Pyrazolo[1,5-a]pyridines: Synthetic approaches to a novel class of antiherpetics

Article abstract of DOI:10.1016/j.tet.2003.02.003

Synthesis of a novel class of 7-amino-3-pyrimidinyl-pyrazolo[1,5-a] pyridine antiherpetic compounds is described. The synthetic methodology is designed to allow for rapid analog synthesis around the C-3 and C-7 positions of the pyrazolo[1,5-a]pyridine. Th

Full text of DOI:10.1016/j.tet.2003.02.003

Tetrahedron 59 (2003) 9001–9011
Pyrazolo[1,5-a]pyridines: synthetic approaches to a novel class
of antiherpetics
*
Brian A. Johns, Kristjan S. Gudmundsson, Elizabeth M. Turner, Scott H. Allen, David K. Jung,
Connie J. Sexton, F. Leslie Boyd, Jr. and Michael R. Peel
Department of Medicinal Chemistry and Department of Virology, GlaxoSmithKline Research and Development, Five Moore Drive,
Research Triangle Park, NC 27709-3398, USA
Received 23 January 2003; accepted 24 February 2003
Abstract—Synthesis of a novel class of 7-amino-3-pyrimidinyl-pyrazolo[1,5-a]pyridine antiherpetic compounds is described. The synthetic
methodology is designed to allow for rapid analog synthesis around the C-3 and C-7 positions of the pyrazolo[1,5-a]pyridine. The
7-chloropyrazolo[1,5-a]pyridine D, produced through an azirine rearrangement, served as a key building block. Two complementary
methodologies for construction of the C-3 pyrimidine are described. These methods include the development of a novel cyclization utilizing
alkynyl ketones or enones to give highly substituted pyrimidines. The outlined strategies facilitated late stage manipulation of either the C-3
or C-7 positions providing flexibility for rapid analog synthesis.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
previous in-house research program6 was observed to have
antiviral activity against HSV-1 and -2 similar to acyclovir
(ACV) in cell culture. The above scaffold was different from
other pyrazolo[1,5-a]pyridines that were screened by virtue
of the 7-amino-3-pyrimidinyl substitution pattern. These
novel antiherpetic compounds led us to believe this scaffold
offered a unique opportunity for treatment of HSV-1 and -27
(Fig. 1).
The herpesvirus family contains more than 100 different
members and can infect most animal species. Within this
class of large double stranded DNA viruses there are 8
herpesviruses that infect humans. Herpes simplex viruses 1
and 2 (HSV-1 and -2) are among the best known members of
this class. HSV-1 is the causative agent of oral fever blisters
(labialis) and it has been estimated that .60% (and as high
as 90%) of the US population is infected.1 Meanwhile,
herpes simplex virus 2 (HSV-2), the cause of genital lesions,
infects one in five individuals or roughly 50 million people
in the US alone.2 The acyclic nucleoside analog acyclovir
was a groundbreaking discovery for the treatment for
HSV infections some 25 years ago,3 however there is still no
cure or effective vaccine for HSV infections. While current
therapies are efficacious and safe, there is room for improve-
ment in several areas including lesion pain relief, time
to healing, viral shedding and reduction in episodes
of reactivation. Another area of concern with HSV-2 is
transmission rates. Recently it has been shown that the
current therapy, valacyclovir, can help reduce rates of
transmission by 50%.4
Originally, GW 3733 was isolated as a by-product during
late stage synthetic manipulations targeting alternative
structures.6 It was our desire to more fully investigate the
C-3 and C-7 positions of the pyrazolopyridine ring system.
Interestingly, few reports appear in the literature regarding
the chemistry of this fused nitrogen heterocycle.8 The C-3
and C-7 positions that we were interested in appeared to
display orthogonal reactivity. We desired to exploit the
differing reactivity at these positions and selectively
Our efforts began through a cell-based high throughput
screen to find novel inhibitors of viral replication.5 The
pyrazolo[1,5-a]pyridine scaffold GW 3733 (1) from a
Keywords: pyrazolo[1,5-a]pyridine; alkynyl ketone; pyrimidine synthesis;
HSV.
*
Corresponding author. Tel.: þ1-919-483-6006; fax: þ1-919-483-6053;
Figure 1.
e-mail: brian.a.johns@gsk.com
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.02.003

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B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
Figure 2. Retrosynthetic strategy.
functionalize these heterocycles to examine the SAR of this
class of antivirals.
The synthesis of intermediate D proceeded smoothly
beginning with a benzoylation of 6-chloropicoline (2) in
the presence of lithium bistrimethylsilyl amide to yield the
desired ketone 3. Subsequent treatment of 3 with hydro-
xylamine gave the oxime 4 as a stable crystalline solid.
Treatment of 4 with trifluoroacetic anhydride and warming
to room temperature in the presence of base facilitated
formation of the azirine intermediate 5. Typically the
azirine intermediate was not isolated however, the isolation
and characterization of this intermediate was possible and
5 proved remarkably stable. Heating the azirine to 1808C
in trichlorobenzene led to the formation of the desired
pyrazolo[1,5-a]pyridine core D, albeit in modest yield. At
these high temperatures numerous undesired by-products
were formed, likely due to the reactive chloro substituent.
Fortunately during the course of our studies, it came to our
attention that the azirine rearrangement could be catalyzed
with an iron(II) salt at a much lower temperature.9 Heating
azirine 5 with a catalytic amount of FeCl2 in DME gave
a clean conversion to the desired pyrazolopyridine inter-
mediate D in good yield (Scheme 1).
2. Synthesis
2.1. Construction of intermediate D
Our synthetic approach was designed to have maximum
flexibility to examine structure–activity relationships
(SAR) around the C-7 and C-3 positions of the pyrazolo-
pyridine ring system. Knowledge gained from the previous
in-house synthetic programs directed our attention to the
common synthetic intermediate D. We envisioned inter-
mediate D would serve as a versatile precursor to allow for
either manipulation of the C-7 chloro substituent prior to
(route 1) or after (route 2) installation of the C-3 pyrimidine.
Addressing the C-7 amine substitution first would allow
for flexible examination of the C-3 pyrimidine substituent.
Alternatively, carrying the C-7 chlorine through to the
final step would facilitate easy access to a variety of C-7
substituents (Fig. 2).
2.2. Route 1: amine first strategy
We now turned our attention to methodology designed to
complete the construction of GW 3733 (1). Our intentions
were to introduce the 7-amino functionality early in the
sequence and carry this through the construction of the C-3
pyrimidine as the last step in the synthesis. Our initial plans
were to build up the pyrimidine via a methyl ketone
intermediate which could then be homologated into a
vinylogous amide and ultimately condensed with the
desired guanidine to produce the pyrimidine moiety. During
our studies we discovered the stage at which the C-7 amine
was introduced proved crucial to the success of the route.
Initial attempts at introducing the amine directly onto
intermediate D under thermal conditions proved satisfactory
for unhindered amines such as n-butylamine, but were
modest at best for more hindered amines such as
cyclopentylamine. The Pd(0) mediated Buchwald–Hartwig
type of amination couplings were found to be preferable for
these systems.10 Treatment of intermediate D with cyclo-
pentylamine under standard coupling conditions (Pd(OAc)2,
rac-BINAP, Cs2CO3, PhMe, 85–1008C) resulted in quanti-
tative conversion to the 7-aminopyrazolopyridine derivative
Scheme 1. (a) LiN(TMS)2, 4-F-C6H4CO2Et, THF, 458C, 66%;
(b) hydroxylamine HCl, NaOH, MeOH, 86%; (c) (CF3CO)2O, Et3N,
CH2Cl2, 08C to rt; (d) 1,2,4-trichlorobenzene, 1808C, 30%; (e) FeCl2,
1,2-dimethoxyethane, 808C, 68%.

