A new synthesis of 4,5,6,7-Tetrahydropyrazolo[1,5-c] pyrimidines by a retro-mannich cascade rearrangement

Article abstract of DOI:10.1071/CH13468

We discovered a new retro-Mannich reaction of in situ prepared pyrazolopyridines to give pyrazolopyrimidines that have hitherto been underrepresented in the heterocyclic chemistry literature. The isolation of a linear hydrolysis product supports a mechani

Full text of DOI:10.1071/CH13468

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 420–425
Full Paper
http://dx.doi.org/10.1071/CH13468
A New Synthesis of 4,5,6,7-Tetrahydropyrazolo[1,5-c]
pyrimidines by a Retro-Mannich Cascade Rearrangement
A
A
B
Raffaele Colombo, Kyu Ok Jeon, Donna M. Huryn,
A
A B C
, ,
Matthew G. LaPorte, and Peter Wipf
A
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Department of Pharmaceutical Sciences, University of Pittsburgh,
Pittsburgh, PA 15260, USA.
B
C
Corresponding author. Email: pwipf@pitt.edu
We discovered a new retro-Mannich reaction of in situ prepared pyrazolopyridines to give pyrazolopyrimidines that have
hitherto been underrepresented in the heterocyclic chemistry literature. The isolation of a linear hydrolysis product
supports a mechanistic hypothesis for this rearrangement process. In order to establish a broader access and explore
potential biological applications for these medicinal chemistry building blocks, we investigated the scope of the reaction
and generated small amine- as well as amide-based libraries through reductive aminations and amide couplings,
respectively.
Manuscript received: 6 September 2013.
Manuscript accepted: 28 September 2013.
Published online: 28 October 2013.
coworkers[17] and subsequently explored by Cecchi et al.[18] as
benzodiazepine receptor ligands and by Poldermann et al.[19] as
analgesic agents (Fig. 2).
Inspired by the novelty of the synthetic transformation from
9 to 11 and motivated by the potentially interesting biological
profile of compounds containing this underutilized building
block, we decided to explore the scope of the transformation
and generate a small collection of derivatives.
Introduction
In spite of the ubiquitous presence of heterocycles in natural
products and their major commercial significance for pharma-
ceutical and agrochemical products, the universe of heterocyclic
compounds has not been exhaustively explored.[1,2] In addition
to improved physicochemical properties such as solubility and
polarity,[3] metabolic stability[4] and patentability[5] are major
driving forces for continued exploration of novel heterocyclic
scaffolds.[6] Serendipitous discoveries of cascade reaction
pathways often provide access to novel compounds,[7] as
exemplified in our own work in the formation of 1,2,4-triazines
1,[8] isoindolinones 2,[9] fused bisazoles 3 and 4 and spirocycles
5,[10,11] pyrrolodiazepines 6,[12] azatricyclononanes 7,[13] and
other heterocycles[14] (Fig. 1).
During a seemingly routine attempt to prepare the 4,5,6,7-
tetrahydro-1H-pyrazolo[4,3-c]pyridine 8 from hydrazine and
a,g-diketoester 9,[15] we obtained instead the 4,5,6,7-
tetrahydropyrazolo[1,5-c]pyrimidine 11 as the major product
(Scheme 1). A subsequent literature search revealed that these
heterocycles are relatively rare, and only a few synthetic
approaches have been reported, none of which used a readily
available precursor such as Claisen product 9. For example, the
structurally most closely related pyrazolopyrimidine 14 was
prepared in a [8p þ 2p] cycloaddition reaction of diazaful-
venium methide 13 with N-benzylidenebenzenesulfonamide
(Scheme 2).[16]
Experimental
General
All moisture-sensitive reactions were performed under an
atmosphere of dry nitrogen and all glassware was either dried in
an oven at 1408C or flame-dried under high vacuum before use.
