Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2007.11.054

General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.

Full text of DOI:10.1016/j.tetlet.2007.11.054

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 305–310
Microwave-assisted protocols for the expedited synthesis
of pyrazolo[1,5-a] and [3,4-d]pyrimidines
R. Nathan Daniels, Kwangho Kim, Evan P. Lebois, Hubert Muchalski,
Mary Hughes and Craig W. Lindsley*
Department of Chemistry and Pharmacology, Vanderbilt University, Vanderbilt Medical Center, Vanderbilt Program in
Drug Discovery, Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
Received 16 October 2007; revised 6 November 2007; accepted 8 November 2007
Available online 17 November 2007
Abstract—General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyr-
azolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strat-
egy for lead optimization.
Ó 2007 Elsevier Ltd. All rights reserved.
In the course of our program in drug discovery, several
high-throughput screens have identified pyrazolo[1,5-
a]pyrimidines 1 and pyrazolo[3,4-d]pyrimidines 2 as lead
compounds for both cancer and neuroscience programs
(Fig. 1). While numerous reports describe the syntheses
of 1 and 2, though the latter is primarily in the patent
literature, yields are typically moderate (<50%) with
prolonged reaction times at high temperatures (steps
requiring >48 h at reflux).1–4 To employ an iterative
analogue library synthesis approach for lead optimiza-
tion, significant refinements were required in the syn-
thetic protocols for 1 and 2.
employing microwave-assisted organic synthesis
(MAOS).5 In recent reports, we have described general,
high-yielding MAOS protocols for the expedient synthe-
sis of 1,2,4-triazines 3,6 imidazoles 4,7 quinoxalines 5,8
pyrazinone 6,9 5-amniooxazoles 7,10 and quinoxalinones
85 from simple starting materials (Fig. 2). Therefore, the
application of MAOS to develop a general, high-yield-
ing and expedient synthesis of pyrazolo[1,5-a]pyr-
imidines 1 and pyrazolo[3,4-d]pyrimidines 2 seem
warranted.
Classical conditions for the synthesis of pyrazolo[1,5-a]-
pyrimidines
pyrazole
1
involve refluxing
a 5-amino-4-aryl-
As many of the leads identified from HTS campaigns are
small heterocyclic compounds, our laboratory has
devoted significant effort to develop efficient protocols
for the preparation of diverse heterocyclic templates
9
with commercially available 2-
a
arylmalondialdehyde 12 in ethanol with catalytic acetic
acid for 24 h to deliver pyrazolo[1,5-a]pyrimidines 1 in
H
R1
R2
R1
R2
N
N
N
N
R1
R2
N
N
NR1R2
4
R3
R3
6
1
N
H
R3
Ar2
N
N
N
N
1
Ar
6
N
3
Ar1
3
4
5
N
N
CO2R1
NR2R3
R1
R2
N
R3
O
N
R1
O
1
2
N
R2
Figure 1. Generic structures of pyrazolo[1,5-a]pyrimidine
pyrazolo[3,4-b]pyrimidine 2 screening leads.
1 and
R4
N
H
N
H
O
6
7
8
*
Corresponding author. Tel.: +1 615 322 8700; fax: +1 615 343
6532; e-mail: craig.lindsley@vanderbilt.edu
Figure 2. Heterocyclic templates accessed through MAOS.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.054

306
R. N. Daniels et al. / Tetrahedron Letters 49 (2008) 305–310
NMe2
CN
MeO
MeO
H
H
N2H4
N
H2N
DMF/DMA
tol, reflux
N
N
Ar1
CN
Ar1
N
O
EtOH, reflux
55-75%
N
16
OH
9
10
N
5% AcOH/EtOH
N
μw irradiation
17
15
H
150 oC, 10 min, 85%
170 oC, 10 min, >98%
Ar2
O
H
N
Ar2
H2N
OH
N
N
12
Scheme 3. MAOS synthesis of pyrazolo[1,5-a]pyrimidine 1.