B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
9003
ation smoothly to give the desired 3-acetyl derivative in
good yield (Scheme 3).
We now returned to the introduction of the C-7 amine and
again found the Pd(0) mediated amination method to be
preferable to thermal conditions to give 8 in near
quantitative yield. Refluxing methyl ketone 8 in neat
dimethylformamide dimethylacetal (DMF-DMA) over sev-
eral days resulted in complete conversion to the vinylogous
amide 10. While the yield was excellent for this reaction, the
long reaction time was undesirable. By using a stoichio-
metric amount of DMF di-tert-butyl acetal (DMF-DTBA) in
DMF instead of the neat dimethyl acetal, a similar
conversion was achieved in only a few hours for related
analogs. Treatment of the keto-enamine 10 with the
cyclopentylamine derived guanidine 1111 resulted in clean
conversion to the desired GW 3733 (1).
Scheme 2. (a) Pd(OAc)2, rac-BINAP, Cs2CO3, c-C5H9NH2, PhMe,
85–1008C, 99%; (b) for 7, NBS, THF 08C to rt; (c) for 8, Ac2O,
BF3·OEt2, PhMe, D.
2.3. Route 2: amine last strategy
6 (Scheme 2). The 7-aminopyrazolopyridine 6 was
subjected to various Friedel–Crafts acetylation conditions
as well as bromination conditions in an attempt to
functionalize the nucleophilic C-3 position for further
elaboration. Unfortunately, these conditions resulted in
several regioisomeric products as well as di- and tri-
substituted products in the case of the bromination attempts.
With a reliable and scalable synthesis of 1 in hand we now
turned our attention to methodology which would allow
access to divergent analog synthesis. The synthesis
previously described allows for easy variation of the C-20
amine via altering the guanidine condensation at the final
step in the sequence.12 However, changes of the C-7 amine
substituent in the aforementioned synthesis requires mul-
tiple additional steps for each analog. Since our goals were
to not only examine the C-20 SAR but also other positions,
introduction of the C-7 substituent as a final step was an
option we sought to explore. As we looked at the existing
route, an obvious permutation was to alter the order of steps
to introduce the amine as a last step and simply carry the
C-7 chloro group through the penultimate intermediate.
We found that homologation of 9 by treatment with DMF-
DMA resulted in production of the desired vinylogous
amide 12 (Scheme 4). However, the major product from this
reaction was the undesired C-7 dimethylamine derivative
13. Use of the more reactive DMF-DTBA minimized
by-product formation to a large degree, primarily by
reducing the reaction time. However, as we considered
this synthetic issue, it became clear that it would be
desirable to have a method that would allow us to tolerate
It was clear at this point that the 7-aminopyrazolopyridine
derivatives such as 6 were too electron rich to allow
satisfactory control during C-3 electrophilic aromatic
substitutions. This observation led us to examine func-
tionalization of the C-3 position prior to introduction of the
C-7 amine. Compound D underwent Friedel–Crafts acyl-
Scheme 3. (a) Ac2O, BF3·OEt2, PhMe, 1008C, 77%; (b) Pd(OAc)2, rac-
BINAP, Cs2CO3, c-C5H9NH2, PhMe, 85–1008C, 95%; (c) DMF-DMA,
reflux, 6d, 99%; (d) t-BuOK, THF, D, 91%.
Scheme 4. (a) DMF-DMA, D; (b) for 12; 11, t-BuOK, THF, D.

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B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
Figure 3. Alternative precursors for pyrimidine synthesis.
sensitive functionality and alter other previously unsubsti-
tuted positions of the pyrimidine ring.
Our attention subsequently focused on modification of
the current condensation methodology which utilized an
intermediate such as E (Fig. 3) produced via the DMF-DMA
conditions. In addition to the harsh conditions required for
formation of the enamine moiety, introducing substitution at
Scheme 6. (a) POCl3, DMF; H2O, 95%; (b) ethynyl–MgBr, THF, 278 to
08C, 88%; (c) MnO2, CHCl3, 77%; (d) 11, K2CO3, NMP, 708C, 44%.
serve as a suitable surrogate. We expected the alkynyl
ketone to be more reactive than either of the previous two
cyclization precursors and speculated that the fragmentation
pathway observed for compounds such as 15 would be
avoided. Considering our intentions for examining
numerous analogs, we felt that the plethora of methods to
form and modify alkynes would give us ample opportunity
to increase the diversity of C-60 substituents. Most impor-
tantly, we anticipated that the mild conditions required to
form an intermediate such as G would tolerate the C-7
chloro substituent and allow us to accomplish our synthetic
goal. Upon examination of the literature, we found a couple
of recent reports of a related pyrimidine construction.13
0
the C-60 (R6 ) position would require preparation of the
appropriately substituted amide acetals or functional
variants. Numerous attempts to condense 8 with dimethyl
acetamide dimethyl acetal to form an intermediate repre-
0
sentative of E (R6 ¼Me) were unsuccessful.
The b-dicarbonyl F was briefly studied. Since we had access
to the methyl ketone 8 it was decided to use this material
for a model study to examine the ease of introduction of the
b-dicarbonyl functionality and its subsequent condensation
with guanidines. The enolate of 8 was acylated with Weinreb
amide 16 to give the cyclization precursor 15. Diketone 15
was treated with guanidine 11 under various conditions and
only low yields of the desired pyrimidine 17 resulted. The
remainder of the material fragmented to produce a signifi-
cant amount of the starting methyl ketone 8 (Scheme 5).
Subjection of intermediate D to standard Vilsmeier–Haack
formylation conditions led to smooth conversion to
aldehyde 18 upon hydrolysis (Scheme 6). Adventitiously,
this aldehyde was highly crystalline and could be stored
indefinitely without any special precautions. As a first
attempt, aldehyde 18 was treated with commercially
available ethynyl Grignard at low temperature and allowed
to warm to 08C resulting in clean conversion to the desired
propargylic alcohol 19a in excellent yield. Oxidation of 19a
to the desired alkynyl ketone 20a occurred without incident
Reflecting on the oxidation state of the vinylogous amide
functionality, it was reasoned that alkynyl ketone G would
Table 1. Alkynyl ketone cyclizations
Entry
M
R6
0
Cyclization yield (%)
Product 14
1
2
3
4
–MgBr
–MgBr
–Li
–H
–Me
–CH2OTHP
–Ph
44
98
71
84
14a
14b
14c
14d
Scheme 5. (a) LiN(TMS)2, THF, 2788C; CH3C(O)NMe(OMe) (16), 26%
(b) 11, K2CO3, DMF, D, 19% of 17, 70% of 8.