1-Benzyl-3-methylpiperidin-4-one,[20] 9-benzyl-9-azabicyclo
[3.3.1]nonan-3-one,[21] 1-benzylazepan-4-one,[22] and 1-benzyl-
2,3-dihydroquinolin-4(1H)-one[23] were prepared according to
literature procedures. THF and Et2O were dried by distillation
over Na/benzophenone, and CH2Cl2 and toluene were purified
using an alumina filtration system. Reactions were monitored by
either 1H NMR at 300 MHz in [D6]DMSO, high-resolution
liquid chromatography–mass spectroscopy (LC-MS) (Thermo
Scientific Exactive spectrometer), or TLC analysis (EM Science
precoated silica gel 60 F254 plates). Visualization of TLCs was
accomplished with a 254-nm UV light and by staining with a
p-anisaldehyde solution (2.5 mL of p-anisaldehyde, 2 mL of
AcOH, and 3.5 mL of conc. H2SO4 in 100 mL of 95 % EtOH) or
a KMnO4 solution (1.5 g of KMnO4 and 1.5 g of K2CO3 in
100 mL of 0.1 % NaOH solution). Chromatography was per-
formed on 40–63-mm silica gel (Silicycle) or on a Teledyne
ISCO CombiFlash Rf. Melting points were determined using a
Laboratory Devices Mel-Temp II and are not corrected. Infrared
As a direct consequence of the rarity of synthetic approaches
to 4,5,6,7-tetrahydropyrazolo[1,5-c]pyrimidines, no informa-
tion about their biological properties is available. However, it
is likely that they can become useful building blocks in medici-
nal chemistry or exhibit biological activities on their own. For
example, the arene-fused tricyclic 5,6-dihydropyrazolo[1,5-c]
quinazolines 15 were first synthesized in 1962 by Blatter and
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

Retro-Mannich Cascade Rearrangement
421
Scientific Exactive spectrometer; Waters XBridgeTM BEH C18
2.5 mm, 2.1 ꢀ 50-mm column). All chiral compounds were
formed as racemic mixtures. Purities were determined using an
Agilent Technologies 385 evaporative light scattering detector.
Microwave reactions were performed in a Biotage Initiator 2.0
microwave reactor. 1H and 13C NMR spectra were obtained on
Bruker Avance 300, 400, 500-MHz instruments at room
temperature unless otherwise noted. Chemical shifts (d) are
reported in parts per million (ppm) with the residual solvent
peak used as an internal standard (CHCl3 d 7.26 ppm for 1H and
1
2
3
4
1
77.00 ppm for 13C; DMSO d 2.50 ppm for H and 40.45 ppm
5
6
7
1
for 13C; CH3OH d 3.34 ppm for H and 49.86 ppm for 13C).
13C NMR spectra were recorded using a proton-decoupled pulse
sequence with d1 of 2–5 s.
Fig. 1. Examples of new heterocyclic scaffolds resulting from cascade
reactions.
Experimental Procedure for the Synthesis
ϩ
ϩ
of 4,5,6,7-Tetrahydropyrazolo[1,5-c]pyrimidine 11
Sodium (0.11 g, 4.7 mmol) was added to ice-cooled EtOH
(15 mL) under a nitrogen atmosphere. After 2 h, the solution
was further cooled to ꢁ108C and diethyl oxalate (0.59 mL,
4.3 mmol) was added dropwise. N-Benzyl-piperidone (0.80 mL,
4.3 mmol) was added dropwise over 1 h. The mixture
was warmed to room temperature (rt) and stirred for 10 h.
The hydrazine monohydrate (0.23 mL, 4.7 mmol) was added
and the mixture was stirred for 5 min. Then, pyridinium
p-toluenesulfonate (PPTs) (2.2 g, 8.6 mmol, 2 equiv.) was added
and the mixture was stirred for 5–6 h at rt. The reaction was
monitored by LC-MS (gradient of 92 % water/0.1 % formic
acid, 3 % acetonitrile/0.1 % formic acid/5 % MeOH to 2 %
water/0.1 % formic acid, 93 % acetonitrile/0.1 % formic acid,
5 % MeOH). The reaction mixture was diluted with sat.
