Three-Component Coupling of Aldehydes, Aminopyrazoles, and Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C-H Activation: Synthesis of Pyrazolo[1,5- a]pyrimidines

Article abstract of DOI:10.1021/acs.joc.8b02606

An efficient, three-component strategy for Rh(III)-catalyzed annulation of readily available 3-aminopyrazoles, aldehydes, and sulfoxonium ylides to give diverse pyrazolo[1,5-a]pyrimidines is disclosed. The reactions were performed under straightforward benchtop conditions using microwave heating with short reaction times. Good yields were obtained for many substituted aminopyrazoles and a very large variety of aromatic and heteroaromatic aldehydes, including those incorporating electron-withdrawing, electron-donating, basic nitrogen, halide and acidic functionality. Ester and methoxy functionalities could also be directly installed on the pyrimidine ring by employing ethyl glyoxylate and trimethyl orthoformate in place of the aldehyde, respectively. In addition, a range of sulfoxonium ylides provided products in good yields to establish that aryl, heteroaryl, and branched and unbranched alkyl substituents can be introduced with this reagent. Finally, the first use of a formyl sulfoxonium ylide in a chemical transformation enabled the preparation of products with only a single substituent on the pyrimidine ring as introduced by the aldehyde coupling partner. For the formyl ylide, a one-pot, stepwise reaction sequence was used to prevent competitive condensation of the formyl group with the aminopyrazole.

Full text of DOI:10.1021/acs.joc.8b02606

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Three-Component Coupling of Aldehydes, Aminopyrazoles, and
Sulfoxonium Ylides via Rhodium(III)-Catalyzed Imidoyl C−H
Activation: Synthesis of Pyrazolo[1,5‑a]pyrimidines
Gia L. Hoang, Andrew D. Streit, and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect St., New Haven, Connecticut 06520, United States
S
* Supporting Information
ABSTRACT: An efficient, three-component strategy for Rh(III)-
catalyzed annulation of readily available 3-aminopyrazoles, alde-
hydes, and sulfoxonium ylides to give diverse pyrazolo[1,5-
a]pyrimidines is disclosed. The reactions were performed under
straightforward benchtop conditions using microwave heating with
short reaction times. Good yields were obtained for many
substituted aminopyrazoles and a very large variety of aromatic
and heteroaromatic aldehydes, including those incorporating
electron-withdrawing, electron-donating, basic nitrogen, halide and
acidic functionality. Ester and methoxy functionalities could also be
directly installed on the pyrimidine ring by employing ethyl
glyoxylate and trimethyl orthoformate in place of the aldehyde,
respectively. In addition, a range of sulfoxonium ylides provided products in good yields to establish that aryl, heteroaryl, and
branched and unbranched alkyl substituents can be introduced with this reagent. Finally, the first use of a formyl sulfoxonium
ylide in a chemical transformation enabled the preparation of products with only a single substituent on the pyrimidine ring as
introduced by the aldehyde coupling partner. For the formyl ylide, a one-pot, stepwise reaction sequence was used to prevent
competitive condensation of the formyl group with the aminopyrazole.
this three-component coupling reaction, imines that are
formed in situ from readily available aldehydes 5 and
aminoazoles 6 undergo Rh-catalyzed annulation with sulfoxo-
nium ylides 7, which are stable, crystalline carbene equivalents
that are increasingly used in Rh(III)-catalyzed C−H
functionalization.8,9 The rapid preparation of diverse pyrazo-
lopyrimidines 8 is further facilitated by the use of a
commercially available and air-stable Rh(III) catalyst, con-
venient benchtop setup, and short reaction times with
microwave heating.
High functional group compatibility is an important aspect
of this three-component reaction, with unhindered basic
heterocycle nitrogens, amides, esters, secondary and tertiary
carbamates, halides, carboxylic acids and acidic secondary
anilides all successfully incorporated. Ester and methoxy
functionalities can be directly installed on the pyrimidine
ring by employing ethyl glyoxylate and trimethyl orthoformate
in place of the aldehyde, respectively.
INTRODUCTION
■
Fused [5,6]-bicyclic bridgehead nitrogen heterocycles are
privileged pharmacophores in drug discovery. The azolopyr-
imidines are the most prevalent subclass and are featured in
many USFDA-approved drugs and even more clinical
candidates.1,2 We have recently reported the first examples of
imidoyl C−H activation via Rh(III)-catalyzed two-component
annulations of N-azolo imines 1 with alkynes, diazoketones
and sulfoxonium ylides to give azolopyrimidines 2 (Scheme
1A).3,4 Moreover, annulations with 1,4,2-dioxazol-5-one
amidating reagents afforded a wide range of azolo[1,3,5]-
triazines 3.5,6 A particularly attractive feature of the
aforementioned approach is the large number of diverse N-
azolo imines 1 that can readily be prepared from commercially
available aminoazoles and aldehydes.
Multicomponent reactions enable access to complex
structures from simple precursors. In work relevant to N-
fused [5,6]-bicyclic heterocycle synthesis, the Groebke−
́
Blackburn−Bienayme (GBBR) reaction is a popular and
We also report the efficient preparation of pyrazolopyr-
imidines 8 with only a single substituent on the pyrimidine ring
(bottom of Scheme 1C). In a one-pot reaction, stepwise
formation of N-azolo imines is followed by the addition of
formyl ylide 7i and the Rh(III) catalyst. To our knowledge,
efficient approach (Scheme 1B).7 In this three-component
reaction, imines formed in situ couple with isocyanides to
afford a wide range of fused imidazole bridgehead nitrogen
heterocycles 4.
Herein, we report the multicomponent synthesis of
pyrazolopyrimidines 8 (Scheme 1C), which are found in
more approved drugs and clinical candidates than any other
subclass of [5,6]-bicyclic bridgehead nitrogen heterocycles.1 In
Received: October 9, 2018
© XXXX American Chemical Society
A
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Scheme 1. Fused [5,6]-Bicyclic Bridgehead Nitrogen
Heterocycle Synthesis
Table 1. Reaction Parameters for Annulation to
Pyrazolopyrimidine 8
a
b
entry
variation
yield (%)
1
2
3
none
[Cp*RhCl2]2 (5%)
no Rh
75
61
0
4
5
6
7
8
9
10
11
12
13
14
15
16
17
NaOAc instead of KOAc
no KOAc
no PivOH
60
39
27
73
57
67
28
21
62
160 °C
chlorobenzene as solvent
ylide 7a (1.1 equiv)
[Cp*IrCl2]2 (5%) and AgSbF6 (20%)
[Cp*Co(MeCN)3](SbF6)2 (10%)
0.1 M
0.4 M
0.4 M, no sieves
0.4 M, [Cp*Rh(MeCN)3](SbF6)2 (5%)
0.4 M, [Cp*Rh(MeCN)3](SbF6)2 (2.5%)
0.4 M, conventional heating, 100 °C, 16 h
c
85 (82)
75
77
38
82
a
Conditions: 5a (0.20 mmol), 6a (0.10 mmol), 7a (0.15 mmol).
b
Yield determined by 1H NMR relative to 1,3,5-trimethoxybenzene as
c
external standard. Isolated yield of a 0.30 mmol scale (see Scheme
2).
Cp*Rh(III) catalysis, Cp*Ir(III) and Cp*Co(III) catalysts
were much less effective (Table 1, entries 10 and 11).
Concentration is important, as might be expected for a
multicomponent reaction (Table 1, entries 12 and 13), with a
higher concentration (0.4 M), resulting in an appreciable
increase in yield (Table 1, entry 13). We did not explore
further increases in the concentration, because of the amount
of 3 Å sieves used (ca. 100 mg per 0.1 mmol of limiting
reagent), although it should be noted that only a modest
reduction in yield was observed when 3 Å sieves were not
added (Table 1, entry 14).
Consistent with our goal to provide access to diverse
pyrazolopyrimidines 8 at short reaction times, we chose 10
mol % catalyst loading for evaluating the substrate scope.
However, 5 and 2.5 mol % catalyst loadings did afford
significant amounts of the desired product (Table 1, entries
15 and 16). Therefore, lower catalyst loadings are likely to be
applicable to many starting material combinations (vide infra),
as well as by employing more forcing reaction conditions.
Finally, an 82% yield for this three-component reaction was
observed by employing conventional heating for 16 h at 100
°C, which is a temperature lower than the boiling point of the
dioxane solvent (Table 1, entry 17).
this is the first chemical transformation of a formyl
sulfoxonium ylide.
RESULTS AND DISCUSSION
■
A large variety of reaction parameters were first examined for
coupling benzaldehyde (5a), aminopyrazole 6a, and sulfoxo-
nium ylide 7a to give pyrazolopyrimidine 8aaa (Table 1). This
investigation established that good yields of 8aaa could be
obtained by benchtop setup using the commercially available
and air-stable cationic catalyst [Cp*Rh(MeCN)3](SbF6)2 with
KOAc, pivalic acid (PivOH), and 3 Å sieves as additives in
dioxane (0.2 M) under microwave (MW) conditions at 150 °C
for 1 h (Table 1, entry 1). When the halide was not abstracted
from [Cp*RhCl2]2, a slight reduction in yield of the product
was observed (Table 1, entry 2). As expected, when a Rh(III)
catalyst was not added, no product was obtained (Table 1,
entry 3). NaOAc was found to be less effective than KOAc
(Table 1, entry 4), and completely removing the base led to a
further reduction in the yield (Table 1, entry 5). Removing the
PivOH also resulted in a significantly lower yield (Table 1,
entry 6). Increasing the temperature to 160 °C did not
improve the yield, indicating that more forcing conditions are
not necessary (Table 1, entry 7). Chlorobenzene, which is a
typical solvent for microwave reactions, was tested and
determined to be less effective (Table 1, entry 8). Reducing
the amount of sulfoxonium ylide (1.1 equiv) only led to a
slightly lower yield (Table 1, entry 9). In comparison to
Using the optimal reaction conditions (i.e., Table 1, entry
13), we first explored aldehyde scope for three-component
coupling with aminopyrazole 6a and sulfoxonium ylide 7a
(Scheme 2). Benzaldehydes with electron-withdrawing and
electron-donating groups at the para-position gave pyrazolo-
pyrimidines 8baa and 8caa in 78% and 80% yields,
respectively, establishing that the reaction is effective,
B
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a
Scheme 2. Aldehyde Scope for Three-Component Synthesis of Pyrazolopyrimidines 8
a
b
Standard conditions with 5 (0.60 mmol), 6a (0.30 mmol), and 7a (0.45 mmol). 0.2 M.
regardless of the electronic properties of the aldehyde input.