–Li

B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
9005
Table 2. Amine displacements
0
Entry
R1R2NH
Condition
R6
–Me
Yield (%)
Product 17
1
2
3
4
5
6
7
8
9
c-C5H9-NH2
c-C5H9-NH2
c-C5H9-NH2
NH2NH2
N-methylpiperazine
N-methylpiperazine
Ethylenediamine
p-anisidine
a
a
a
b
b
b
a
a
a
64
82
97
46
70
96
48
60
90
17b
17c
17d
17e
17f
17g
17h
17i
–CH2OTHP
–Ph
–Me
–Me
–Ph
–Ph
–H
Methyl glycinate HCl
–Me
17j
a
Condition (a) Pd(OAc)2, rac-BINAP, Cs2CO3, R1R2NH, PhMe, 85–1008C.
b
Conditions (b) R1R2NH, heat.
upon exposure to an excess of MnO2. Other oxidation
methods were attempted but gave lower yields or were
complicated by undesirable work-up conditions. We found
that treatment of alkynyl ketone 20a with guanidine 11 led
to clean formation of the desired pyrimidine 14a with the
requisite C-7 chloro substituent intact. As was alluded to
above, our primary goal was establishment of a route that
could facilitate installation of the pyrimidine moiety while
retaining a C-7 chlorine. However the current route also
provides a nice opportunity to introduce a vast array of
substituents at the C-60 position. Table 1 surveys some of the
groups that have been exemplified using this method.
The dihydropyrimidine intermediate proved resistant to
air oxidation, but did undergo dehydrogenation upon the
addition of palladium on carbon catalyst to afford the
desired pyrimidine 23. The C-7 amine substituent was then
introduced by heating0 23 in neat cyclopentylamine to
provide the desired C-5 substituted target 24. Interestingly,
Manipulation of the C-7 chloro group at the last stage in the
synthesis allowed for rapid construction of amine analogs. It
was determined that simply heating 7-chloropyrazolopyri-
dine derivatives such as 14 in the neat amine at 130–1508C
led to clean conversion to the 7-amino products 17.
Alternatively, the Buchwald–Hartwig methodology was
also employed to convert aryl chloride 14 to amino
derivatives 17 (Table 2).
Figure 4. Oxidative enone cyclization.
2.4. Oxidative enone cyclization method
The C-50 position remained the last pyrimidine position
for analog derivatization. As we again thought about the
existing strategy of pyrimidine ring synthesis it seemed
reasonable that replacement of the alkynyl ketone G with an
enone such as I could, upon oxidation, lead to the desired
pyrimidines in a similar manner (Fig. 4). Of course, the
added feature of substitution at either or both the C-50 and
C-60 positions present in the enone greatly extends the
versatility of the method. To that end, aldehyde 18 was
treated with commercially available isopropenyl Grignard
reagent at low temperature to produce alcohol 21 in
excellent yield (Scheme 7). Oxidation as before with
activated manganese dioxide led to smooth formation of
the desired enone 22 which was subsequently subjected to
guanidinium salt 11 in ethanol under free basing conditions.
Scheme 7. (a) Isopropenyl–MgBr, THF, 278 to 08C, 90%; (b) MnO2,
CHCl3, 74%; (c) 11, NaOEt, EtOH, rt; Pd/C, 44%. (d) c-C5H9-NH2, 1308C,
90%.

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B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
introduction of the C-50 methyl substituent manifested a
significant effect on the interaction of the pyrimidine with
the 2-aryl substituent. Introduction of the C-50 methyl
appears to flip the 2-(p-fluorophenyl) substituent out of
plane as is suggested by the upfield 1H (1.64 ppm) and 13C
NMR (15.16 ppm) chemical shift of the C-50 methyl group.
The significant upfield shift in both the proton and carbon
spectra imply that the methyl group is experiencing the
shielding cone of the fluorophenyl ring. We found this to be
of significance because previous crystallographic data for
related C-50 protio analogs had shown that the 2-phenyl and
3-pyrimidyl rings existed in a near flat conformation with
the pyrazolopyridine core. This presumably allows for
maximal overlap of the highly conjugated system. However,
crystallographic data has not been obtained to verify this
conformational analysis. In addition, C-50 protio analogs
196.0 mmol) and ethyl 4-fluorobenzoate (57.5 mL, 391.2
mmol) in THF (311 mL) was added lithium bis(trimethyl-
silyl)amide (391 mL, 1.0 M in THF, 391.0 mmol) dropwise
via a pressure equalizing funnel over 1 h. Upon complete
addition, the cold bath was removed and the resultant
solution was heated at 458C for 15 h. The mixture was
cooled to room temperature and quenched by the addition of
water. Ether was added and the organic layer was washed
with brine. The aqueous layer was extracted with ether and
the combined organics were dried over magnesium sulfate.
Filtration and concentration gave a solid residue which
was purified by recrystallization from EtOAc–hexanes to
provide ketone 3 (32.2 g, 66%) as a tinted off-white solid
existing as a keto–enol tautomeric mixture. 1H NMR
(CDCl3): for the keto tautomer d 8.11 (m, 2H), 7.66 (t, 1H),
7.30–7.25 (m 2H), 7.17 (t, 2H), 4.48 (s 2H); 19F NMR
(CDCl3) d 2104.72 (keto), 2111.64 (enol); MS m/z 250
(Mþ1).
1
such as 1 showed H and 13C NMR chemical shifts for the
pyrimidine portion of the scaffold which were consistent
with what would be predicted by the crystal structure.
4.2.2. 2-(6-Chloro-2-pyridinyl)-1-(4-fluorophenyl)etha-
none oxime (4). To a solution of ketone 3 (74.9 g,
299.8 mmol) in MeOH (900 mL) was added hydroxylamine
hydrochloride (104 g, 1.49 mol) followed by NaOH
(600 mL, 10% aqueous, 1.5 mol). The resultant suspension
was heated to reflux for 2 h and then cooled to rt. The
mixture was concentrated in vacuo and the residue taken up
in ether and water. The organic layer was washed with brine.
The aqueous layer was extracted with ether and the com-
bined organics were dried over magnesium sulfate.
Filtration and concentration gave a solid residue which
was purified by recrystallization from EtOAc–hexanes to
provide 4 (67.9 g, 86%) as a white solid. 1H NMR (CDCl3):
d 8.69 (s, 1H), 7.71 (dd, 2H), 7.53 (t, 1H), 7.18–7.16 (m,
2H), 7.03 (t, 2H), 4.37 (s, 2H); 19F NMR (CDCl3) d
2111.77; MS m/z 265 (Mþ1).
3. Conclusions
We have described synthetic approaches to 7-amino-3-
pyrimidinyl-pyrazolo[1,5-a]pyridine analogs. A key inter-
mediate 7-chloropyrazolo[1,5-a]pyridine was prepared via a
mild azirine rearrangement and provided a versatile
building block for analog synthesis. During the course of
our work, we developed novel methodologies to construct
highly substituted pyrimidines based on the condensation of
an alkynyl ketone or enone with a guanidine. Our strategy
provides facile access to numerous analogs by last step
introduction of the C-3 or C-7 substitutent. Detailed SAR of
the pyrazolopyridine scaffold along with antiviral data will
be the subject of future publications.
4.2.3. 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
dine (intermediate D). To a solution of 4 (109.2 g,
414 mmol) in 1,2-dimethoxyethane (500 mL) at 08C was
added trifluoroacetic anhydride (59 mL, 414 mmol), keep-
ing the temperature below 108C. After the addition was
complete, the reaction was warmed to 158C. The solution
was then cooled to 48C and a solution of triethylamine
(116 mL, 828 mmol) in 1,2-dimethoxyethane (60 mL) was
added over 0.5 h. After warming to rt, the mixture was
stirred for 1.5 h. To this was added iron(II) chloride (0.52 g,
4.1 mmol) and the reaction was heated to reflux for 3 h.