N
cat. AcOH, EtOH
reflux
Ar1
N
Ar1
EtOH at 150 °C for 10 min afforded pyrazolo[1,5-
a]pyrimidine 17, one of our HTS leads, in 85% isolated
yield (Scheme 3). Product 17 precipitated from solution
upon the end-of-run rapid cooling to 40 °C in the micro-
wave synthesizer, providing analytically pure material
by filtration. Further optimization of time and tempera-
ture identified 10 min microwave irradiation at 170 °C
as the optimal reaction conditions to deliver 17 in
>98% yield on either a 50 mg or 1 g reaction scale.11
Thus, a 3-step reaction sequence that required >72 h
and provided 40–60% yield has been optimized to
require only 30 min total reaction time with overall
yields in excess of 80%.
40-60%
11
1
Scheme 1. Classical synthesis of pyrazolo[1,5-a]pyrimidines 1.
40–60% yield.1,2 The starting 5-amino-4-arylpyrazoles
11 were prepared in two steps from the corresponding
acetonitriles 9 by refluxing in DMF/DMA (dimethyl-
formamide–dimethlyacetal) to afford 10, followed by
treatment with hydrazine in refluxing ethanol to afford
11 in 55–75% yield. The overall sequence required three
overnight (72 h) reflux reactions1,2 (Scheme 1).
Our attention first focused on improving the synthesis of
the requisite starting 5-amino-4-arylpyrazoles 11, as few
of these analogs are commercially available, and those
that can be purchased are expensive (ꢀ$100/g). To
improve the synthesis, we employed MAOS. In the
event, nitrile 13 was heated at 160 °C in DMF/DMA
to afford complete conversion to 14 in 10 min, as judged
by analytical LCMS. To the same microwave vial was
added hydrazine via syringe and the vial heated again
under microwave irradiation to 140 °C for 10 min to
deliver the desired 5-amino-4-pyridylpyrazole 15 in
85% isolated yield (Scheme 2). This represents a
significant improvement over the conventional thermal
protocol that required 48 h of reaction time and
55–75% yield.1,2 In a similar fashion, the 5-amino-4-
phenylpyrazole was also prepared (88%).
As shown in Table 1, the MAOS conditions proved to
be general for the reacting malondialdehyde providing
Table 1. Representative pyrazolo[1,5-a]pyrimidines 1
H
H
Ar2
N
H2N
N
Ar2
12
N
N
O
N
Ar1
OH
Ar1
5% AcOH/EtOH
mw irradiation
170 oC, 10 min
11
1
Entry
Ar1
Ar2
Yielda (%)
99
MeO
N
1a
Once 15 was in hand, conventional thermal conditions
were quickly adapted and optimized on a single-mode
microwave synthesizer. In the event, exposing amino-
pyrazole 15 and malondialdehyde 16 in 5% AcOH/
MeO
MeO
Cl
1b
1c
1d
1e
1f
82
94
95
89
84
N
NMe2
DMF/DMA
PhCF3
CN
CN
microwave
150 ºC,10 min
N
N
N
13
14
H
N
N
H2N
N
N2H4
microwave
N
N
N
140 ºC,10 min
N
85%
15
a Isolated yields for analytically pure material after neutralization and
filtration. All give >90% conversion by analytical LCMS.
Scheme 2. MAOS synthesis of 5-amino-4-pyridylpyrazole 15.