Benzaldehydes substituted at the meta- and ortho-positions
were also effective coupling partners, as exemplified by the
halo-substituted products 8daa and 8eaa, respectively.
However, a moderate reduction in yield was observed for
ortho-substituted product 8eaa.
Five-membered furancarboxaldehydes, thiophenecarboxalde-
hydes, and pyrazolecarboxaldehydes provided 8laa−8naa in
excellent yields (81%−85%). Notably, the N-alkyl pyrazolyl
motif in 8naa is incorporated into several approved kinase
inhibitor drugs and drug candidates with [5,6]-bicyclic
nitrogen heterocycle pharmacophores, such as the approved
janus kinase inhibitor drugs ruxolitinib and baricitinib.11 Lastly,
enolizable aldehydes provide the desired pyrazolopyrimidines
8 in poor yields, as exemplified by 8oaa obtained in 13% yield
from acetaldehyde.
We next investigated the scope for the sulfoxonium ylides 7
(Scheme 3). Significantly, these ylides can readily be prepared
by straightforward one-step protocols from trimethylsulfoxo-
nium iodide and acid chlorides or activated esters.8,9 In
addition to employing N-Boc-piperidine ylide 7a, another
example of the incorporation of an α-branched substituent is
provided by the isopropyl substituted pyrazolopyrimidine
product 8aab, which was obtained in 79% yield. Methyl, β-
branched and N-Boc-ethyl substituted products 8aac−8aae
were also obtained in excellent yields (80%−94%). Electron-
rich and electron-poor aryl-substituted ylides efficiently
coupled to give 8aaf (89%) and 8aag (87%), respectively.
These results, when considered along with the successful
incorporation of electron-poor and electron-rich benzalde-
hydes, such as 8baa and 8caa (Scheme 2), clearly establish that
the regiospecific introduction of aromatic substituents,
Benzaldehydes bearing a large variety of useful functional
groups were effective inputs. For example, good yields were
obtained for pyrazolopyrimidine products displaying ester
(8faa), carboxylic acid (8gaa), and acidic secondary anilide
(8haa) functionality. Pyridinecarboxaldehydes were also
effective inputs. Notably, unhindered basic heterocyclic
nitrogens do not interfere with this directed C−H function-
alization reaction, as demonstrated by the incorporation of 4-
pyridinecarboxaldehyde to give 8iaa in 58% yield. The 4-
acetamido- and 4-chloro-substituted 3-pyridinecarboxalde-
hydes also coupled effectively to give 8jaa and 8kaa in 77%
and 66% yields, respectively. The chloropyridine substituent in
8kaa, as well as the bromophenyl substituent in 8daa, provide
versatile sites for incorporating additional functionality. These
examples highlight the compatibility of haloarene functionality
with the three-component reaction conditions. This outcome
contrasts with methods to elaborate pyrazolopyrimidine
frameworks by using cross-coupling to introduce aromatic
substituents, which inherently rely on reactions that proceed
via aryl halide oxidative addition.10
C
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Scheme 3. Sulfoxonium Ylide Scope for Three-Component
Synthesis of Pyrazolopyrimidines 8
Scheme 4. Aminopyrazole Scope for Three-Component
a
a
Synthesis of Pyrazolopyrimidines 8
a
Standard conditions with 5a (0.60 mmol), 6a (0.30 mmol), and 7
(0.45 mmol).
regardless of electronic properties, can be achieved. In contrast,
while the efficient preparation of pyrazolopyrimidines can be
accomplished by condensations of 3-aminopyrazole with
symmetrical 1,3-dicarbonyl compounds, this approach gen-
erally provides mixtures of regioisomers when unsymmetrical
diketones are employed.12 Finally, the effective incorporation
of a heteroaryl-substituted ylide was demonstrated by the
preparation of thiophenyl-substituted 8aah in 85% yield.
As depicted in Scheme 4, we next evaluated the scope for the
aminopyrazoles, many of which are commercially available or
straightforward to prepare in high yields.13 Using standard
conditions for 4-phenyl-substituted 3-aminopyrazole (6a), 4-
methyl-substituted 3-aminopyrazole efficiently provided pyr-
azolopyrimidine 8aba in 71% yield. Disubstituted amino-
pyrazoles also coupled efficiently to give 8aca and 8ada.
Unsubstituted and 5-tert-butyl-substituted aminopyrazoles
were also effective inputs providing 8aea in 62% and 8afa in
73% yields, respectively. Note that, for these inputs, modest
improvements in the product yields were achieved by lowering
the concentration to 0.2 M. Therefore, 0.2 M was chosen for
the evaluation of other 5-substituted-3-aminopyrazoles, includ-
ing those with methyl, isopropyl, cyclopropyl, and phenyl
substituents, which gave 8aga−8aja in reasonable yields
(49%−65%). In addition, electron-deficient 5-trifluoromethyl-
3-aminopyrazole (6k) efficiently underwent standard coupling
reaction conditions at both concentrations (0.4 and 0.2 M),
affording bicyclic product 8aka in good yield (76% and 71%,
respectively). In contrast, 2-aminoimidazoles are not effective
coupling partners, presumably because more forcing conditions
are required for aldehyde condensation to give imines.
However, we have previously reported that imines from 2-
aminoimidazoles can be prepared using Ti(OEt)4 as an acid
catalyst and water scavenger. After isolation, the imines can
then be subjected to Rh(III)-catalyzed coupling with
sulfoxonium ylides to give imidazopyrimidines in high yields.3
In some drug discovery efforts, pyrazolopyridimines with
only a single substituent on the pyrimidine ring might be
a
Standard conditions with 5a (0.60 mmol), 6 (0.30 mmol), and 7a
b
(0.45 mmol). 0.2 M.
desired. Therefore, we explored formyl sulfoxonium ylide 7i as
a potential input to give pyrazolopyrimidines 8 having only one
pyrimidine ring substituent, as introduced by the aldehyde
(Scheme 5). To the best of our knowledge, formyl sulfoxonium
ylides have never previously been employed in a chemical
transformation.
Under the optimized one-step three-component reaction
conditions, we found that the aldehyde functionality in formyl
ylide 7i effectively competes with the aldehyde input for
condensation with the aminopyrazoles. To circumvent this side
reaction, a two-step one-pot sequence was implemented
instead. The aldehyde 5 and aminopyrazole 6 are first
condensed by microwave heating at 150 °C for 30 min in
the presence of molecular sieves and PivOH. Formyl ylide 7i,
KOAc, and [Cp*Rh(MeCN)3](SbF6)2 are then added,
followed by microwave heating at 150 °C for 1 h. Note that
PivOH is added in the first step to catalyze imine formation. In
addition, the use of only 1.1 equiv rather than 1.5 equiv of
formyl ylide 7i resulted in moderately higher yields, because it
minimized competitive imine exchange during the annulation
step.
The effect of reaction concentration on this two-step, one-
pot protocol was evaluated for the preparation of pyrazolopyr-
D
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a
Scheme 5. Annulations with Formyl Ylide To Give
Pyrazolopyrimidines 8
Scheme 6. Ethyl Glyoxylate as the Aldehyde
a
a
b
5p (0.60 mmol), 6a (0.30 mmol), 7 (0.45 mmol). 7i (1.1 equiv).
(1.1 equiv). Note that the reaction was completely shut down
at high glyoxylate loading (5 equiv). In addition, this stepwise
approach was successfully applied to formyl sulfoxonium
ylide 7i to give pyrazolopyrimidine 8pai in 81%.
To directly install a methoxy group onto the pyrimidine ring,
trimethyl orthoformate (5q) was used in place of the aldehyde
input 5 (Scheme 7). For this transformation, a one-pot
a
Scheme 7. Methoxy Group Introduction
a
Standard conditions 5 (0.60 mmol), 6 (0.30 mmol), 7i (0.33 mmol).
b0.4 M. 0.1 M.
c
imidine 8aai from benzaldehyde (5a), 4-phenyl-3-amino-
pyrazole (6a), and formyl ylide 7i. At concentrations of 0.1
and 0.2 M, comparable 80% and 78% yields were obtained,
respectively. However, in contrast to the higher yield obtained
at higher concentrations for the three-component reaction of
β-keto sulfoxonium ylide 7a (see Table 1, entries 12 and 13),
at 0.4 M, a significantly lower 63% yield was observed.
Therefore, we used a reaction concentration of 0.2 M for
evaluating the coupling of formyl ylide 7i with 4-phenyl-3-
aminopyrazole 6a and different aldehydes 5. Good yields of
pyrazolopyrimidines were obtained for benzaldehydes incor-
porating the electron-deficient trifluoromethyl (8bai), elec-
tron-rich methoxy (8cai), and bromo (8dai) functionality. In
addition, pyrazolopyrimidine 8kai was obtained from 6-
chloronicotinaldehyde in 80% yield, and pyrazolopyrimidine
8nai was obtained from N-methyl-4-pyrazolecarboxaldehyde in
66% yield. Disubstituted aminopyrazoles also gave 8aci and
8adi in 82% and 72%, respectively.
Unsubstituted aminopyrazole and 5-substituted amino-
pyrazoles gave higher yields at lower concentrations. At a
concentration of 0.1 M, pyrazolopyrimidines 8aei and 8afi
were obtained in 30% and 61% yields, respectively.
To directly install an ester group onto the pyrimidine ring of
the product, we sought to employ ethyl glyoxylate (5p) as the
aldehyde input (Scheme 6). The standard one-step three-
component conditions provided the desired pyrazolopyrimi-
dine 8paa, but in <15% yield. Because of the reactive nature of
ethyl glyoxylate, we speculated that a two-step, one-pot
procedure for imine formation followed by Rh(III)-catalyzed
annulation might be more successful. Indeed, pyrazolopyr-
imidine 8paa was obtained in 82% yield by employing this
stepwise approach using only a slight excess of ethyl glyoxylate
a
b
5q (3.0 mmol), 6a (0.30 mmol), 7 (0.45 mmol). 7i (1.1 equiv).
stepwise approach was also the most effective. Consistent with
the use of trimethyl orthoformate as a low-cost dehydrating
agent, the highest yields were achieved by employing 10 equiv
of trimethyl orthoformate without the addition of sieves.
Under these conditions, pyrazolopyridimines 8qaa and 8qai
were obtained in 78% and 36% yields, respectively.
Finally, pyrazolopyrimidine 8naa was prepared on a 3-fold
larger 1 mmol scale with a benchtop setup and a lower catalyst
loading of 5 mol % (Scheme 8). Note that this lower catalyst
loading resulted in only a slight reduction in the yield to 77%
at a standard reaction temperature of 150 °C and a time of 1 h.