The reaction was concentrated and the resulting solid
was recrystallized from ethyl acetate–hexanes to give
intermediate D (69.7 g, 68%) as off-white needles. 1H
NMR (CDCl3): d 8.03 (m, 2H), 7.54 (d, 1H), 7.16 (m, 3H),
6.93 (d, 1H), 6.91 (s, 1H); MS m/z 247 (Mþ1); mp
156–1578C.
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained on Varian Unity
Plus NMR spectrometers at 300 or 400 MHz, and 75 or
100 MHz, respectively. 19F NMR spectra were recorded at
282 MHz. Mass spectra were obtained on Micromass
Platform, or ZMD mass spectrometers from Micromass
Ltd. Altrincham, UK, using either Atmospheric Chemical
Ionization (APCI) or Electrospray Ionization (ESI). Sol-
vents were purchased as anhydrous grade and used without
further purification. Unless otherwise stated, column
chromatography for the purification of some compounds,
used Merck Silica gel 60 (230–400 mesh), and the stated
solvent system under pressure. All compounds were
characterized as their free-base form unless otherwise
stated. On occasion the corresponding hydrochloride salts
were formed to generate solids where noted. Combustion
analyses were performed by Atlantic Microlabs, Inc.
Norcross, Ga.
4.3. Synthesis of 1—Route 1
4.3.1. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]ethanone (9). To a solution of intermediate D
(10.0 g, 40.5 mmol) in toluene (225 mL) at rt was added
acetic anhydride (4.6 mL, 48.6 mmol). Boron trifluoride
diethyletherate (5.6 mL, 44.6 mmol) was then added drop-
wise and the resultant solution was heated to reflux for 3.5 h.
The reaction mixture was cooled to rt and quenched by the
4.2. Synthesis of intermediate D
4.2.1. 2-Chloro-2-pyridinyl)-1-(4-fluorophenyl)ethanone
(3). To a cold (08C) solution of 6-chloro-2-picoline (21.4 mL,

B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
9007
1
dropwise addition of aqueous sodium bicarbonate. Ether
was added and the organic layer was washed with brine.
The aqueous layer was extracted with ether and the com-
bined organics were dried over magnesium sulfate,
filtered and concentrated. The residue was purified by
recrystallization from EtOAc–hexanes to give methyl
ketone 9 (9.0 g, 77%) as redish needles. 1H NMR
(CDCl3): d 8.41 (d, 1H), 7.59 (m, 2H), 7.45 (dd, 1H),
7.26–7.13 (m 3H), 2.15 (s, 3H); 19F NMR (CDCl3) d
2112.06; MS m/z 289 (Mþ1).
hydrochloride (7.0 g, 86%) as a fine white solid. H NMR
(D2O): d 3.62 (m, 1H), 1.75 (m, 2H), 1.52–1.32 (m, 6H);
13C NMR (D2O) d 156.23, 53.11, 32.15, 23.13; MS m/z 128
(Mþ1).
4.3.5. N-Cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimi-
dinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-
amine (1). To a solution of 10 (3.5 g, 8.9 mmol) in
THF (36 mL, 0.25 M) was added N-cyclopentylguanidine
hydrochloride (11) (1.89 g, 11.6 mmol), followed by solid
potassium tert-butoxide (2.6 g, 23.2 mmol) in two portions.
The resultant solution was heated to reflux for 23 h. Upon
cooling to rt, ether was added followed by water. The
organics were washed with brine, and the aqueous layer was
extracted with ether. The combined organics were dried
over magnesium sulfate, filtered and concentrated in vacuo.
The residue was purified by flash chromatography on silica
to give 1 (3.7 g, 91%) as an off white solid. 1H NMR
(CDCl3): d 7.97 (d, 1H), 7.68 (d, 1H), 7.59 (dd, 2H), 7.27
(t, 1H), 7.10 (t, 2H), 6.24 (d, 1H), 5.99 (d, 1H), 5.96 (d, 1H),
5.01 (d, 1H), 4.28 (m, 1H), 3.97 (m, 1H), 2.12–1.99 (m,
4H), 1.79–1.44 (m, 12H); 13C NMR (CDCl3) d 163.12 (d,
JCF¼246.6 Hz), 162.09, 161.53, 156.67, 152.15, 142.66,
141.09, 131.46 (d, JCF¼8.0 Hz), 129.92 (d, JCF¼3.1 Hz),
128.39, 115.45 (d, JCF¼21.3 Hz),108.68, 107.13, 105.15,
90.13, 53.84, 52.87, 33.50, 33.30, 24.05, 23.70; 19F NMR
(CDCl3) d 2113.49; MS m/z 457 (Mþ1); Anal. Calcd for
C27H29FN6: C, 71.03; H, 6.40; N, 18.41. Found: C, 71.20;
H, 6.37; N, 18.52.
4.3.2. 1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)pyra-
zolo[1,5-a]pyridin-3-yl]ethanone (8). To a solution of
ketone 9 (2.7 g, 9.5 mmol) in toluene (50 mL) was added
successively racemic-BINAP (378 mg, 0.6 mmol), cesium
carbonate (4.7 g, 14.3 mmol), cyclopentylamine (4.7 mL,
47.5 mmol), and palladium(II) acetate (86 mg, 0.4 mmol).
The resultant mixture was heated to 958C for 2.5 h at which
time the reaction was judged complete by thin layer
chromatography. The solution was cooled to rt and ether
was added. The organic layer was washed with water and
brine. The aqueous layer was extracted with ether and the
combined organics dried over magnesium sulfate. Filtration
and concentration followed by flash chromatography (4:1
hexanes–EtOAc) provided 7-amino derivative 8 (3.1 g,
1
95%) as a yellow solid. H NMR (CDCl3): d 7.62 (d, 1H),
7.55 (dd, 2H), 7.40 (t, 1H), 7.15 (t, 2H), 6.10 (d, 1H), 5.99
(d, 1H), 3.94 (m, 1H), 2.09 (s, 3H), 2.12–2.04 (m, 2H),
1.78–1.58 (m, 6H); 13C NMR (CDCl3) d 192.63, 163.28
(d, JCF¼247.3 Hz), 154.89, 142.65, 142.38, 131.66
(d, JCF¼8.3 Hz), 131.09, 130.03 (d, JCF¼3.8 Hz), 115.33
(d, JCF¼22.0 Hz), 111.32, 105.41, 91.97, 53.81, 33.21,
30.10, 23.96; 19F NMR (CDCl3) d 2112.70; MS m/z 338
(Mþ1).
4.4. Amine last strategy—Route 2
4.4.1. 7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
dine-3-carbaldehyde (18). DMF (100 mL) was cooled to
08C and treated with phosphorous oxychloride (5.7 mL,
60.8 mmol). After the addition was complete, the mixture
was warmed to room temperature and stirred for 1 h. To this
was added 7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
dine (10.0 g, 40.5 mmol) and the resultant solution was
stirred overnight. Water was added, followed by dichloro-
methane. The aqueous layer was extracted with dichloro-
methane. The combined organics were washed with brine,
dried over magnesium sulfate, filtered and concentrated.