R. N. Daniels et al. / Tetrahedron Letters 49 (2008) 305–310
307
C-6 functionalized pyrazolo[1,5-a]pyrimidines 1 in excel-
lent isolated yields by simple filtration to afford the
acetate salts. Neutral products could be obtained by
neutralization of the crude reaction with concentrated
NH4OH and filtration.7 Pyridine heterocycles (entries
1a, 1b, 1d and 1f) were tolerated in the pyrazole compo-
nent 11, as were unsubstituted phenyl congeners (entries
1c and 1e). A 5-amino-4-bromopyrazole derivative 11
(where Ar1 = Br) afforded the desired product 1, but
in low yield and was found to rapidly decompose upon
standing. This was unfortunate as the bromo analogue
offered opportunities for further analogue libraries
through MAOS–Suzuki couplings. With respect to the
malonoaldehyde component 12, both aryl and hetero-
aryl congeners provided uniformly good results. Thus,
our new MAOS protocol (10 min, 170 °C) afforded the
desired products 1 in >80% yield.
diverse collection of functionalized alkyl chlorides
delivered analogues 19 in only 20 min in 70–90% yield
(as compared to 24 h at reflux and 30–60% yield). With
this protocol, we quickly prepared several 24-member
libraries of analogues 19, for which biological data will
be disclosed soon.
Classical conditions for the synthesis of pyrazolo[3,4-d]-
pyrimidines 2 involve the treatment of an aryl hydrazine
21 with ethoxymethylenemalonitrile 20 in refluxing
ethanol for 2–6 h to provide 4-cyano-5-aminopyrazole
22 in 50–70% yields (Scheme 5).3,4 Hydrolysis of the
nitrile with aqueous H2SO4 delivers the corresponding
carboxamide 23 which is then heated at reflux for 48 h
in neat formamide to provide the 1-aryl pyrazolo[3,4-d]-
pyrimidin-4-ol 24 in 40–65% yield. Conversion to the
chloride with POCl3 and subsequent SNAr with an
amine provides pyrazolo[3,4-d]pyrimidine 2 in two oper-
ations without isolation of the chloride.3,4
For the initial screening lead 17, we also hoped to opti-
mize a protocol to elaborate the methyl ether moiety
with diverse alkyl chain lengths and functional groups
as demonstrated in the literature for KDR kinase inhib-
itors.1,2 Once again, we employed MAOS protocols for
both the deprotection and the alkylation steps (Scheme
4). Lead 17 was deprotected in the microwave in
10 min at 180 °C to afford quantitative yield of phenol
18, similar in yield to conventional heating, but with
accelerated reaction time.2 Alkylation of 18 with a
Similar to our work with optimizing the synthesis of 1,
our attention now focused on optimizing the synthesis
of the requisite 4-cyano-5-aminopyrazoles 22 employing
MAOS. After varying time and temperature, optimal
conditions employed a 1:1 ratio of 20:21 under micro-
wave irradiation at 105 °C for 20 min to deliver
4-cyano-5-aminopyrazoles 22 (Table 2). In this instance,
MAOS had little effect on chemical yields (as pure prod-
ucts were ultimately obtained by recrystallization), but
did, once again, shorten the reaction time from 2–6 h
to only 20 min. Analogues 22 were smoothly converted
into the carboxamide derivative 23 by treatment with
concentrated H2SO4 at 0 °C for 1 h (yields averaged
95%).
HO
N
48% HBr, HOAc
N
17
Conv: reflux, 6 h (100%)
mw irrad: 180 oC, 10 min (100%)
N
Once analogues 23 were in hand, conventional thermal
conditions were quickly adapted and optimized on a sin-
gle-mode microwave synthesizer. In the event, exposing
carboxamide aminopyrazoles 23 in neat formamide to
microwave irradiation at 200 °C for 20 min afforded
pyrazolo[3,4-d]pyrimidines 24 in 48–92% isolated yield
(Table 3). Importantly, these conditions afforded equiv-
alent results on either a 50 mg or 1 g reaction scale.
Thus, a reaction step that required >48 h at reflux and
provided 40–65% yield has been optimized to 20 min
with yields generally in excess of 74%.3,4,12
18
N
RO
N
N
CsCO3, R-Cl, NaI, DMF
Conv: 50 oC, 24 h (30-60%)
mw irrad: 160 oC, 20 min (70-90%)
N
19
N
Scheme 4. MAOS synthesis of pyrazolo[1,5-a]pyrimidine 16.
