10.0 Hz, 1H), 4.11
(m, 1H), 3.96 (m, 1H), 3.91 (s, 3H), 3.33 (m, 1H), 1.08 (t,
J = 6.8 Hz, 3H), 1.04 (d, J = 6.4 Hz, 3H), 0.92 (d,
J = 6.8 Hz, 3H); LCMS m/z 380.2 (M+1). Anal. Calcd
for C20H21N5O3: C, 63.31; H, 5.58; N, 18.46. Found: C,
63.13; H, 5.46; N, 18.43.
was collected by vacuum filtration and rinsed with small
portions of cold water. Drying of the precipitate to
constant weight under high vacuum, provided 291 mg
(65%) of 2-[1-(5-ethyl-1-methyl-4-oxo-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-6-yl)-2-methylpropyl]-1H-iso-
indole-1,3(2H)-dione (14) as a white powder. Rf 0.42 (1:1