The residue was recrystallized from ether and hexanes to
4.3.3. (2E)-1-[7-(Cyclopentylamino)-2-(4-fluorophenyl)-
pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-pro-
pen-1-one (10). A solution of 8 (3.1 g, 9.2 mmol) in N,N-di-
methylformamide dimethyl acetal (25 mL) was heated to
reflux for 6 days. The mixture was cooled to room
temperature, EtOAc was added followed by water. The
organic layer was washed with brine. The aqueous layer was
extracted with EtOAc and the combined organics were dried
over magnesium sulfate. Filtration and concentration
followed by flash chromatography (EtOAc) provided
enamine 10 (3.6 g, 99%) as a tinted oil. 1H NMR
(CDCl3): d 7.73–7.61 (m, 4H), 7.32 (t, 1H), 7.14 (t, 2H),
6.03 (d, 1H), 5.96 (d, 1H), 5.05 (d, 1H), 3.99 (m, 1H), 5.15–
2.42 (broad, 6H), 2.19–2.08 (m, 2H), 1.86–1.62 (m, 6H);
19F NMR (CDCl3) d 2113.75; MS m/z 393 (Mþ1).
1
give aldehyde 18 (10.6 g, 95%) as a fluffy white solid. H
NMR (CDCl3): d 10.07 (s, 1H), 8.37 (d, 1H), 7.78 (m, 2H),
7.48 (t, 1H), 7.20 (m, 3H); 19F NMR (CDCl3) d 2111.25;
MS m/z 275 (Mþ1); Anal. Calcd for C14H8ClFN2O: C,
61.22; H, 2.94; N, 10.20. Found: C, 61.34; H, 2.90; N,
10.15; mp 212–2138C (decomp.).
4.3.4. N-Cyclopentylguanidine hydrochloride (11). To a
solution of 2-methyl-2-thiopseudourea sulfate (13.9 g,
50.0 mmol) in water (40 mL) was added cyclopentylamine
(14.8 mL, 150 mmol). The resultant mixture was heated to
558C for 20 min and then to reflux for 2.5 h. The mixture
was cooled to room temperature and concentrated in vacuo
and azeotroped with MeOH. Water was added (,100 mL)
and Amberlite IRA 400 (Cl2) resin was added. The mixture
was stirred for 1 hour and then the resin was removed by
filtration. The solution was concentrated in vacuo and
azeotroped with MeOH. The residue was recrystallized
from MeOH–acetone to yield N-cyclopentylguanidine
4.5. General procedure A. Addition of alkynyl/alkenyl
Grignard or lithium reagents to aldehyde 18
To a cold (2788C) solution of aldehyde 18 (1 equiv.) in
THF (0.15 M) was added alkynyl magnesium bromide or
alkynyl lithium reagent (2.5 equiv.) in THF (0.5–1.0 M)
dropwise. The resultant mixture was allowed to warm to 08C
and stirred at that temperature until the reaction judged
complete by TLC or LC/MS methods. The resultant solution
was poured into water and extracted with ether. The organic
layer was washed with water and brine and the combined
organics were dried over sodium sulfate. Filtration and

9008
B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
concentration followed by flash chromatography or recrys-
tallization provide the desired alcohol 19.
to general procedure A using propynyl magnesium bromide
to give after flash chromatography (4:1 hexanes/EtOAc to 1:1
hexanes/EtOAc) alcohol 19b (1.3 g, 72%) as a white solid. Rf
0.44 (2:1 hexanes/ethyl acetate). 1H NMR (CDCl3) d 7.99 (d,
1H), 7.78 (m, 2H), 7.14 (m, 3H), 6.95 (d, 1H), 5.70 (m, 1H),
2.21 (d, 1H), 1.85 (d, 3H); MS m/z 315 (Mþ1).
4.6. General procedure B. MnO2 oxidation
To a solution of alcohol 19 (1 equiv.) in CH2Cl2 (0.05 M)
was added manganese dioxide (40 equiv.). The reaction
mixture was stirred at room temperature until judged
complete by TLC or LC/MS methods. The suspension
was filtered through a pad of Celite and the filtrate was
concentrated in vacuo to give ketone 20. This material is
used without further purification.
4.7.5. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-butyn-1-one (20b). Alcohol 19b was oxidized
according to general procedure B to give ketone 20b (950 mg,
91%). Rf 0.44 (3:1 hexanes/EtOAc). 1H NMR (CDCl3) d 8.49
(d, 1H), 7.73(m, 2H), 7.50(t, 1H), 7.19(m, 3H), 1.71(3H);19F
NMR (CDCl3) d 2112.58; mp 182–1838C.
4.7. General procedure C. Alkynyl ketone/guanidine
cyclization
4.7.6. 4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-N-cyclopentyl-6-methyl-2-pyrimidinamine
(14b). Ketone 20a was treated with guanidine 11 according
to general procedure C to provide after flash chroma-
tography pyrimidine 14b (1.11 g, 98%) as a yellow foam. Rf
0.45 (3:1 hexanes/EtOAc). 1H NMR (CDCl3) d 8.35 (d, 1H),
7.64 (m, 2H), 7.24 (m, 1H), 7.13 (m, 2H), 7.03 (d, 1H), 6.22
(s, 1H), 5.10 (m, 1H), 4.35 (m, 1H), 2.19 (s, 3H), 2.03 (m,
2H), 1.60 (m, 6H); MS m/z 422 (Mþ1).
To a dry round bottom flask was added sodium metal
(1.3 equiv.). Ethanol (0.15 M) was added and allowed to
react with sodium at room temperature until completely
dissolved. Guanidinium salt 11 (1.3 equiv.) was added and
the mixture was allowed to stir at room temperature for
10 min. To the resultant mixture was added ketone 20
(1 equiv.) and the reaction mixture was stirred at rt or heated
to 708C until judged complete by TLC or LC/MS. The
reaction mixture was cooled to room temperature and
diluted with water. The mixture was extracted with ethyl
acetate, and the combined extracts were washed with water
and brine. The organic layer was dried over sodium sulfate.
Filtration and concentration followed by flash chroma-
tography or recrystallization provided pyrimidine 14.
4.7.7. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-ol
(19c). To a cold (2788C) solution of tetrahydro-2-
(2-propynyloxy)-2H-pyran (0.5 mL, 3.6 mmol) in THF
(10 mL) was added n-butyllithium (2.05 mL, 1.6 M in
hexanes, 3.3 mmol) dropwise. The reaction mixture was
allowed to warm to 08C, then cooled to 2788C. This reagent
was used to treat aldehyde 18 according to general
procedure A to give alcohol 19c (301 mg, 99%) as a
mixture of diastereomers. 1H NMR (CDCl3) d 8.00 (d, 1H),
7.79 (m, 2H), 7.17 (m 3H), 6.99 (m, 1H), 5.79 (s, 1H), 4.81–
4.74 (m, 1H), 4.39–4.25 (m, 2H), 3.81 (m, 1H), 3.52 (m,
1H), 3.15 (broad, 1H), 1.90–1.48 (m, 6H); 19F NMR
(CDCl3) d 2113.01; MS m/z 437 (MþNaþ).
An alternative method involved heating a solution of
alkynyl ketone 20 (1 equiv.) guanidine 11 (1.3 equiv.) and
K2CO3 (1.3 equiv.) in NMP or DMF (0.15 M) at 1208C.