A plausible mechanism for this three-component coupling
reaction is depicted in Scheme 9. In accordance to our
publication on Rh(III)-catalyzed two-component annulations
of N-azolo imines with alkynes, diazoketones, and sulfoxonium
ylides,3 we propose that imine A, formed in situ from aldehyde
5 and aminopyrazole 6, undergoes concerted metalation−
deprotonation to give rhodacycle B. In this publication, we
reported the X-ray structural characterization of a catalytically
competent neutral rhodacycle analogous to B.3 Carbene
insertion of sulfoxonium ylide 7 with the release of dimethyl
sulfoxide (DMSO) then provides the six-membered rhodacycle
C. Proto-demetalation releases ketone D to regenerate the
E
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1
NMR) and (CD3)2SO (2.47 ppm for H NMR and 39.94 ppm for
13C NMR). Flash chromatography was performed with silica gel with
Scheme 8. Benchtop Reaction Setup at 1 mmol Scale
a particle size of 40−63 μm and 230−400 mesh. Partial data are
provided for infrared (IR) spectra. Melting points are reported
uncorrected. High-resolution mass spectroscopy (HRMS) spectra
were obtained using electrospray ionization (ESI) on a time-of-flight
(TOF) mass spectrometer (Yale University) or electron ionization
(EI) that was performed at the University of Illinois SCS Mass
Spectrometry Laboratory.
Preparation of Catalysts and Reactants. All aldehydes 5 and
aminopyrazoles 6 were purchased and used as received. [Cp*Rh-
(MeCN)3](SbF6)2 was synthesized according to literature proce-
dures.14 Sulfoxonium ylides 7a−7d and 7f−7h were synthesized
according to literature procedures.9f Sulfoxonium ylides 7e and 7i
were prepared according to a literature procedure used for a related
compound, with slight modifications.9f
Scheme 9. Proposed Mechanism for Annulation
tert-Butyl (4-(dimethyl(oxo)-λ6-sulfaneylidene)-3-oxobutyl)-
carbamate (7e). Ylide 7e was prepared from a literature procedure
for a related compound with slight modification.9f A mixture of
trimethylsufoxonium iodide (3.52 g, 16.0 mmol, 3.2 equiv) and
potassium tert-butoxide (1.68 g, 15.0 mmol, 3.0 equiv) in THF (125
mL) was heated to reflux (67 °C) for 2 h under nitrogen. After
cooling to room temperature (rt), a solution of 4-nitrophenyl 3-((tert-
butoxycarbonyl)amino)propanoate (1.55 g, 5.00 mmol, 1.00 equiv) in
THF (25 mL) was slowly added to the above mixture. The resulting
mixture was stirred at rt for 2 h, filtered through a pad of Celite,
washed thoroughly with CH2Cl2 and concentrated under reduced
pressure. Purification by silica gel column chromatography (5%
MeOH/CH2Cl2) afforded ylide 7e (591 mg, 45%) as a yellow solid.
Melting point (mp): 114−116 °C. FTIR (neat): 3369, 3001, 1682,
1
1553, 1523, 1391, 1364, 1276, 1170, 1033, 990, 848, 449 cm−1. H
NMR (600 MHz, CDCl3): δ 5.22 (s, 1H), 4.43 (s, 1H), 3.39 (s, 6H),
3.36 (q, J = 6.1 Hz, 2H), 2.37 (t, J = 6.1 Hz, 2H), 1.43 (s, 9H). 13C
NMR (151 MHz, CDCl3): δ 189.2, 156.1, 79.0, 70.2, 42.3, 40.0, 37.3,
28.5. HRMS (ESI): m/z [M + H]+ calcd for C11H22NO4S+, 264.1264;
found 264.1278.
active Rh(III) catalyst. Finally, under the reaction conditions,
ketone D undergoes cyclodehydration to afford the pyrazolo-
pyrimidine 8.
2-(Dimethyl(oxo)-λ6-sulfaneylidene)acetaldehyde (7i). Ylide 7i
was prepared from a literature procedure for a related compound with
slight modification.9f A mixture of trimethylsufoxonium iodide (10.6
g, 48.0 mmol, 3.2 equiv) and potassium tert-butoxide (5.05 g, 45.0
mmol, 3.0 equiv) in THF (100 mL) was heated at reflux (67 °C) for 2
h under nitrogen. After cooling to rt, to the above mixture was slowly
added a solution of ethyl formate (1.11 g, 15.0 mmol, 1.0 equiv) in
THF (10 mL). The resulting mixture was stirred at rt for 1 h, filtered
through a pad of Celite, washed thoroughly with CH2Cl2, and
concentrated under reduced pressure. Purification by silica gel column
chromatography (10% MeOH/CH2Cl2) afforded formyl ylide 7i as a
97:3 cis/trans ratio of stereoisomers (1.12 g, 62%) as a white solid.
mp: 71−73 °C. Fourier transform infrared (FTIR) spectroscopy
(neat): 3394, 3082, 3005, 2914, 2788, 1565, 1309, 1296, 1162, 1028,
949, 833, 466 cm−1. 1H NMR (400 MHz, CDCl3): δ 9.09 (trans, d, J
= 9.6 Hz, 0.03H), 8.61 (cis, d, J = 2.6 Hz, 1H), 4.61 (trans, d, J = 9.6
Hz, 0.03H), 4.35 (cis, d, J = 2.6 Hz, 1H), 3.41 (s, 6H). 13C NMR
In conclusion, we have reported the Rh(III)-catalyzed three-
component coupling of aldehydes 5, aminopyrazoles 6, and
sulfoxonium ylides 7 to generate diverse pyrazolopyrimidines
8. This method is operationally convenient with benchtop
setup and a short reaction time with microwave heating. Many
aromatic and heteroaromatic aldehydes 5 displaying diverse
functionality are effective inputs, as are numerous amino-
pyrazole derivatives 6. The reaction also proceeds in good
yields for a range of aryl, heteroaryl, and alkyl ylides 7. In
addition, the first examples of the application of a formyl
sulfoxonium ylide in a metal-catalyzed transformation were
implemented for the preparation of pyrazolopyrimidines 8 with
only a single substituent on the pyrimidine ring. Ester and
methoxy functionalities were also installed directly onto the
pyrimidine ring of the bicyclic product by employing ethyl
glyoxylate and trimethyl orthoformate in place of the aldehyde
input, respectively.
1
(101 MHz, CDCl3): δ 178.1, 71.9, 42.5. H NMR in (CD3)2SO was
also obtained to provide a different ratio of sulfoxonium ylide cis/
trans isomers (0.74:0.26), which also equilibrated slowly on the NMR
time scale as has previously been noted by Kondo and Tunemoto:15
1H NMR (400 MHz, (CD3)2SO): δ 8.84 (trans, d, J = 9.9 Hz,
0.24H), 8.46 (cis, d, J = 2.6 Hz, 0.64H), 4.70 (cis, d, J = 2.3 Hz,
0.74H), 4.53 (trans, d, J = 9.9 Hz, 0.26H), 3.47 (s, 6H). HRMS (EI):
m/z [M]+ calcd for C4H8O2S, 120.0245; found 120.0244.
General Procedure for Three-Component Reaction of
Aminopyrazoles, Aldehydes, and β-Keto Sulfoxonium Ylides
(0.3 mmol scale). Aminopyrazole (0.300 mmol, 1.00 equiv),
aldehyde (0.600 mmol, 2.00 equiv), [Cp*Rh(MeCN)3](SbF6)2 (10
mol %, 0.030 mmol, 25 mg), PivOH (1.20 mmol, 4.00 equiv, 123
mg), KOAc (0.30 mmol, 1.0 equiv, 29 mg), 3 Å molecular sieves
(∼300 mg), sulfoxonium ylide (0.450 mmol, 1.50 equiv) and dioxane
(0.400 M, 0.750 mL) were added to a flame-dried 2−5 mL Biotage
microwave vial (No. 351521) charged with a stir bar on the benchtop.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all commercially
available reagents were purchased and used as received. Solvents
including 1,4-dioxane, tetrahydrofuran (THF), and dichloromethane
(CH2Cl2) were deoxygenated by sparging with argon. Chlorobenzene
was purified by passing through a plug of alumina before use.
Microwave reactions were performed using a microwave reactor with
an external IR sensor and in a closed reaction vessel. 1H, 13C, and 19
F
NMR spectra were recorded on 400 or 600 MHz spectrometers.
Chemical shifts [δ (ppm)], coupling constants [J (Hz)], multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, pent = pentet, m =
multiplet, br = broad), and integration are reported. Chemical shifts
1
for H and 13C NMR are reported relative to residual undeuterated
1
solvent in CDCl3 (7.24 ppm for H NMR and 76.99 ppm for 13C
F
DOI: 10.1021/acs.joc.8b02606
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The Journal of Organic Chemistry
Article
The vial was capped with a Teflon-lined cap, flushed with nitrogen for
∼2 min, and then heated with a Biotage Initiator+ (No. 356007),
which employs an external IR sensor and a closed reaction vessel. The
resultant mixture was stirred in the microwave reactor for 1 h at 150
°C, using the following settings (absorption level, low; vial type, 2−5
mL; prestirring, 0; initial power, 0; dynamic deflector optimization,
ON; pressure: OFF; power, OFF; fixed hold time, ON; stir rate, 600).