NaHCO3 (100 mL) and extracted with EtOAc (3ꢀ). The com-
bined organic layers were washed with brine, dried (Na2SO4),
and concentrated. The crude residue was purified by chroma-
tography on SiO2 (solid load, EtOAc/hexanes, 1 : 1, then EtOAc,
and finally EtOAc/MeOH, 4 : 1) to give ethyl 6-benzyl-4,5,6,7-
tetrahydropyrazolo[1,5-c]pyrimidine-2-carboxylate 11 (0.77 g,
2.7 mmol, 62 %), ethyl 5-benzyl-4,5,6,7-tetrahydro-2H-
pyrazolo[4,3-c]pyridine-3-carboxylate 8 (0.17 g, 0.60 mmol,
14 %), and ethyl 5-(2-(benzylamino)ethyl)-1H-pyrazole-3-
carboxylate 16 (0.12 g, 0.44 mmol, 10 %) as viscous oils.
Characterization data and 1H and 13C NMR spectra for
these products and all new compounds are provided as Sup-
plementary Material.
9
8
10
11
Scheme 1. Unexpected formation of pyrazolopyrimidine 11.
CO2Me
CO2Me
N
Δ
N
ϩ
N
N
R
CO2Me
CO2Me
HC
R
Ϫ
O2S
12 R ϭ H, Me
13
[8π ϩ 2π]
PhO2SNϭCHPh
CO2Me
N
R
CO2Me
N
N
PhO2S
14
Results and Discussion
Ph
In an attempt to prepare pyrazolopyridine 8, the commercially
available piperidone 10 was treated with diethyl oxalate in the
presence of sodium ethoxide in ethanol to afford the sodium salt
of diketoester 9 (Scheme 3).[24] In order to avoid the isolation of
polar intermediate 9-Na, we treated the reaction mixture directly
with hydrazine hydrate and acetic acid at room temperature for
3 h (Scheme 3). After workup and chromatographic purification,
11 was obtained in 43 % yield in addition to 19 % of the origi-
nally expected pyrazolopyridine 8 and ,35 % of the pyrazole
amine 16. The 1H NMR and 13C NMR spectra of 11 showed the
presence of methylene protons (6.60 and 106.1 ppm respec-
tively) that were inconsistent with structure 8.
Scheme 2. Cycloaddition approach to pyrazolopyrimidine 14.
15a:
15b:
15c:
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
–
ϭ
Fig. 2. Biologically active 5,6-dihydropyrazolo[1,5-c]quinazolines.
spectra were obtained on either a Nicolet Avatar 360, a Smiths
Detection IdentifyIR Fourier-transform (FT)-IR spectrometer,
or Perkin Elmer attenuated total reflection IR. Mass spectra were
obtained on a high resolution LC-MS instrument (Thermo
The isolation of pyrazole 16 suggested a possible reac-
tion pathway involving a retro-Mannich fragmentation of
pyrazolopyridine 8-t to generate the pyrazolopyrimidine 11

422
R. Colombo et al.
Ϫ
ϩ
ϩ
Ϫ
Њ
Ϫ
19
20
21
9
10
ϩ
ϩ
11
Scheme 3. One-pot synthesis of pyrazoles 8, 11, and 16.
8
16
22
23
Scheme 5. Formation of pyrrolodiazepine 23 by a piperidine retro-
Mannich reaction.
ϩ
Ϫ
ϩ
Ϫ
ϩ
24
25
26
ϭ
Hϩ
ϪHϩ
Scheme 6. Formation of pyrrole 27.