4.7.1. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-propyn-1-ol (19a). Aldehyde 18 was subjected
to general procedure A using ethynyl magnesium bromide
to give after recrystallization from dichloromethane alcohol
19a (5.3 g, 88%) as a pale yellow crystalline solid. 1H NMR
(CDCl3): d 8.04 (d, 1H), 7.79 (m, 2H), 7.20 (m, 3H), 7.01
(d, 1H), 5.77 (m, 1H), 2.69 (d, 1H), 2.32 (d, 1H); MS m/z
301 (Mþ1).
4.7.8. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-4-(tetrahydro-2H-pyran-2-yloxy)-2-butyn-1-
one (20c). Alcohol 19c was oxidized according to general
procedure B to give ketone 20c (280 mg, 93%) as a white
solid. 1H NMR (CDCl3) d 8.48 (d, 1H), 7.71 (m, 2H), 7.50
(m, 1H), 7.17 (m, 3H), 4.59 (m, 1H), 4.11 (s, 2H), 3.72 (m,
1H), 3.49 (m, 1H), 1.82–1.50 (m, 6H); 19F NMR (CDCl3) d
2111.89; MS m/z 435 (MþNaþ).
4.7.2. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-propyn-1-one (20a). Alcohol 19a was oxidized
according to general procedure B to give ketone 20a (4.04 g,
1
77%) as a yellow solid. H NMR (CDCl3): d 8.45 (d, 1H),
7.67 (m, 2H), 7.50 (t, 1H), 7.19 (d, 1H), 7.12 (t, 2H), 2.93 (s,
4.7.9. 4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-N-cyclopentyl-6-[(tetrahydro-2H-pyran-2-yl-
oxy)methyl]-2-pyrimidinamine (14c). Ketone 20a was
treated with guanidine 11 according to general procedure C
to provide pyrimidine 14c (165 mg, 71%) as a clear oil. Rf
0.12 (4:1 hexanes/EtOAc). 1H NMR (CDCl3) d 8.46 (d, 1H),
7.65 (m, 2H), 7.24 (m, 1H), 7.11 (t, 2H), 7.02 (d, 1H), 6.51
(s, 1H), 5.09 (d, 1H), 4.58 (m, 1H), 4.50 (d, 1H), 4.37 (m,
1H), 4.08 (d, 1H), 3.66 (m, 1H), 3.45 (m, 1H), 2.06 (m, 2H),
1.58 (m, 12H); 19F NMR (CDCl3) d 2113.16; MS m/z 522
(Mþ1).
1H); MS m/z 299 (Mþ1).
4.7.3. 4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-N-cyclopentyl-2-pyrimidinamine (14a). Ketone
20a was treated with guanidine 11 according to general
procedure C to provide after flash chromatography pyrimi-
dine 14a (125 mg, 44%) as a white foam. 1H NMR (CDCl3)
d 8.42 (d, 1H), 8.09 (d, 1H), 7.67 (dd, 2H), 7.30 (m, 1H),
7.17 (t, 2H), 7.06 (d, 1H), 6.33 (d, 1H), 5.30 (d, 1H), 4.35
(m, 1H), 2.18–2.05 (m, 2H), 1.84–1.52 (m, 6H); 19F NMR
(CDCl3) d 2112.78; MS m/z 408 (Mþ1).
4.7.10. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]-
pyridin-3-yl]-3-phenyl-2-propyn-1-ol (19d). Aldehyde
18 was subjected to general procedure A using phenyl
4.7.4. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-butyn-1-ol (19b). Aldehyde 18 was subjected

B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
9009
acetylene and n-butyllithium to provide alcohol 19d
(250 mg, 96%) as a white solid. 1H NMR (CDCl3) d
8.10 (d, 1H), 7.87 (dd, 2H), 7.44–7.41 (m, 2H), 7.37–7.33
(m, 3H), 7.25–7.19 (m, 3H), 7.02 (d, 1H), 6.02 (d, 1H), 2.66
(d, 1H); 19F NMR (CDCl3) d 2113.02; MS m/z 399
(MþNaþ).
1H), 4.53 (d, 1H), 4.40 (m, 1H), 4.31 (d, 1H), 4.05 (m, 1H),
3.74 (m, 1H), 3.50 (m, 1H), 2.24–1.44 (m, 22H); 19F NMR
(CDCl3) d 2113.75; MS m/z 571 (Mþ1).
4.8.3. N-Cyclopentyl-3-[2-(cyclopentylamino)-6-phenyl-
pyrimidin-4-yl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-7-amine (17d). Aryl chloride 14d was reacted
according to general procedure D to provide derivative
4.7.11. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]-
pyridin-3-yl]-3-phenyl-2-propyn-1-one (20d). Alcohol
19d was oxidized according to general procedure B to
1
17d (64.1 mg, 97%) as a clear oil. H NMR (CDCl3): d
7.84–7.46 (m, 5H), 7.44–7.33 (m, 4H), 7.22 (t, 2H), 6.81 (s,
1H), 6.10–6.07 (m, 2H), 5.24 (d, 1 h), 4.49 (m, 1H), 4.05
(m, 1H), 2.17 (m, 4H), 1.87–1.59 (m, 12H); 19F NMR
(CDCl3): d 2113.49; MS m/z 533 (Mþ1). This material
was treated with anhydrous hydrogen chloride in ether to
give the corresponding HCl salt as a orange solid.
1
give ketone 20d (246 mg, 99%) as a white solid. H NMR
(CDCl3) d 8.47 (d, 1H), 7.76 (dd, 2H), 7.47 (dd, 1H), 7.34 (t,
1H), 7.24 (m, 2H), 7.16 (d, 1H), 7.13–7.05 (m, 4H).
4.7.12. 4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]-
pyridin-3-yl]-N-cyclopentyl-6-phenyl-2-pyrimidinamine
(14d). Ketone 20a was treated with guanidine 11 according
to general procedure C to provide after flash chroma-
tography (4:1, hexanes/EtOAc) pyrimidine 14d (265 mg,
84%) as a solid. 1H NMR (CDCl3) d 8.49 (d, 1H), 7.80–7.75
(m, 4H), 7.44–7.41 (m, 3H), 7.33 (m, 1H), 7.22 (t, 2H), 7.09
(d, 1H), 6.82 (s, 1H), 5.25 (d, 1H), 4.49 (m, 1H), 2.22–2.12
(m, 2H), 1.88–1.61 (m, 6H); 19F NMR (CDCl3) d 2112.89;
MS m/z 484 (Mþ1).
4.8.4. N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-hydrazino-
pyrazolo[1,5-a]pyridin-3-yl]-6-methyl-2-pyrimidin-
amine (17e). To a solution of 14b (100 mg, 0.237 mmol) in
ethanol (1 mL) was added hydrazine (500 uL, 15.9 mmol).
The reaction mixture was heated in a sealed tube at 908C
for 72 h. The mixture was cooled and diluted with EtOAc
and washed with saturated aqueous sodium bicarbonate,
water and brine. The combined organics were dried over
magnesium sulfate. Filtration and concentration followed
by flash chromatography (38:2 dichloromethane/MeOH)
provided hydrazine 17e (45 mg, 46%) as a yellow solid. Rf
0.43 (38:2 CH2Cl2–MeOH). 1H NMR (CDCl3) d 7.78 (1H),
7.62 (2H), 7.35 (1H), 7.20 (1H), 7.12 (2H), 6.45 (1H), 6.24
(1H), 5.03 (1H), 4.35 (1H), 3.85 (2H), 2.18 (3H), 2.02 (2H),
1.62 (6H); MS m/z 418 (Mþ1).