NC
NC
EtOH, reflux
H2SO4
95%
+
Ar NHNH2
N
NC
OEt
N
2-6 hrs.
40-70%
H2N
Ar
20
21
22
NR1R2
O
OH
neat
1) POCl3, DCE
H2N
H2N
H2NCHO
N
N
N
N
N
reflux, 48 hrs.
40-65%
2) HNR1R2
DMF, reflux
N
N
N
N
N
Ar
Ar
Ar
23
Scheme 5. Classical synthesis of pyrazolo[3,4-d]pyrimidines 2.
24
2

308
R. N. Daniels et al. / Tetrahedron Letters 49 (2008) 305–310
Table 2. Representative 4-cyano-5-aminopyrazoles 22
Table 3. Representative pyrazolo[3,4-d]pyrimidines 24
NC
NC
O
OH
NC
H2N
H2N
N
OEt
H2NCHO
N
N
EtOH, mw
N
20
N
N
mw, 200 oC
20 min
N
N
105 oC
20 min
+
H2N
Ar
Ar
Ar
Ar NHNH2
23
24
21
22
Yielda (%)
Entry
Ar
Yielda (%)
Entry
Ar
24a
74
F
22a
71
42
F
22b
24b
92
Cl
Cl
F
F
24c
21d
81
88
22c
22d
54
64
F
F
MeO
F3C
MeO
F3C
Cl
Cl
24e
24f
24g
77
48
91
22e
70
Cl
Cl
22f
65
77
22g
a Isolated yields for analytically pure material after recrystallization.
a Isolated yields for analytically pure material after recrystallization.
Final elaboration into analogues for biological testing
involved conversion to the chloride and a subsequent
SNAr reaction with a set of diverse amines to deliver
analogues 2. For example, pyrazolo[3,4-d]pyrimidine
24g was treated with POCl3 in DCE. When conversion
to the chloride was judged complete by LCMS, the
reaction was concentrated, re-dissolved in DMF and
transferred to a 5 mL microwave reaction vessel.
3-Methylpiperidine 25 was added along with Et3N and
the reaction was heated in the microwave at 90 °C for
15 min to afford 26 in 84% isolated yield for the two step
sequence (Scheme 6). In a similar fashion, all analogues
24 were converted to their corresponding chloride and
subjected to SNAr reactions with 24 diverse amines to
produce 168 analogues of 2 in 52–94% yields (two step
library synthesis).12 Biological data for all final products
will soon be disclosed.
In summary, we have applied MAOS to the preparation
of pyrazolo[1,5-a] and pyrazolo[3,4-d]pyrimidines, 1 and
2, respectively, as well as the aminopyrazole precursors
11 and 19, respectively. In each case, reaction time
and/or yield was dramatically improved under these
MAOS protocols. Moreover, these new protocols allow
for an iterative analogue library synthesis approach for
lead optimization to be employed for the rapid synthesis
OH
N
1) POCl3, DCE
N
N
N
N
2)
DMF, Et3N
mw, 90 oC,
20 min
N
N
N
N
N
H
25
84%
24g
26
Scheme 6. MAOS synthesis of 4-piperidinyl pyrazolo[3,4-d]pyrimidine 26.