ϩ
8-t
18
11
explain the isolation of 27 after treatment of tropenone 24 with
ethylene glycol in the presence of catalytic amounts of
p-toluenesulfonic acid (Scheme 6).[25j] The 2-alkylated pyrrole
27 was obtained as the major product after acetalization of the
intermediate ketone 26.
ϩ
We investigated the scope of this new reaction by subjecting
substrates 28, 30, and 32 to the reaction with diethyl oxalate and
sodium ethoxide, followed by hydrazine in the presence of
acetic acid (Scheme 7). Moderate yields of the retro-Mannich
products 29 and 31 were obtained from the a-methylated
piperidone 28 and the bicyclic ketone 30, respectively, in
addition to minor amounts of the corresponding pyrazolopyr-
idines and unidentified side products that were not quantified. In
contrast, treatment of the dihydroquinolone 32 under identical
reaction conditions resulted in the exclusive formation of the
pyrazoloquinoline 34 (95 % based on recovered 32, 40 %
isolated yield), presumably formed by air oxidation of the
intermediate dihydroquinoline 33. It is likely that the stabiliza-
tion resulting from the conjugation of the pyrazole to the
benzene ring, in addition to the inductive decrease in the
electron density of the aniline nitrogen, prevents the retro-
Mannich ring opening of 33 before oxidation to 34.
We also evaluated the effect of the ring size in the
b-aminoketone starting materials (Scheme 8). The five-membered
substrate 35 underwent a smooth Claisen condensation with
diethyl oxalate to give sodium salt 36, but cyclocondensation
with hydrazine was sluggish under the standard conditions and
stopped at hydrazone 37. More forcing conditions were nece-
ssary to convert 37 into the pyrrolopyrazole 38; however, no
16
Scheme 4. Mechanistic hypothesis for the formation of 11 and 16.
(Scheme 4).[25] Cyclization of hydrazone 17 leads to the
expected 8 via its tautomer 8-t; however, this compound can
undergo a ring-opening retro-Mannich reaction to give iminium
ion 18. Hydrolysis of 18 results in the formation of the observed
pyrazole side product 16, whereas an addition reaction by the
proximal pyrazole nitrogen leads to 11. Interestingly, a similar
reaction sequence was previously observed in our laboratory in
the nitrile ylide cycloaddition with acetylenedicarboxylate
(Scheme 5).[12]
Microwave heating of oxazolinone 19 generated the sulfur-
stabilized nitrile ylide 20, which underwent a 1,3-dipolar
cycloaddition with dimethyl acetylenedicarboxylate to give
2H-pyrrole 21, a tautomer that is isoelectronic with the key
4H-pyrazole 8-t. The retro-Mannich reaction of the piperidine
ring in intermediate 21 resulted in iminium ion 22, which
cyclized to give the seven-membered aminal 23.
A related retro-Mannich process that is also in agreement
with the reaction mechanism proposed in Scheme 4 was used to

Retro-Mannich Cascade Rearrangement
423
Њ
Њ
Ϫ
Ϫ
35
36
28
29
Њ
Њ
Ϫ
37
38
30
31
(1)
(2)
ϩ
Њ
Ϫ
32
33
39
40
air oxidation
ϩ
ϩ
34
41
42
43
Scheme 7. Reaction scope with substituted N-benzylpiperidones. brsm:
based on recovered starting material.
Scheme 8. Reaction scope of five- and seven-membered b-aminoketones.
retro-Mannich product was detected in the reaction mixture.
Similarly, the seven-membered substrate 39 was converted into
the regioisomeric mixture of sodium salts 40, and although the
subsequent conversion into the corresponding pyrazoles fol-
lowed standard conditions, only a minor amount (8 %) of the
retro-Mannich product, azepinopyrazole 43, was isolated.
Instead, the straightforward cyclocondensation products 41
and 42 were formed in high combined yield.
As an explanation of these results, we hypothesize that
the retro-Mannich reaction requires the formation of an sp3-
hybridized ring carbon b to the amine (i.e. intermediate 8-t).