4.8. General procedure D. Amination of 14
To a solution of aryl chloride 14 (1 equiv.) in toluene
(0.2 M) was added successively racemic-BINAP (6 mol%),
cesium carbonate (1.5 equiv.), cyclopentylamine (5 equiv.),
and palladium (II) acetate (4 mol%). The resultant mixture
was heated to 958C until the reaction was judged complete
by TLC or LC/MS. The solution was cooled to room
temperature and ether was added. The organic layer was
washed with water and brine. The aqueous layer was
extracted with ether and the combined organics dried over
sodium sulfate. Purification by flash chromatography or
recrystallization provided 7-amino derivative 17.
4.8.5. N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-
1-piperazinyl)-pyrazolo[1,5-a]pyridin-3-yl]-6-methyl-2-
pyrimidinamine (17f). Aryl chloride 14b was reacted
according to general procedure D to provide derivative 17f
(80 mg, 70%) as a clear oil. Rf 0.31 (3:2 hexanes/EtOAc).
1H NMR (CDCl3) d 8.00 (d, 1H), 7.66 (m, 2H), 7.25 (d, 1H),
7.08 (t, 2H), 6.31 (d, 1H), 6.27 (s, 1H), 5.02 (d, 1H), 4.34 (m,
1H), 3.50 (m, 4H), 2.72 (m, 4H), 2.41 (s, 3H), 2.18 (s, 3H),
2.03 (m, 2H), 1.65 (m, 6H); MS m/z 486 (Mþ1). This
material was taken up in ether and treated with hydrochloric
acid in ether to yield an orange precipitate which was
isolated by filtration as a hydrochloride salt.
Alternatively, aryl chloride 14 was heated in either neat
amine at 130–1508C or a solution of excess amine in
ethanol at reflux followed by similar workup to provide
derivative 17.
4.8.1. N-Cyclopentyl-3-[2-(cyclopentylamino)-6-methyl-
4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-7-amine (17b). Aryl chloride 14b was reacted accord-
ing to general procedure D to provide derivative 17b
(41 mg, 64%) as a clear oil. 1H NMR (CDCl3): d 7.69–7.62
(m, 3H), 7.28 (t, 1H), 7.12 (t, 2H), 6.21 (s, 1H), 6.02–5.99
(m, 2H), 5.05 (d, 1H), 4.33 (m, 1H), 3.99 (m, 1H), 2.15
(s, 3H), 2.15–1.45 (m, 16H); 19F NMR (CDCl3) d 2113.70;
MS m/z 471 (Mþ1). This material was treated with
anhydrous hydrochloric acid in ether to provide a hydro-
chloride salt as a yellow solid.
4.8.6. N-Cyclopentyl-4-[2-(4-fluorophenyl)-7-(4-methyl-
1-piperazinyl)pyrazolo[1,5-a]pyridin-3-yl]-6-phenyl-2-
pyrimidinamine hydrochloride (17g). Aryl chloride 14d
was reacted according to general procedure D to provide
derivative 17g (70 mg, 99%) as an oil. This material was
taken up in ether and treated with hydrochloric acid in ether
to yield a yellow precipitate which was isolated by filtration
as a hydrochloride salt. 1H NMR (DMSO-d6) d 11.18
(broad, 1H), 8.22 (d, 1H), 7.78–7.73 (m, 4H), 7.63–7.36
(m, 6H), 6.77 (s, 1H), 4.29 (broad, 1H), 4.19–4.16 (m, 2H),
3.55 (m, 2H), 3.39–3.29 (m, 4H), 2.83 (d, 3H), 1.95 (m,
2H), 1.73–1.59 (m, 6H); 19F NMR (DMSO-d6) d 2112.68;
MS m/z 548 (Mþ1).
4.8.2. N-Cyclopentyl-3-{2-(cyclopentylamino)-6-[(tetra-
hydro-2H-pyran-2-yloxy)-methyl]-4-pyrimidinyl}-2-(4-
fluorophenyl)pyrazolo[1,5-a]pyridin-7-amine (17c). Aryl
chloride 14c was reacted according to general procedure D
to provide derivative 17c (146 mg, 82%) as a white solid. 1H
NMR (CDCl3) d 7.80 (d, 1H), 7.68 (m, 2H), 7.37–7.13 (m,
3H), 6.53 (s, 1H), 6.06 (m, 2H), 5.04 (d, 1H), 4.63 (broad,
4.8.7. N 1-[3-[2-(Cyclopentylamino)-6-phenyl-4-pyrimi-
dinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-7-yl]-
1,2-ethanediamine (17h). Aryl chloride 14d was reacted
according to general procedure D to provide derivative 17h

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B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
(30 mg, 48%) as an oil. 1H NMR (CDCl3) d 7.84–7.72 (m,
6H), 7.42–7.40 (m, 3H), 7.33 (t, 1H), 7.18 (t, 1H), 6.80 (s,
1H), 6.44 (m, 1H), 6.05 (d, 1H), 5.26 (d, 1H), 4.47 (m, 1H),
3.48 (m, 2H), 3.09 (broad, 2H), 2.93 (broad, 2H), 2.13
(m, 2H), 1.83–1.56 (m, 6H); 19F NMR (CDCl3) d 2113.21;
MS m/z 508 (Mþ1). This material was taken up in ether and
treated with hydrochloric acid in ether to yield an orange
precipitate which was isolated by filtration as a hydro-
chloride salt.
atmosphere of air, at which point additional palladium on
carbon (10%, 100 mg) was added. The reaction mixture was
allowed to stir at rt 16 h. The suspension was diluted with
EtOAc and filtered through Celite. Concentration followed
by flash chromatography (4:1 hexanes/ethyl acetate)
provided pyrimidine 23 (57 mg, 43%) as a clear oil. Rf
1
0.24 (4:1 hexanes/ethyl acetate); H NMR (CDCl3) d 8.14
(s, 1H), 7.64 (m, 2H), 7.57 (d, 1H), 7.17 (m, 1H), 7.08 (t,
2H), 7.00 (d, 1H), 5.09 (d, 1H), 4.26 (m, 1H), 2.03 (m, 2H),
1.82–1.45 (m, 9H); MS m/z 422 (Mþ1). To a solution of the
product in ether was added 1 M hydrochloride in ether. The
precipitated solid was isolated to give the corresponding
hydrochloride salt.
4.8.8. 3-[2-(Cyclopentylamino)-4-pyrimidinyl]-2-(4-
fluorophenyl)-N-(4-methoxyphenyl)pyrazolo[1,5-a]pyri-
din-7-amine (17i). Aryl chloride 14a was reacted according
to general procedure D to provide derivative 17i (35 mg,
60%) as a white solid. 1H NMR (CDCl3) d 7.99 (d, 1H), 7.84
(d, 1H), 7.70–7.64 (m, 3H), 7.32–7.26 (m, 3H), 7.17 (t, 2H),
9.67 (d, 2H), 6.34–6.31 (m, 2H), 5.43 (broad, 1H), 4.35 (m,
1H), 3.85 (s, 3H), 2.11–2.03 (m, 2H), 1.83–1.55 (m, 6H);
19F NMR (CDCl3) d 2112.97; MS m/z 495 (Mþ1).