R. N. Daniels et al. / Tetrahedron Letters 49 (2008) 305–310
309
4 mmol) was dissolved in 3.5 mL of 5% AcOH/EtOH
and then 2-(4methoxyphenyl)malonaldehyde 16 (712 mg,
4 mmol) was added. The microwave reaction vessel was
capped and then heated at 170 °C for 10 min. Upon rapid
cooling to 40 °C, the product precipitated from solution
NH4OH was added to neutralize the AcOH, and the
product collected by filtration and washed with water to
afford 1.18 g of 6-(4-methoxyphenyl)-3-(pyridin-4-yl)pyr-
azolo[1,5-a]pyrimidine, 17, (98%) as a white solid. 1H
NMR (CDCl3, 400 Hz): d (ppm): 8.87 (d, J = 2 Hz, 1H),
8.82 (d, J = 2 Hz, 1H), 8.64 (d, J = 5.6 Hz, 2H), 8.53 (s,
1H), 8.01 (d, J = 6 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.07
(d, J = 8.8 Hz, 2H), 3.88 (s, 3H); 13C NMR (CDCl3,
100 MHz): d (ppm): 160, 150.3, 150.1, 144.4, 143.2, 139.6,
131.6, 128, 125.7, 123.2, 120.2, 115, 107.7, 55.4; LCMS,
single peak, 2.27 min, m/e, 303.1 (M+1).
of 100 s of analogues of 1 and 2. Further refinements
and biological data for these analogues will be reported
in due course.
Acknowledgments
The authors warmly thank the A. B. Hancock, Jr. Fam-
ily Foundation for Cancer Research, the Sartain-Lanier
Family Foundation and the American Cancer Society
for an Institutional Research Grant (#IRG-58-009-49)
for support of this research.
12. Typical MAOS experimental for pyrazolo[3,4-d]pyr-
imidine, 1-(3,5-dimethylphenyl)-4-(3-methylpiperidin-1-yl)-
1H-pyrazolo[3,4-d]pyrimidin-4-ol 26. 3,5-Dimethylhydra-
zine hydrochloride was partitioned between 2 M sodium
hydroxide solution and dichloromethane. The organic
layer was separated, dried and reduced under vacuum to
give the free hydrazine (1.90 g, 14 mmol). The free
hydrazine and ethoxymethylenemalononitrile (1.70 g,
14 mmol) in ethanol were irradiated at 105 °C for 20 min
by microwave. The crude product was recrystallized from
ethanol to yield 22g, 5-amino-1-(3,5-dimethylphenyl)-1H-
pyrazole-4-carbonitrile, as a yellow solid (2.30 g, 77%). 1H
NMR (CDCl3, 400 MHz) d 7.58 (s, 1H), 7.08 (s, 3H), 4.81
(s, 2H), 2.37 (s, 6H); 13C NMR (CDCl3, 100 MHz) d
149.87, 140.99, 139.87, 136.62, 130.48, 121.80, 114.25,
75.38, 21.15; LCMS, single peak, 2.73 min, m/e, 213.1
(M+1). Compound 22g (4.6 g, 21.7 mmol) was then
treated with concentrated H2SO4 (30 mL), followed by
pouring over ice and neutralized with NH4OH to provide,
after filtration, 23g, 5-amino-1-(3,5-dimethylphenyl)-1H-
pyrazole-4-carboxamide as a yellow solid. 1H NMR
(DMSO-d6, 400 MHz) d (ppm): 7.86 (s, 1H), 7.14 (s,
2H), 6.99 (s, 1H), 6.32 (s, 2H), 2.32 (s, 6H); 13C NMR
(DMSO-d6, 100 MHz): d (ppm): 166.1, 149.1, 138.7, 138,
128.4, 120.7, 97, 20.8; LCMS, single peak, 2.33 min,
m/e, 231.1 (M+1). A suspension of 5-amino-1-(3,5-
dimethylphenyl)-1H-pyrazole-4-carboxamide 23g (2.30 g,
10 mmol) in formamide was irradiated at 200 °C for
20 min by microwave. The cooled solution was diluted
with water. The product was filtered, washed with water
and dried over in vacuo to afford 24g, 1-(3,5-dimethyl-
phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ol, as a gray solid
(2.18 g, 91%). 1H NMR (CDCl3, 400 MHz) d 8.22 (s, 1H),
8.19 (s, 1H), 7.63 (s, 2H), 7.02 (s, 1H), 2.35 (s, 6H); 13C
NMR (CDCl3, 100 MHz) d (ppm) 156.76, 148.14, 138.05,
137.98, 135.22, 128.14, 119.27, 107.21, 20.57; LCMS,
single peak, 2.66 min, m/e, 241.1 (M+1). 24g (2.18 g,
9.1 mmol) was dissolved in DCE and cooled to 0 °C.