However, five- and seven-membered cycloalkanes have a stron-
ger preference[26] for tautomers containing sp2-hybridized car-
bons than the six-membered 8 and are therefore thought to be
more resistant to the b-fragmentation process.
Table 1. Variation of acid promotor in the conversion of 9 into 8, 11,
and 16 (Scheme 3)
Entry
Acid
Products (isolated yield)
1
2
3
4
AcOH (3 equiv.)
–
11 (43 %), 8 (19 %), 16 (,35 %A)
B
–
AcOH (1.2 equiv.)
AcOH (2 equiv.),
NaOAc (5 equiv.)
PPTs (2 equiv.)
11 (33 %), 8 (16 %), 16 (,30 %A)
11 (49 %), 8 (16 %), 16 (,20 %A)
5
11 (62 %), 8 (14 %), 16 (,10 %A)
ACrude yield.
BThe intermediate 9-Na was the only compound observed by LC-MS.
Based on the apparent need to stabilize tautomer 8-t, or
accelerate the pyrazole tautomerization from 8 to 8-t while
suppressing the hydrolysis of 18 (Scheme 4), we decided to
revisit the formation of 11 in various acidic media (Table 1).
Whereas the original protocol used 3 equiv. of acetic acid (entry 1),
the reaction did not proceed in the absence of acid promotor and
the sodium salt of b-diketone 9 was the sole product observed by
LC-MS analysis (entry 2). In the presence of 1.2 equiv. of acetic
acid (entry 3), both pyrazoles 11 and 8 were formed but yields
were slightly reduced. Increasing the acetic acid content to
2 equiv. and adding sodium acetate as a buffer had a significant
positive effect on the formation of the retro-Mannich reaction.
Product 11 was now isolated in 49 % yield and increased
selectivity over 8 and 16 (entry 4). In contrast, the use of
stronger acids such as p-toluenesulfonic acid (TsOH), triflic
acid, and Lewis acids such as BF3–etherate led to general
decomposition and only trace amounts of 11 (not shown).
Pyridinium p-toluenesulfonate (2 equiv.) ultimately provided
the best yield of the pyrazolopyrimidine 11 (62 %), with only
10–14 % of each of the side products 8 and 16 formed (entry 5).
In spite of its aminal substructure, pyrazolopyrimidine 11
proved to be quite resistant to hydrolysis. A 0.7 mM test solution
in phosphate buffered saline (PBS) at pH 7.3 did not show any

424
R. Colombo et al.
Conclusions
In the course of a standard conversion of b-diketone 9 to
pyrazolopyridines, we found that six-membered fused pyrazoles
such as 9 can rearrange to pyrazolopyrimidines 11 through a
retro-Mannich reaction followed by an intramolecular aminal
formation. The mechanistic subtleties of the retro-Mannich
fragmentation currently limit this process to six-membered
fused-ring systems among the five-, six-, and seven-membered
heterocycles investigated here. In spite of the present limitation
in scope, the substitution pattern of the pyrazolopyrimidines is
well suited for further derivatization, as demonstrated in the
generation of two small amine- and amide-based libraries.
The resulting building blocks will likely be useful for future
medicinal chemistry structure–activity relationship studies.
Ϫ
Њ
45
46
47
48
49
50
51
ϭ
ϭ
11
44
ϭ
ϭ
ϭ
ϭ
ϭ
Scheme 9. Reductive aminations. DCE: 1,2-dichloroethane.
Supplementary Material
Experimental details, and 1H and 13C NMR spectra for all
compounds are available on the Journal’s website.
Acknowledgements
The authors thank the NIH (in particular the NIGMS CMLD Program
GM067082, P50 Centers for Chemical Methodologies and Library Devel-
opment, as well as P41GM081275) for financial support and Mr Peter
Chambers for LC-MS analyses.
ϭ
11
52
53
54
55
56
57
58
59
60
61
62
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
ϭ
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