After cooling to rt, the crude mixture was transferred to a separatory
funnel with CH2Cl2 (50 mL). PivOH was removed by extracting with
saturated NaHCO3 (100 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic extracts were washed with saturated NaHSO3 (10
wt %, 100 mL) to remove the remaining aldehyde.16 The organic layer
was dried (anhydrous Na2SO4) and concentrated under reduced
pressure. The product was purified by silica gel column chromatog-
raphy.
tert-Butyl 4-(3,5-diphenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8aaa). The reaction was performed
according to the general procedure employing 47.8 mg (0.300
mmol, 1.00 equiv) of aminopyrazole 6a, 61.0 μL (0.600 mmol, 2.00
equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a. Purification by silica gel column chromatography (10%−30%
Et2O/hexanes) afforded 8aaa (112 mg, 82%) as a yellow solid. 1H and
13C NMR spectra matched with previously reported literature.3 1H
2.00 equiv) of aldehyde 5d, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (10%−40%
Et2O/hexanes) afforded 8daa (114 mg, 71%) as a yellow solid. mp:
168−171 °C. FTIR (neat): 1682, 1563, 1429, 1234, 1166, 1126,
1078, 946, 795, 760, 623, 533 cm−1. 1H NMR (400 MHz, CDCl3): δ
8.44 (s, 1H), 8.26 (t, J = 1.8 Hz, 1H), 8.16−8.11 (m, 2H), 8.09 (ddd,
J = 7.9, 1.8, 1.0 Hz, 1H), 7.61 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.47 (t, J
= 7.8 Hz, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.31−7.25 (m, 1H), 7.06 (s,
1H), 4.55−4.20 (m, 2H), 3.78 (tt, J = 12.1, 3.4 Hz, 1H), 3.15−2.77
(m, 2H), 2.28−2.16 (m, 2H), 1.84−1.66 (m, 2H), 1.49 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 154.6, 154.2, 152.5, 144.9, 142.6, 139.5,
133.2, 132.1, 130.4, 130.3, 128.8, 126.3, 126.3, 125.9, 123.1, 111.1,
101.2, 79.8, 43.9, 36.7, 29.3, 28.5. HRMS (ESI): m/z [M + H]+ calcd
+
for C28H30BrN4O2 , 533.1547; found 533.1573.
tert-Butyl 4-(5-(2-chlorophenyl)-3-phenylpyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8eaa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 67.6 μL (0.600 mmol,
2.00 equiv) of aldehyde 5e, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (5%−20%
EtOAc/hexanes) afforded 8eaa (67.5 mg, 46%) as a yellow solid. mp:
194−196 °C. FTIR (neat): 1688, 1609, 1564, 1425, 1231, 1163,
1126, 946, 758, 696, 516 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.46
(s, 1H), 8.14−8.05 (m, 2H), 7.81−7.74 (m, 1H), 7.55−7.47 (m, 1H),
7.46−7.37 (m, 4H), 7.26−7.20 (m, 1H), 7.10 (s, 1H), 4.49−4.20 (m,
2H), 3.79 (tt, J = 12.1, 3.3 Hz, 1H), 3.08−2.89 (m, 2H), 2.30−2.17
(m, 2H), 1.80−1.65 (m, 2H), 1.47 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 156.1, 154.7, 151.1, 144.9, 142.2, 137.8, 132.3, 132.1,
131.8, 130.6, 130.4, 128.7, 127.2, 126.3, 126.2, 111.3, 106.0, 79.8,
43.8, 36.5, 29.2, 28.4. HRMS (ESI): m/z [M + H]+ calcd for
NMR (400 MHz, CDCl3): δ 8.43 (s, 1H), 8.22−8.09 (m, 4H), 7.59−
7.39 (m, 5H), 7.26 (t, J = 7.3 Hz, 1H), 7.12 (s, 1H), 4.51−4.14 (m,
2H), 3.78 (tt, J = 12.2, 3.4 Hz, 1H), 2.98 (m, 2H), 2.32−2.11 (m,
2H), 1.86−1.65 (m, 2H), 1.49 (s, 9H). 13C NMR (101 MHz,
CDCl3): δ 155.9, 154.6, 152.1, 145.1, 142.3, 137.5, 132.3, 130.4,
128.9, 128.7, 127.3, 126.2, 126.1, 110.7, 101.4, 79.8, 43.7, 36.6, 29.4,
28.5.
+
C28H30ClN4O2 , 489.2052; found 489.2042.
tert-Butyl 4-(5-(4-(methoxycarbonyl)phenyl)-3-phenylpyrazolo-
[1,5-a]pyrimidin-7-yl)piperidine-1-carboxylate (8faa). The reaction
was performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 98.5 mg (0.600 mmol,
2.00 equiv) of aldehyde 5f, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (2%−10%
EtOAc/CH2Cl2) afforded 8faa (108 mg, 70%) as a yellow solid. mp:
>240 °C. FTIR (neat): 1716, 1692, 1406, 1274, 1233, 1166, 1119,
tert-Butyl 4-(3-phenyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-
a]pyrimidin-7-yl)piperidine-1-carboxylate (8baa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 82.0 μL (0.600 mmol,
2.00 equiv) of aldehyde 5b, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (10%−30%
Et2O/hexanes) afforded 8baa (123 mg, 78%) as a yellow foam. FTIR
(neat): 1681, 1422, 1314, 1237, 1157, 1113, 1063, 768, 725, 692
1
1109, 947, 767, 699 cm−1. H NMR (400 MHz, CDCl3): δ 8.45 (s,
1
cm−1. H NMR (400 MHz, CDCl3): δ 8.46 (s, 1H), 8.26 (d, J = 8.2
1H), 8.26−8.12 (m, 6H), 7.47 (t, J = 7.7 Hz, 2H), 7.28 (t, J = 7.4 Hz,
1H), 7.14 (s, 1H), 4.49−4.22 (m, 2H), 3.95 (s, 3H), 3.78 (tt, J = 12.1,
3.4 Hz, 1H), 3.09−2.86 (m, 2H), 2.29−2.16 (m, 2H), 1.86−1.68 (m,
2H), 1.49 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 166.6, 154.6,
154.5, 152.5, 144.9, 142.6, 141.4, 132.1, 131.5, 130.1, 128.8, 127.2,
126.3, 111.3, 101.4, 79.8, 52.3, 43.8, 36.7, 29.3, 28.5. HRMS (ESI):
Hz, 2H), 8.18−8.09 (m, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.52−7.43 (m,
2H), 7.32−7.26 (m, 1H), 7.12 (s, 1H), 4.51−4.17 (m, 2H), 3.79 (tt, J
= 12.1, 3.3 Hz, 1H), 3.10−2.87 (m, 2H), 2.28−2.15 (m, 2H), 1.85−
1.69 (m, 2H), 1.49 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 154.6,
154.2, 152.6, 144.9, 142.6, 140.8, 132.0, 131.9 (q, J = 32.6 Hz), 128.8,
127.6, 126.34, 126.30, 125.8 (q, J = 3.8 Hz), 124.0 (q, J = 272.2 Hz),
111.3, 101.3, 79.9, 43.7, 36.7, 29.3, 28.4. 19F NMR (376 MHz,
CDCl3): δ −62.8. HRMS (ESI): m/z [M + H]+ calcd for
+
m/z [M + H]+ calcd for C30H33N4O4 , 513.2496; found 513.2520.
4-(7-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-3-phenylpyrazolo-
[1,5-a]pyrimidin-5-yl)benzoic acid (8gaa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 90.1 mg (0.600 mmol,
2.00 equiv) of aldehyde 5g, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a with slight modification in reaction concentration (0.200 M,
1.50 mL of dioxane) and workup procedure; the reaction mixture
after diluting with CH2Cl2 was washed with citric acid monohydrate
(1 wt %, 100 mL) instead of saturated NaHCO3. Purification by silica
gel column chromatography (10%−50% EtOAc/CH2Cl2) afforded
8gaa (92.7 mg, 62%) as a yellow solid. mp: >240 °C. FTIR (neat):
1716, 1615, 1439, 1366, 1243, 1163, 1131, 1113, 787, 692, 663, 515,
526 cm−1. 1H NMR (600 MHz, (CD3)2SO): δ 13.12 (br s, 1H), 8.76
(s, 1H), 8.43 (d, J = 8.5 Hz, 2H), 8.23−8.16 (m, 2H), 8.08 (d, J = 8.5
Hz, 2H), 7.62 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.26−7.21 (m, 1H),
4.27−4.05 (m, 2H), 3.72 (tt, J = 12.1, 3.4 Hz, 1H), 3.08−2.73 (m,
2H), 2.13−1.99 (m, 2H), 1.89−1.72 (m, 2H), 1.41 (s, 9H). 13C NMR
(151 MHz, (CD3)2SO): δ 167.4, 154.8, 154.1, 153.2, 144.6, 143.1,
141.0, 132.7, 132.5, 130.2, 129.2, 128.0, 126.4, 126.2, 110.2, 102.8,
79.2, 44.2, 43.2, 36.7, 29.0, 28.6. HRMS (ESI): m/z [M + H]+ calcd
+
C29H30F3N4O2 , 523.2315; found 523.2291.
tert-Butyl 4-(5-(4-methoxyphenyl)-3-phenylpyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8caa). The reaction was
performed according to the general procedure, employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 73.0 μL (0.600 mmol,
2.00 equiv) of aldehyde 5c, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (10%−30%
Et2O/hexanes) afforded 8caa (116 mg, 80%) as a yellow solid. mp:
191−193 °C. FTIR (neat): 1693, 1602, 1426, 1388, 1250, 1173,
1
1128, 1032, 945, 823, 699, 563, 509 cm−1. H NMR (400 MHz,
CDCl3): δ 8.40 (s, 1H), 8.23−8.05 (m, 4H), 7.45 (t, J = 7.8 Hz, 2H),
7.25 (t, J = 7.3 Hz, 1H), 7.11−6.90 (m, 3H), 4.49−4.17 (m, 2H),
3.88 (s, 3H), 3.75 (tt, J = 12.2, 3.4 Hz, 1H), 2.98 (broad t, J = 10.6
Hz, 2H), 2.28−2.15 (m, 2H), 1.86−1.64 (m, 2H), 1.49 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 161.6, 155.5, 154.7, 151.9, 145.1, 142.2,
132.5, 130.0, 128.8, 128.7, 126.2, 125.9, 114.3, 110.3, 100.9, 79.8,
55.4, 43.8, 36.6, 29.4, 28.5. HRMS (ESI): m/z [M + H]+ calcd for
+
C29H33N4O3 , 485.2547; found 485.2547.
tert-Butyl 4-(5-(3-bromophenyl)-3-phenylpyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8daa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 70.0 μL (0.600 mmol,
+
for C29H31N4O4 , 499.2340; found 499.2358.
tert-Butyl 4-(5-(4-acetamidophenyl)-3-phenylpyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8haa). The reaction was
G
DOI: 10.1021/acs.joc.8b02606
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The Journal of Organic Chemistry
Article
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 97.9 mg (0.600 mmol,
2.00 equiv) of aldehyde 5h, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (10%−40%
EtOAc/CH2Cl2) afforded 8haa (128 mg, 83%) as a yellow solid. mp:
130−133 °C. FTIR (neat): 1667, 1596, 1522, 1387, 1366, 1235,
1161, 1124, 945, 768, 693, 507 cm−1. 1H NMR (400 MHz, CDCl3): δ
8.39 (s, 1H), 8.16−8.06 (m, 4H), 7.73 (br s, 1H), 7.66 (d, J = 8.4 Hz,
2H), 7.44 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.4 Hz, 1H), 7.02 (s, 1H),
4.45−4.19 (m, 2H), 3.71 (tt, J = 12.2, 3.4 Hz, 1H), 3.07−2.81 (m,
2H), 2.21 (s, 3H), 2.25−2.14 (m, 2H), 1.82−1.62 (m, 2H), 1.48 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 168.6, 155.0, 154.7, 152.0,
145.0, 142.2, 140.0, 132.9, 132.3, 128.7, 128.1, 126.1, 126.0, 119.7,
110.5, 101.0, 79.9, 43.9, 36.6, 29.3, 28.5, 24.7. HRMS (ESI): m/z [M
1.00 equiv) of aminopyrazole 6a, 49.7 μL (0.600 mmol, 2.00 equiv) of
aldehyde 5l, and 137 mg (0.450 mmol, 1.50 equiv) of ylide 7a.