POCl3 (1.4 g, 9.3 mmol) added and reaction monitored by
LCMS. Reaction washed with water and concentrated to
afford pure 4-chloro-1-(3,5-dimethylphenyl)-1H-pyrazolo-
References and notes
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11. Typical MAOS experimental for pyrazolo[1,5-a]pyrimi-
dine 1, 6-(4-methoxy)-3-(pyridin-4-yl)pyrazolo[1,5-a]-
pyrimidine. To a 5 mL microwave reaction vessel was
placed 13 (565 mg, 5 mmol) in a 3 mL solution of
dimethylformamide–dimethlyacetal:DMF:PhCF3 (1:1:2).
The vial was heated in a microwave synthesizer to
150 °C for 10 min. LCMS (single peak, 1.1 min, m/e,
174.1 (M+1)) indicated that all 13 was consumed affording
14. Hydrazine (160 lL, 5.1 mmol) was then added via
syringe and the vial heated to 140 °C for 10 min. Aqueous
work-up, followed by preparative LCMS afforded 680 mg
(85%) of 4-(pyridin-4-yl)-1H-pyrazol-5-amine, 15 as a
purple solid. 1H NMR (DMSO-d6, 400 MHz): d (ppm):
8.38 (d, J = 6 Hz, 2H), 7.84 (s, 1H), 7.47 (d, J = 6 Hz, 2H),
5.14 (br s, 2H); 13C NMR (DMSO-d6, 100 MHz): d (ppm)
154, 149.5, 141.4, 132, 124, 119; LCMS, single peak,
0.39 min, m/e, 161.1 (M+1). Compound 15 (644 mg,
1
[3,4-d]pyrimidine. H NMR (CDCl3, 300 MHz) d 8.92 (s,
1H), 8.45 (s, 1H), 7.72 (s, 2H), 7.06 (s, 1H), 2.43 (s, 6H);
13C NMR (CDCl3 75 MHz) d 153.5, 152.7, 152, 139.3,
137.3, 134, 129.8, 119.6, 114.8, 21.4; LCMS, single peak,
3.81 min, m/e, 259.1 (M+1). Then,4-chloro-1-(3,5-di-
methylphenyl)-1nH-pyrazolo[3,4-d]pyrimidine (1.9 g, 7.36
mmol) was dissolved in 5 mL of DMF and 1 mL of Et3N
in a 10 mL microwave reaction vessel, followed by 3-
methylpiperidine 25 (1 mL, 11 mmol, 1.5 equiv) The
reaction was irradiated with microwaves for 20 min at
200 °C. The final product was purified by mass-directed
HPLC to afford 26, 1-(3,5-dimethylphenyl)-4-(3-methyl-

310
R. N. Daniels et al. / Tetrahedron Letters 49 (2008) 305–310
piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine, as an off-
white solid (1.98 g, 84%). H NMR (CDCl3, 400 MHz) d
8.42 (s, 1H), 8.08 (s, 1H), 7.69 (s, 2H), 6.96 (s, 1H), 4.62 (s,
2H), 3.19 (dd, J = 11.6, 12.0 Hz, 1H), 2.84 (dd, J = 11.6,
12.0 Hz, 1H), 2.40 (s, 6H), 1.95–1.56 (m, 4H), 1.35–1.23
(m, 1H), 1.02 (d, J = 6.8 Hz, 3H); 13C NMR (CDCl3,
125 MHz) d 156.79, 155.61, 154.28, 138.75, 138.68, 133.70,
128.46, 120.01, 101.43, 53.05, 46.37, 32.99, 31.19, 25.11,
21.43, 19.05; LCMS, single peak, 3.35 min, m/e, 322.1
(M+1).
1