4.9.4. N-Cyclopentyl-3-[2-(cyclopentylamino)-5-methyl-
4-pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-7-amine (24). Aryl chloride 23 was reacted according
to general procedure D to provide 50 methyl derivative 24
(47 mg, 90%) as a yellow oil. Rf 0.15 (4:1 hexanes/ethyl
1
acetate). H NMR (DMSO-d6) d 8.51 (broad, 1H), 8.27 (s,
4.8.9. Methyl {[3-[2-(cyclopentylamino)-6-methyl-4-
pyrimidinyl]-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-
7-yl]amino}acetate (17j). Aryl chloride 14b was reacted
according to general procedure D to provide derivative 17j
1H), 7.65 (m, 2H), 7.41 (t, 1H), 7.28 (t, 2H), 6.97 (d, 1H),
6.74 (br, 1H), 6.25 (d, 1H), 4.14 (br, 1H), 4.05 (br, 1H), 2.09
(m, 2H), 1.96–1.42 (m, 14H), 1.64 (s, 3H); MS m/z 471
(Mþ1). To a solution of the product in ether was added 1 M
hydrochloride in ether. The precipitated solid was isolated
to give the corresponding hydrochloride salt.
1
(95 mg, 90%) as a yellow foam. H NMR (CDCl3) d 7.74
(d, 1H), 7.67 (dd, 2H), 7.30 (m, 1H), 7.13 (m, 2H), 6.56
(m, 1H), 6.24 (s, 1H), 5.90 (d, 1H), 5.07 (broad, 1H), 4.35
(m, 1H), 4.17 (d, 2H), 3.82 (s, 3H), 2.17 (s, 3H), 2.03 (m,
2H), 1.75–1.50 (m, 6H); 19F NMR (CDCl3) d 2113.61; MS
m/z 475 (Mþ1).
References
4.9. Enone cyclization method
1. Corey, L.; Spear, P. New Engl. J. Med. 1986, 314, 686.
2. Corey, L.; Handsfield, H. H. J. Am. Med. Assoc. 2000, 283,
791.
4.9.1. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-methyl-2-propen-1-ol (21). In a similar manner
as described in general procedure A from aldehyde 18
(510 mg, 1.9 mmol) and isopropenyl magnesium bromide
was obtained alcohol 21 (530 mg, 90%) as an off-white
3. (a) Elion, G. B.; Furman, P. A.; Fyfe, J. A.; De Miranda, P.;
Beauchamp, L.; Schaeffer, H. J. Proc. Natl Acad. Sci. USA
1977, 74, 5716. (b) Elion, G. B. J. Med. Virol. Suppl. 1993, 1,
2.
1
solid. Rf 0.26 (4:1 hexanes/EtOAc). H NMR (CDCl3) d
4. Corey, L.; Tyring, S.; Sacks, S.; Warren, T.; Beutner, K.; Patel,
R.; Wald, A.; Mertz, G.; Paavonen, J. Abstract of papers, 42nd
Interscience Conference on Antimicrobial Agents and Chemo-
therapy, San Diego, CA; American Society for Microbiology:
Washington, DC. 2002, LB3.
7.81–7.70 (m, 3H), 7.21–7.08 (m, 3H), 6.95 (d, 1H), 5.41
(s, 1H), 5.30 (s, 1H), 5.08 (s, 1H), 1.62 (s, 3H); MS m/z 317
(Mþ1).
4.9.2. 1-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-2-methyl-2-propen-1-one (22). In a similar
manner as in general procedure B was formed enone 22
(390 mg, 74%) as a white solid. Rf 0.29 (4:1 hexanes/
EtOAc). H NMR (CDCl3) d 7.96 (d, 1H), 7.59 (m, 2H),
7.34 (t, 1H), 7.18–7.07 (m, 3H), 5.48 (s, 1H), 5.40 (s, 1H),
1.98 (s, 3H).
5. Sexton, C. J.; Selleseth, D. W.; Jansen, R.W. Unpublished
results.
6. Alberti, M. J.; Baldwin, I. R.; Cheung, M.; Cockerill, S.; Flack,
S.; Harris, P. A.; Jung, D. K.; Peckham, G.; Peel, M. R.;
Stanford, J. B.; Stevens, K.; Veal, J. M. WO 02/16359, 2002;
Chem Abstr. 2002, 136, 200184.
1
7. Discussions of the biological profiles of these compounds will
be the subject of future publications.
4.9.3. 4-[7-Chloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyri-
din-3-yl]-N-cyclopentyl-5-methyl-2-pyrimidinamine
(23). To a suspension of guanidinium salt 11 (68 mg,
0.42 mmol) in ethanol (1 mL) was added sodium ethoxide
(138 mL, 3 M in ethanol, 0.41 mmol). A solution of enone
22 in ethanol (1 mL) was added and the reaction mixture
was allowed to stir at rt for 16 h. An additional aliquot of 11
(68 mg, 0.42 mmol) and sodium ethoxide (138 mL, 3 M in
ethanol, 0.41 mmol) in ethanol (1 mL) was added to
reaction mixture and allowed to stir an additional 24 h.
Palladium on carbon (10%, 30 mg) was added to reaction
mixture and allowed to stir at rt for 30 min under an
8. For some leading references on pyrazolo[1,5-a]pyridines see
(a) Miki, Y.; Nakamura, N.; Hachiken, H.; Takemura, S.
J. Heterocycl. Chem. 1989, 26, 1739. (b) Awano, K.; Suzue, S.
Chem. Pharm. Bull. 1992, 40, 631. (c) Akahane, A.;
Katayama, H.; Mitsunaga, T.; Kita, Y.; Kusunoki, T.; Terai,
T.; Yoshida, K.; Shiokawa, Y. Bioorg. Med. Chem. Lett. 1996,
6, 2059. (d) Zanka, A.; Uematsu, R.; Morinaga, Y.; Yasuda,
H.; Yamazaki, H. Org. Proc. Res. Dev. 1999, 3, 389.
9. Fitzgerald, R. N.; Jung, D. K.; Eaddy, J. F. WO 01/83479,
2001; Chem Abstr. 2001, 135, 357918.
10. (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem.
Soc. 1996, 118, 7215. (b) Harris, M. C.; Geis, O.; Buchwald,

B. A. Johns et al. / Tetrahedron 59 (2003) 9001–9011
9011
S. L. J. Org. Chem. 1999, 64, 6019. (c) Wolfe, J. P.; Buchwald,
S. L. J. Org. Chem. 2000, 65, 1144. (d) Hartwig, J. F. Angew.
Chem. Int. Ed. 1998, 37, 2046.
vinylogous amides such as 10 and will be discussed in future
SAR publications.
13. (a) Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard,
G. J. J. Chem. Soc. Chem. Commun. 1997, 1757. (b)
Adlington, R. M.; Baldwin, J. E.; Catterick, D.; Pritchard,
G. J. J. Chem. Soc. Perkin Trans. 1 1999, 855–866.
11. Guanidine 11 was made via a modification of methods
described in Bannard, R. A. B.; Casselman, A. A.; Cockburn,
W. F.; Brown, G. M. Can. J. Chem. 1958, 36, 1541.
12. Numerous guanidines and amidines have been condensed with