Purification by silica gel column chromatography (10%−40% Et2O/
hexanes) afforded 8laa (108 mg, 81%) as a yellow solid. mp: 201−203
°C. FTIR (neat): 1681, 1610, 1426, 1292, 1229, 1167, 1005, 937,
1
765, 743, 515 cm−1. H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H),
8.15−8.07 (m, 2H), 7.59 (dd, J = 1.8, 0.8 Hz, 1H), 7.44 (t, J = 7.8 Hz,
2H), 7.31 (dd, J = 3.5, 0.8 Hz, 1H), 7.29−7.20 (m, 1H), 7.10 (s, 1H),
6.59 (dd, J = 3.5, 1.8 Hz, 1H), 4.48−4.21 (m, 2H), 3.74 (tt, J = 12.1,
3.4 Hz, 1H), 3.06−2.86 (m, 2H), 2.27−2.13 (m, 2H), 1.84−1.64 (m,
2H), 1.48 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 154.6, 152.5,
152.3, 147.7, 144.9, 144.5, 142.3, 132.3, 128.7, 126.2, 126.1, 112.7,
111.5, 110.4, 100.1, 79.7, 43.8, 36.5, 29.3, 28.5. HRMS (ESI): m/z [M
+
+ H]+ calcd for C26H29N4O3 , 445.2240; found 445.2263.
+
+ H]+ calcd for C30H34N5O3 , 512.2656; found 512.2661.
tert-Butyl 4-(3-phenyl-5-(thiophen-3-yl)pyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8maa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 52.6 μL (0.600 mmol,
2.00 equiv) of aldehyde 5m, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (5%−25%
EtOAc/hexanes) afforded 8maa (117 mg, 85%) as a yellow solid. mp:
182−185 °C. FTIR (neat): 1691, 1672, 1608, 1418, 1366, 1291,
tert-Butyl 4-(3-phenyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidin-
7-yl)piperidine-1-carboxylate (8iaa). The reaction was performed
according to the general procedure employing 47.8 mg (0.300 mmol,
1.00 equiv) of aminopyrazole 6a, 56.5 μL (0.600 mmol, 2.00 equiv) of
aldehyde 5i, and 137 mg (0.450 mmol, 1.50 equiv) of ylide 7a.
Purification by silica gel column chromatography (10%−40% EtOAc/
CH2Cl2) afforded 8iaa (78.8 mg, 58%) as a yellow solid. mp: 169−
171 °C. FTIR (neat): 1682, 1604, 1566, 1428, 1387, 1295, 1234,
1166, 1129, 942, 817, 768, 692 cm−1. 1H NMR (400 MHz, CDCl3): δ
8.79 (d, J = 5.6 Hz, 2H), 8.47 (s, 1H), 8.16−8.08 (m, 2H), 8.06−7.96
(m, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.33−7.24 (m, 1H), 7.12 (s, 1H),
4.51−4.22 (m, 2H), 3.80 (tt, J = 12.1, 3.3 Hz, 1H), 3.10−2.89 (m,
2H), 2.30−2.19 (m, 2H), 1.86−1.68 (m, 2H), 1.48 (s, 9H). 13C NMR
(101 MHz, CDCl3): δ 154.6, 153.0, 152.9, 150.7, 144.8, 144.4, 142.8,
131.8, 128.8, 126.5, 126.4, 121.1, 111.7, 101.0, 79.9, 43.8, 36.7, 29.3,
1
1237, 1163, 1134, 1068, 762, 691, 515 cm−1. H NMR (400 MHz,
CDCl3): δ 8.40 (s, 1H), 8.17−8.09 (m, 2H), 8.03 (dd, J = 3.0, 1.3 Hz,
1H), 7.84 (dd, J = 5.1, 1.3 Hz, 1H), 7.50−7.40 (m, 3H), 7.30−7.22
(m, 1H), 6.96 (s, 1H), 4.50−4.17 (m, 2H), 3.75 (tt, J = 12.1, 3.4 Hz,
1H), 3.08−2.84 (m, 2H), 2.27−2.17 (m, 2H), 1.83−1.64 (m, 2H),
1.49 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 154.7, 152.1, 151.9,
144.9, 142.3, 140.9, 132.4, 128.7, 126.7, 126.7, 126.2, 126.0, 125.9,
110.5, 101.7, 79.8, 43.8, 36.5, 29.4, 28.5. HRMS (ESI): m/z [M + H]+
calcd for C26H29N4O2S+, 461.2006; found 461.2000.
+
28.4. HRMS (ESI): m/z [M + H]+ calcd for C27H30N5O2 , 456.2394;
tert-Butyl 4-(5-(1-methyl-1H-pyrazol-4-yl)-3-phenylpyrazolo[1,5-
a]pyrimidin-7-yl)piperidine-1-carboxylate (8naa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 66.1 mg (0.600 mmol,
2.00 equiv) of aldehyde 5n, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (5%−30%
EtOAc/CH2Cl2) afforded 8naa (114 mg, 83%) as a light yellow solid.
mp: >240 °C. FTIR (neat): 1684, 1616, 1551, 1427, 1235, 1168,
1126, 999, 863, 767, 751, 695, 516 cm−1. 1H NMR (600 MHz,
CDCl3): δ 8.37 (s, 1H), 8.12−8.09 (m, 2H), 8.07 (s, 1H), 8.05 (s,
1H), 7.47−7.43 (m, 2H), 7.30−7.21 (m, 1H), 6.78 (s, 1H), 4.51−
4.14 (m, 2H), 3.99 (s, 3H), 3.73 (tt, J = 12.2, 3.4 Hz, 1H), 3.12−2.86
(m, 2H), 2.27−2.15 (m, 2H), 1.79−1.65 (m, 2H), 1.49 (s, 9H). 13C
NMR (151 MHz, CDCl3): δ 154.6, 152.0, 150.9, 145.1, 142.2, 138.4,
132.5, 130.1, 128.7, 126.1, 125.9, 122.5, 109.7, 101.4, 79.8, 44.1, 43.4,
39.4, 36.4, 29.4, 28.5. HRMS (ESI): m/z [M + H]+ calcd for
found 456.2401.
tert-Butyl 4-(5-(6-acetamidopyridin-3-yl)-3-phenylpyrazolo[1,5-
a]pyrimidin-7-yl)piperidine-1-carboxylate (8jaa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 98.5 mg (0.600 mmol,
2.00 equiv) of aldehyde 5j, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (10%−40%
EtOAc/CH2Cl2) afforded 8jaa (118 mg, 77%) as a yellow solid. mp:
>240 °C. FTIR (neat): 1696, 1598, 1520, 1384, 1364, 1305, 1232,
1167, 1122, 9945, 767, 691, 509 cm−1. 1H NMR (400 MHz, CDCl3):
δ 9.07 (d, J = 1.8 Hz, 1H), 8.47 (s, 1H), 8.46−8.40 (m, 2H), 8.39−
8.31 (m, 1H), 8.15−8.07 (m, 2H), 7.45 (t, J = 7.8 Hz, 2H), 7.29−
7.22 (m, 1H), 7.04 (s, 1H), 4.47−4.18 (m, 2H), 3.77 (tt, J = 12.1, 3.3
Hz, 1H), 3.06−2.88 (m, 2H), 2.26 (s, 3H), 2.29−2.17 (m, 2H),
1.82−1.66 (m, 2H), 1.48 (s, 9H). 13C NMR (101 MHz, CDCl3): δ
168.8, 154.6, 152.9, 152.6, 152.6, 147.1, 144.9, 142.5, 137.1, 132.1,
129.1, 128.7, 126.3, 126.2, 113.5, 110.9, 100.5, 79.8, 43.7, 36.7, 29.3,
+
C26H31N6O2 , 459.2503; found 459.2507.
+
28.5, 24.8. HRMS (ESI): m/z [M + H]+ calcd for C29H33N6O3 ,
513.2609; found 513.2619.
tert-Butyl 4-(5-methyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8oaa). The reaction was performed
according to the general procedure employing 47.8 mg (0.300
mmol, 1.00 equiv) of aminopyrazole 6a, 26.5 mg (0.600 mmol, 2.00
equiv) of aldehyde 5o and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a with slight modification in reaction concentration (0.200 M, 1.50
mL of dioxane) and in order of addition; after nitrogen flush,
acetaldehyde was added in one portion as a solution in dioxane (1.50
mL) via syringe. Purification by preparative TLC plate (UV254, 20 cm
× 20 cm, 1000 μm; 20:80:1 EtOAc/hexanes/Et3N) afforded 8oaa
(15.2 mg, 13%) as a white solid. mp: 194−196 °C. FTIR (neat):
1679, 1605, 1566, 1441, 1427, 1365, 1289, 1234, 1156, 1125, 864,
tert-Butyl 4-(5-(6-chloropyridin-3-yl)-3-phenylpyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8kaa). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 84.9 mg (0.600 mmol,
2.00 equiv) of aldehyde 5k, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (2%−10%
EtOAc/CH2Cl2) afforded 8kaa (96.3 mg, 66%) as a yellow solid. mp:
199−202 °C. FTIR (neat): 1692, 1567, 1426, 1235, 1164, 1129,
1105, 945, 826, 771, 692, 497, 474 cm−1. 1H NMR (400 MHz,
CDCl3): δ 9.11 (d, J = 2.1 Hz, 1H), 8.45 (s, 1H), 8.43 (dd, J = 8.3, 2.5
Hz, 1H), 8.14−8.05 (m, 2H), 7.52−7.40 (m, 3H), 7.32−7.25 (m,
1H), 7.05 (s, 1H), 4.49−4.20 (m, 2H), 3.78 (tt, J = 12.1, 3.3 Hz, 1H),
3.09−2.83 (m, 2H), 2.31−2.13 (m, 2H), 1.84−1.68 (m, 2H), 1.48 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 154.6, 153.1, 153.0, 152.0,
148.5, 144.8, 142.7, 137.3, 132.0, 131.8, 128.77, 126.5, 126.3, 124.5,
111.4, 100.6, 79.9, 43.7, 36.8, 29.2, 28.4. HRMS (ESI): m/z [M + H]+
1
771, 699 cm−1. H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.10−
7.95 (m, 2H), 7.41 (t, J = 7.8 Hz, 2H), 7.27−7.18 (m, 1H), 6.51 (s,
1H), 4.45−4.15 (m, 2H), 3.69 (tt, J = 12.1, 3.4 Hz, 1H), 2.94 (t, J =
13.2 Hz, 2H), 2.61 (s, 3H), 2.21−2.10 (m, 2H), 1.69−1.58 (m, 2H),
1.47 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 159.1, 154.6, 151.3,
144.9, 141.9, 132.4, 128.7, 126.2, 126.0, 109.6, 105.1, 79.8, 43.7, 36.2,
+
29.3, 28.4, 25.2. HRMS (ESI): m/z [M + H]+ calcd for C23H29N4O2 ,
+
calcd for C27H29ClN5O2 , 490.2004; found 490.2022.
393.2285; found 393.2289.
7-Isopropyl-3,5-diphenylpyrazolo[1,5-a]pyrimidine (8aab). The
reaction was performed according to the general procedure employing
tert-Butyl 4-(5-(furan-2-yl)-3-phenylpyrazolo[1,5-a]pyrimidin-7-
yl)piperidine-1-carboxylate (8laa). The reaction was performed
according to the general procedure employing 47.8 mg (0.300 mmol,
H
DOI: 10.1021/acs.joc.8b02606
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
47.8 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 61.0 μL
(0.600 mmol, 2.00 equiv) of aldehyde 5a, and 78.8 mg (0.486 mmol,
1.5 equiv) of ylide 7b. Purification by silica gel column
chromatography (25%−50% CH2Cl2/hexanes) afforded 8aab (74.1
mg, 79%) as a yellow solid. mp: 105−107 °C. FTIR (neat): 1606,
1564, 1523, 1492, 1386, 1253, 1201, 1176, 828, 763, 692, 657, 603
3,5-Diphenyl-7-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]-
pyrimidine (8aag). The reaction was performed according to the
general procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a, 61.0 μL (0.600 mmol, 2.00 equiv) of aldehyde 5a,
and 124 mg (0.469 mmol, 1.5 equiv) of ylide 7g. Purification by silica
gel column chromatography (25%−50% CH2Cl2/hexanes) afforded
8aag (109 mg, 87%) as a yellow solid. 1H, 13C, and 19F NMR spectra
matched with previously reported literature.3 1H NMR (400 MHz,
CDCl3): δ 8.48 (s, 1H), 8.27−8.16 (m, 6H), 7.87 (d, J = 8.2 Hz, 2H),
7.60−7.47 (m, 5H), 7.39 (s, 1H), 7.32 (t, J = 7.4 Hz, 1H). 13C NMR
(101 MHz, CDCl3): δ 156.0, 146.0, 145.5, 143.2, 137.2, 135.0, 132.9
(q, J = 32.9 Hz), 132.2, 130.8, 129.9, 129.2, 128.9, 127.5, 126.6, 126.5,
125.9 (q, J = 3.7 Hz), 123.9 (q, J = 272.5 Hz), 111.3, 105.5. 19F NMR
(376 MHz, CDCl3): δ −63.0.
1
cm−1. H NMR (600 MHz, CDCl3): δ 8.48 (s, 1H), 8.23−8.20 (m,
4H), 7.58−7.47 (m, 5H), 7.29 (tt, J = 7.3, 1.2 Hz, 1H), 7.20 (s, 1H),
3.95 (hept, J = 6.9 Hz, 1H), 1.54 (d, J = 7.0 Hz, 6H). 13C NMR (151
MHz, CDCl3): δ 155.9, 155.2, 145.2, 142.3, 137.7, 132.6, 130.2,
128.9, 128.7, 127.4, 126.2, 126.0, 110.5, 100.9, 28.7, 20.1. HRMS
+
(ESI): m/z [M + H]+ calcd for C21H20N3 , 314.1652; found
314.1654.
7-Isobutyl-3,5-diphenylpyrazolo[1,5-a]pyrimidine (8aac). The
reaction was performed according to the general procedure employing
47.8 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 61.0 μL
(0.600 mmol, 2.00 equiv) of aldehyde 5a, and 80.1 mg (0.454 mmol,
1.5 equiv) of ylide 7c. Purification by silica gel column
chromatography (25%−50% CH2Cl2/hexanes) afforded 8aac (85.0
mg, 87%) as a yellow solid. mp: 114−116 °C. FTIR (neat): 1607,
1564, 1523, 1389, 1197, 763, 685, 643, 595, 516 cm−1. 1H NMR (600
MHz, CDCl3): δ 8.47 (s, 1H), 8.24−8.18 (m, 4H), 7.59−7.46 (m,
5H), 7.31−7.26 (m, 1H), 7.16 (s, 1H), 3.12 (d, J = 7.3 Hz, 2H),
2.54−2.43 (m, 1H), 1.09 (d, J = 6.6 Hz, 6H). 13C NMR (151 MHz,
CDCl3): δ 155.6, 149.1, 145.4, 142.6, 137.7, 132.7, 130.4, 129.0,
128.8, 127.5, 126.3, 126.1, 110.6, 104.9, 40.2, 26.0, 22.8. HRMS
3,5-Diphenyl-7-(thiophen-2-yl)pyrazolo[1,5-a]pyrimidine
(8aah). The reaction was performed according to the general
procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a, 61.0 μL (0.600 mmol, 2.00 equiv) of aldehyde
5a, and 91.1 mg (0.450, 1.50 equiv mmol) of ylide 7h. Purification by
silica gel column chromatography (25%−50% CH2Cl2/hexanes)
afforded 8aah (89.8 mg, 85%) as a red solid. mp: 162−164 °C.
FTIR (neat): 1603, 1554, 1529, 1494, 1380, 820, 763, 715, 690, 668,
1
491 cm−1. H NMR (600 MHz, CDCl3): δ 8.56 (s, 1H), 8.39−8.37
(m, 1H), 8.26−8.19 (m, 4H), 7.74−7.71 (m, 1H), 7.69 (s, 1H),
7.59−7.47 (m, 5H), 7.33−7.27 (m, 2H). 13C NMR (151 MHz,
CDCl3): δ 155.4, 146.1, 142.6, 140.2, 137.6, 132.5, 132.1, 131.9,
131.3, 130.4, 129.0, 128.8, 127.7, 127.4, 126.5, 126.2, 110.7, 101.7.
HRMS (ESI): m/z [M + H]+ calcd for C22H16N3S+, 354.1059; found
354.1063.
+
(ESI): m/z [M + H]+ calcd for C22H22N3 , 328.1808; found
328.1803.
7-Methyl-3,5-diphenylpyrazolo[1,5-a]pyrimidine (8aad). The
reaction was performed according to the general procedure employing
47.8 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6a, 61.0 μL
(0.600 mmol, 2.00 equiv) of aldehyde 5a, and 65.2 mg (0.486 mmol,
1.5 equiv) of ylide 7d. Purification by silica gel column
chromatography (50% CH2Cl2/hexanes) afforded 8aad (68.5 mg,
80%) as a yellow solid. mp: 142−144 °C. FTIR (neat): 1605, 1563,
tert-Butyl 4-(3-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8aba). The reaction was performed
according to the general procedure employing 29.2 mg (0.300
mmol, 1.00 equiv) of aminopyrazole 6b, 61.0 μL (0.600 mmol, 2.00
equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a. Purification by silica gel column chromatography (2%−5%
EtOAc/CH2Cl2) afforded 8aba (83.6 mg, 71%) as a light yellow
solid. mp: 150−152 °C. FTIR (neat): 1673, 1616, 1430, 1381, 1238,
1
1369, 1200, 765, 692, 640, 596, 515 cm−1. H NMR (400 MHz,
1
1162, 1125, 968, 773, 690, 639, 538 cm−1. H NMR (400 MHz,
CDCl3): δ 8.46 (s, 1H), 8.23−8.10 (m, 4H), 7.56−7.41 (m, 5H),
7.31−7.22 (m, 1H), 7.17 (s, 1H), 2.84 (s, 3H). 13C NMR (101 MHz,
CDCl3): δ 155.5, 146.0, 145.0, 142.5, 137.4, 132.5, 130.3, 128.9,
128.7, 127.3, 126.2, 126.0, 110.6, 105.0, 17.5. HRMS (ESI): m/z [M
CDCl3): δ 8.10−8.04 (m, 2H), 7.95 (s, 1H), 7.53−7.41 (m, 3H), 7.01
(s, 1H), 4.47−4.15 (m, 2H), 3.73 (tt, J = 12.1, 3.3 Hz, 1H), 3.07−
2.83 (m, 2H), 2.42 (s, 3H), 2.27−2.14 (m, 2H), 1.80−1.61 (m, 2H),
1.47 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 154.6, 154.6, 151.5,
146.5, 144.5, 137.9, 130.0, 128.8, 127.2, 106.2, 100.8, 79.7, 43.7, 36.4,
+
+ H]+ calcd for C19H16N3 , 286.1339; found 286.1338.
tert-Butyl (2-(3,5-diphenylpyrazolo[1,5-a]pyrimidin-7-yl)ethyl)-
carbamate (8aae). The reaction was performed according to the
general procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a, 61.0 μL (0.600 mmol, 2.00 equiv) of aldehyde 5a,
and 129 mg (0.488, 1.5 equiv mmol) of ylide 7e. Purification by silica
gel column chromatography (25% EtOAc/hexanes) afforded 8aae
(118 mg, 94%) as a yellow solid. mp: 153−155 °C. FTIR (neat):
+
29.3, 28.5, 7.7. HRMS (ESI): m/z [M + H]+ calcd for C23H29N4O2 ,
393.2285; found 393.2298.
tert-Butyl 4-(2-methyl-3,5-diphenylpyrazolo[1,5-a]pyrimidin-7-
yl)piperidine-1-carboxylate (8aca). The reaction was performed
according to the general procedure employing 52.0 mg (0.300 mmol,
1.00 equiv) of aminopyrazole 6c, 61.0 μL (0.600 mmol, 2.00 equiv) of
aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide 7a.
Purification by silica gel column chromatography (5%−20% acetone/
hexanes) afforded 8aca (84.4 mg, 60%) as a light yellow solid. mp:
156−158 °C. FTIR (neat): 1680, 1606, 1420, 1364, 1233, 1165,
1125, 745, 768, 696, 621 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.11
(d, J = 6.7 Hz, 2H), 7.85 (d, J = 6.8 Hz, 2H), 7.53−7.40 (m, 5H),
7.31 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 4.50−4.20 (s, 2H), 3.80 (tt, J =
12.2, 3.4 Hz, 1H), 3.12−2.89 (bs, 2H), 2.68 (s, 3H), 2.35−2.16 (m,
2H), 1.82−1.70 (m, 2H), 1.50 (s, 9H). 13C NMR (151 MHz,
CDCl3): δ 155.6, 154.7, 152.2, 151.4, 146.3, 137.6, 132.8, 130.1,
128.8, 128.8, 128.4, 127.2, 126.0, 109.4, 100.9, 79.8, 44.2, 43.4, 36.3,
1
1698, 1565, 1530, 1271, 1160, 1137, 765, 685, 596, 495 cm−1. H
NMR (600 MHz, CDCl3): δ 8.44 (s, 1H), 8.25−8.13 (m, 4H), 7.56−
7.45 (m, 5H), 7.31−7.26 (m, 2H), 4.93 (br s, NH, 1H), 3.76 (q, J =
6.6 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H), 1.42 (s, 9H). 13C NMR (151
MHz, CDCl3): δ 155.9, 155.7, 146.6, 145.1, 142.5, 137.2, 132.3,
130.4, 128.9, 128.7, 127.4, 126.2, 126.1, 110.8, 104.9, 79.6, 37.5, 31.6,
+
28.3. HRMS (ESI): m/z [M + H]+ calcd for C25H27N4O2 , 415.2129;
found 415.2138.
7-(4-Methoxyphenyl)-3,5-diphenylpyrazolo[1,5-a]pyrimidine
(8aaf). The reaction was performed according to the general
procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a, 61.0 μL (0.600 mmol, 2.00 equiv) of aldehyde
5a, and 107 mg (0.473 mmol, 1.5 equiv) of ylide 7f. Purification by
silica gel column chromatography (25%−50% CH2Cl2/hexanes)
+
29.4, 28.5, 14.7. HRMS (ESI): m/z [M + H]+ calcd for C29H33N4O2 ,
469.2598; found 469.2601.
tert-Butyl 4-(2-ethyl-3-methyl-5-phenylpyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8ada). The reaction was
performed according to the general procedure employing 37.6 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6d, 61.0 μL (0.600 mmol,
2.00 equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of
ylide 7a. Purification by silica gel column chromatography (5%−20%
EtOAc/hexanes) afforded 8ada (82.0 mg, 65%) as a light yellow solid.
mp: 120−122 °C. FTIR (neat): 1689, 1617, 1425, 1364, 1292, 1232,
1
afforded 8aaf (101 mg, 89%) as a yellow solid. H and 13C NMR
spectra matched with previously reported literature.3 1H NMR (600
MHz, CDCl3): δ 8.49 (s, 1H), 8.28−8.20 (m, 4H), 8.13−8.07 (m,
2H), 7.58−7.47 (m, 5H), 7.38 (s, 1H), 7.32−7.27 (m, 1H), 7.15−
7.09 (m, 2H), 3.92 (s, 3H). 13C NMR (151 MHz, CDCl3): δ 161.9,
156.0, 146.9, 146.2, 143.0, 137.7, 132.7, 131.1, 130.5, 129.1, 128.9,
127.5, 126.5, 126.2, 123.8, 114.3, 110.6, 104.5, 55.7.
I
DOI: 10.1021/acs.joc.8b02606
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The Journal of Organic Chemistry
Article
1
1165, 1119, 770, 688 cm−1. H NMR (600 MHz, CDCl3): δ 8.13−
(s, 1H), 4.43−4.17 (m, 2H), 3.75 (tt, J = 12.1, 3.4 Hz, 1H), 3.17
(hept, J = 6.9 Hz, 1H), 3.02−2.92 (m, 2H), 2.27−2.16 (m, 2H),
1.81−1.64 (m, 2H), 1.48 (s, 9H), 1.37 (d, J = 7.0 Hz, 6H). 13C NMR
(101 MHz, CDCl3): δ 165.2, 155.7, 154.7, 151.6, 149.4, 137.9, 129.9,
128.8, 127.2, 100.6, 93.3, 79.7, 43.9, 36.4, 29.2, 28.8, 28.5, 22.9.
8.01 (m, 2H), 7.53−7.38 (m, 3H), 6.92 (s, 1H), 4.50−4.14 (m, 2H),
3.74 (tt, J = 12.1, 3.4 Hz, 1H), 3.08−2.90 (m, 2H), 2.85 (q, J = 7.6
Hz, 2H), 2.36 (s, 3H), 2.26−2.13 (m, 2H), 1.80−1.63 (m, 2H), 1.48
(s, 9H), 1.33 (t, J = 7.6 Hz, 3H). 13C NMR (151 MHz, CDCl3): δ
158.4, 154.7, 154.3, 151.2, 147.0, 138.2, 129.8, 128.8, 127.1, 102.9,
99.9, 79.7, 44.1, 43.4, 36.2, 29.3, 28.5, 21.0, 13.7, 7.0. HRMS (ESI):
+
HRMS (ESI): m/z [M + H]+ calcd for C25H33N4O2 , 421.2598;
found 421.2596.
m/z [M + H]+ calcd for C25H33N4O2 , 421.2598; found 421.2604.
tert-Butyl 4-(2-cyclopropyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-
yl)piperidine-1-carboxylate (8aia). The reaction was performed
according to the general procedure employing 37.0 mg (0.300 mmol,
1.00 equiv) of aminopyrazole 6i, 61.0 μL (0.600 mmol, 2.00 equiv) of
aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide 7a with
slight modification in reaction concentration (0.200 M, 1.50 mL of
dioxane). Purification by silica gel column chromatography (2%−10%
EtOAc/CH2Cl2) afforded 8aia (70.4 mg, 56%) as a white solid. mp:
108−110 °C. FTIR (neat): 1964, 1611, 1557, 1419, 1366, 1272,
+
tert-Butyl 4-(5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)piperidine-
1-carboxylate (8aea). The reaction was performed according to
the general procedure employing 25.0 mg (0.300 mmol, 1.00 equiv)
of aminopyrazole 6e, 61.0 μL (0.600 mmol, 2.00 equiv) of aldehyde
5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide 7a with slight
modification in reaction concentration (0.200 M, 1.50 mL of
dioxane). Purification by silica gel column chromatography (5%−
20% EtOAc/CH2Cl2) afforded 8aea (69.9 mg, 62%) as an off-white
foam. FTIR (neat): 1670, 1613, 1432, 1240, 1163, 1129, 1002, 903,
771, 693, 640, 540 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.11 (d, J =
2.4 Hz, 1H), 8.08−7.97 (m, 2H), 7.54−7.40 (m, 3H), 7.06 (s, 1H),
6.71 (d, J = 2.3 Hz, 1H), 4.47−4.21 (m, 2H), 3.77 (tt, J = 12.2, 3.2
Hz, 1H), 3.06−2.87 (m, 2H), 2.27−2.16 (m, 2H), 1.81−1.66 (m,
2H), 1.47 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 156.2, 154.6,
152.0, 148.9, 144.6, 137.6, 130.2, 128.9, 127.2, 101.5, 97.1, 79.7, 43.7,
1
1226, 1159, 1120, 981, 769, 685, 661 cm−1. H NMR (400 MHz,
CDCl3): δ 8.07−7.95 (m, 2H), 7.54−7.37 (m, 3H), 6.95 (s, 1H), 6.30
(s, 1H), 4.46−4.16 (m, 2H), 3.74 (tt, J = 12.1, 3.2 Hz, 1H), 2.96 (m,
2H), 2.27−2.08 (m, 3H), 1.77−1.64 (m, 2H), 1.48 (s, 9H), 1.11−
1.01 (m, 2H), 0.95−0.85 (m, 2H). 13C NMR (101 MHz, CDCl3): δ
161.5, 155.8, 154.7, 151.3, 149.6, 137.9, 130.0, 128.8, 127.1, 100.5,
92.4, 79.7, 43.8, 36.4, 29.3, 28.5, 10.2, 9.4. HRMS (ESI): m/z [M +
+
+
36.6, 29.3, 28.4. HRMS (ESI): m/z [M + H]+ calcd for C22H27N4O2 ,
H]+ calcd for C25H31N4O2 , 419.2442; found 419.2445.
379.2129; found 379.2131.
tert-Butyl 4-(2,5-diphenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8aja). The reaction was performed
according to the general procedure employing 47.8 mg (0.300
mmol, 1.00 equiv) of aminopyrazole 6j, 61.0 μL (0.600 mmol, 2.00
equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a with slight modification in reaction concentration (0.200 M, 1.50
mL of dioxane). Purification by silica gel column chromatography
(2%−10% EtOAc/CH2Cl2) afforded 8aja (70.6 mg, 52%) as an off-
white solid. mp: 171−173 °C. FTIR (neat): 1662, 1612, 1464, 1420,
1236, 1165, 1134, 764, 744, 691 cm−1. 1H NMR (600 MHz, CDCl3):
δ 8.07 (d, J = 6.7 Hz, 2H), 8.03 (d, J = 6.9 Hz, 2H), 7.55−7.44 (m,
5H), 7.40 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 7.01 (s, 1H), 4.51−4.23
(m, 2H), 3.86 (tt, J = 12.1, 3.4 Hz, 1H), 3.09−2.90 (m, 2H), 2.33−
2.24 (m, 2H), 1.86−1.71 (m, 2H), 1.50 (s, 9H). 13C NMR (151
MHz, CDCl3): δ 156.1, 155.9, 154.7, 151.8, 150.1, 137.7, 133.1,
130.2, 128.9, 128.7, 127.2, 126.6, 101.5, 93.8, 79.8, 44.3, 43.4, 36.7,
tert-Butyl 4-(2-(tert-butyl)-5-phenylpyrazolo[1,5-a]pyrimidin-7-
yl)piperidine-1-carboxylate (8afa). The reaction was performed
according to the general procedure employing 41.8 mg (0.300 mmol,
1.00 equiv) of aminopyrazole 6f, 61.0 μL (0.600 mmol, 2.00 equiv) of
aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide 7a with
slight modification in reaction concentration (0.200 M, 1.50 mL of
dioxane). Purification by silica gel column chromatography (2%−5%
EtOAc/CH2Cl2) afforded 8afa (95.0 mg, 73%) as a white foam. FTIR
(neat): 2961, 1690, 1610, 1533, 1449, 1364, 1233, 1164, 1120, 771,
692, 591 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.10−7.92 (m, 2H),
7.54−7.38 (m, 3H), 6.96 (s, 1H), 6.54 (s, 1H), 4.46−4.19 (m, 2H),
3.73 (tt, J = 12.1, 3.4 Hz, 1H), 3.06−2.86 (m, 2H), 2.28−2.16 (m,
2H), 1.82−1.65 (m, 2H), 1.48 (s, 9H), 1.41 (s, 9H). 13C NMR (101
MHz, CDCl3): δ 167.7, 155.5, 154.7, 151.5, 149.2, 138.0, 129.9,
128.8, 127.1, 100.5, 92.9, 79.7, 43.9, 36.7, 32.9, 30.4, 29.0, 28.5.
HRMS (ESI): m/z [M + H]+ calcd for C26H35N4O2 , 435.2755;
29.3, 28.5. HRMS (ESI): m/z [M + H]+ calcd for C28H31N4O2 ,
+
+
found 435.2760.
455.2442; found 455.2434.
tert-Butyl 4-(2-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8aga). The reaction was performed
according to the general procedure employing 29.2 mg (0.300
mmol, 1.00 equiv) of aminopyrazole 6g, 61.0 μL (0.600 mmol, 2.00
equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a with slight modification in reaction concentration (0.200 M, 1.50
mL of dioxane). Purification by silica gel column chromatography
(2%−10% EtOAc/CH2Cl2) afforded 8aga (57.6 mg, 49%) as an off-
white solid. mp: 165−167 °C. FTIR (neat): 1685, 1610, 1533, 1470,
1415, 1364, 1235, 1156, 999, 867, 772, 695, 586 cm−1. 1H NMR (400
MHz, CDCl3): δ 8.05−7.99 (m, 2H), 7.52−7.41 (m, 3H), 6.97 (s,
1H), 6.48 (s, 1H), 4.48−4.13 (m, 2H), 3.76 (tt, J = 12.2, 3.4 Hz, 1H),
3.12−2.84 (m, 2H), 2.52 (s, 3H), 2.25−2.15 (m, 2H), 1.80−1.62 (m,
2H), 1.48 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 155.9, 154.9,
154.7, 151.5, 149.7, 137.9, 130.0, 128.8, 127.2, 100.6, 96.4, 79.7, 43.8,
36.4, 29.4, 28.5, 14.8. HRMS (ESI): m/z [M + H]+ calcd for
tert-Butyl 4-(5-phenyl-2-(trifluoromethyl)pyrazolo[1,5-a]-
pyrimidin-7-yl)piperidine-1-carboxylate (8aka). The reaction was
performed according to the general procedure employing 45.6 mg
(0.300 mmol) of aminopyrazole 6k, 61.0 μL (0.600 mmol, 2.00
equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a. Purification by silica gel column chromatography (100% CH2Cl2,
then 10−25% EtOAc/hexanes) afforded 8aka (102 mg, 76%) as an
off-white solid. mp: 164−167 °C. FTIR (neat): 1684, 1612, 1423,
1232, 1161, 1128, 1103, 955, 774, 692 cm−1. H NMR (400 MHz,
1
CDCl3): δ 8.10−8.05 (m, 2H), 7.56−7.50 (m, 3H), 7.23 (s, 1H), 6.98
(s, 1H), 4.52−4.19 (m, 2H), 3.80 (tt, J = 12.1, 3.4 Hz, 1H), 3.10−
2.91 (m, 2H), 2.28−2.19 (m, 2H), 1.83−1.68 (m, 2H), 1.50 (s, 9H).
13C NMR (101 MHz, CDCl3): δ 157.8, 154.8, 152.9, 149.2, 146.8 (q,
J = 38.2 Hz), 137.1, 131.0, 129.2, 127.5, 121.4 (q, J = 269.7 Hz),
103.8, 95.9, 80.0, 43.8, 36.6, 29.4, 28.6. 19F NMR (376 MHz, CDCl3):
+
δ −62.4. HRMS (ESI): m/z [M + H]+ calcd for C23H26F3N4O2 ,
+
C23H29N4O2 , 393.2285; found 393.2286.
447.2002; found 447.1996.
tert-Butyl 4-(2-isopropyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8aha). The reaction was performed
according to the general procedure employing 37.6 mg (0.300
mmol, 1.00 equiv) of aminopyrazole 6h, 61.0 μL (0.600 mmol, 2.00
equiv) of aldehyde 5a, and 137 mg (0.450 mmol, 1.50 equiv) of ylide
7a with slight modification in reaction concentration (0.200 M, 1.50
mL of dioxane). Purification by silica gel column chromatography
(10%−40% Et2O/hexanes) afforded 8aha (81.7 mg, 65%) as a white
solid. mp: 100−102 °C. FTIR (neat): 2957, 1704, 1613, 1554, 1417,
General Procedure for Two-Step, One-Pot Annulations with
Aminopyrazoles, Aldehydes, and Formyl Sulfoxonium Ylide
7i (0.3 mmol scale). Aminopyrazole (0.300 mmol, 1.00 equiv),
aldehyde (0.600 mmol, 2.00 equiv), PivOH (1.20 mmol, 4.00 equiv,
123 mg), 3 Å molecular sieves (∼300 mg), and dioxane (0.200 M,
1.50 mL) were added to a flame-dried 2−5 mL Biotage microwave
vial (No. 351521) charged with a stir bar on the benchtop. The vial
was capped with a Teflon-lined cap, flushed with nitrogen for ∼2 min,
and then heated with a Biotage Initiator+ (No. 356007), which
employs an external IR sensor and a closed reaction vessel. The
resultant mixture was stirred in the microwave reactor for 30 min at
1
1365, 1232, 1170, 1124, 766, 683, 439 cm−1. H NMR (400 MHz,
CDCl3): δ 8.06−7.96 (m, 2H), 7.51−7.41 (m, 3H), 6.97 (s, 1H), 6.51
J
DOI: 10.1021/acs.joc.8b02606
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The Journal of Organic Chemistry
Article
150 °C using the following settings (absorption level, low; vial type,
2−5 mL; prestirring, 0; initial power, 0; dynamic deflector
optimization, ON; pressure: OFF; power, OFF; fixed hold time,
ON; stir rate, 600). After cooling to rt, the cap was opened, and
[Cp*Rh(MeCN)3](SbF6)2 (10 mol %, 0.030 mmol, 25 mg), KOAc
(0.30 mmol, 1.0 equiv, 29 mg) and formyl sulfoxonium ylide 7i
(0.330 mmol, 1.10 equiv, 39.7 mg) were added. The vial was capped
with a Teflon-lined cap, flushed with nitrogen for ∼2 min and then
heated in the microwave reactor for 1 h at 150 °C using the above
settings. After cooling to rt, the crude mixture was transferred to a
separatory funnel with CH2Cl2 (50 mL). PivOH was removed by
extracting with saturated NaHCO3 (100 mL). The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2 (2 × 50
mL). The combined organic extracts were washed with saturated
NaHSO3 (10 wt %, 100 mL) to remove remaining aldehyde.16 The
organic layer was dried (anhydrous Na2SO4) and concentrated under
reduced pressure. The product was purified by silica gel column
chromatography.
130.4, 130.3, 128.8, 126.4, 126.3, 125.9, 123.2, 111.1, 105.1. HRMS
+
(ESI): m/z [M + H]+ calcd for C18H13BrN3 , 350.0287; found
350.0294.
5-(6-Chloropyridin-3-yl)-3-phenylpyrazolo[1,5-a]pyrimidine
(8kai). The reaction was performed according to the general
procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a and 84.9 mg (0.600 mmol, 2.00 equiv) of aldehyde
5k. Purification by silica gel column chromatography (2%−10%
EtOAc/CH2Cl2) afforded 8kai (73.9 mg, 80%) as a yellow solid. mp:
>240 °C. FTIR (neat): 1612, 1560, 1413, 1314, 1129, 1104, 1022,
1
971, 817, 768, 500, 472 cm−1. H NMR (400 MHz, CDCl3): δ 9.10
(d, J = 2.5 Hz, 1H), 8.71 (d, J = 7.4 Hz, 1H), 8.46 (s, 1H), 8.43 (dd, J
= 8.4, 2.6 Hz, 1H), 8.16−8.02 (m, 2H), 7.52−7.40 (m, 3H), 7.31−
7.25 (m, 1H), 7.23 (d, J = 7.4 Hz, 1H). 13C NMR (101 MHz,
CDCl3): δ 153.3, 152.0, 148.4, 144.4, 143.6, 137.2, 135.9, 131.62,
131.58, 128.8, 126.6, 126.2, 124.6, 111.3, 104.5. HRMS (ESI): m/z
+
[M + H]+ calcd for C17H12ClN4 , 307.0745; found 307.0748.
5-(1-Methyl-1H-pyrazol-4-yl)-3-phenylpyrazolo[1,5-a]pyrimidine
(8nai). The reaction was performed according to the general
procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a and 66.1 mg (0.600 mmol, 2.00 equiv) of aldehyde
5n. Purification by silica gel column chromatography (10%−35%
EtOAc/CH2Cl2) afforded 8nai (54.3 mg, 66%) as a yellow solid. mp:
172−174 °C. FTIR (neat): 1616, 1583, 1551, 1514, 1236, 1187, 992,
887, 863, 808, 768, 690, 555, 516 cm−1. 1H NMR (400 MHz,
CDCl3): δ 8.54 (d, J = 7.3 Hz, 1H), 8.37 (s, 1H), 8.12−8.06 (m, 2H),
8.04 (d, J = 1.9 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.30−7.20 (m, 1H),
6.93 (d, J = 7.3 Hz, 1H), 3.98 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ 151.0, 144.7, 143.0, 138.5, 135.1, 132.3, 130.1, 128.7, 126.1, 126.0,
122.2, 109.6, 105.4, 39.4. HRMS (ESI): m/z [M + H]+ calcd for
3,5-Diphenylpyrazolo[1,5-a]pyrimidine (8aai). The reaction was
performed according to the general procedure employing 47.8 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6a and 61.0 μL (0.600
mmol, 2.00 equiv) of aldehyde 5a. Purification by silica gel column
chromatography (2%−5% EtOAc/CH2Cl2) afforded 8aai (63.5 mg,
78%) as a yellow solid. mp: 135−137 °C. FTIR (neat): 1612, 1559,
1521, 1493, 1413, 1267, 1192, 972, 815, 758, 682, 635, 549 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.66 (d, J = 7.4 Hz, 1H), 8.44 (s, 1H),
8.22−8.12 (m, 4H), 7.57−7.42 (m, 5H), 7.32−7.25 (m, 2H). 13C
NMR (101 MHz, CDCl3): δ 155.9, 144.7, 143.2, 137.0, 135.3, 132.2,
130.6, 128.9, 128.7, 127.3, 126.2, 126.2, 110.7, 105.3. HRMS (ESI):
+
m/z [M + H]+ calcd for C18H14N3 , 272.1182; found 272.1183.
+
3-Phenyl-5-(4-(trifluoromethyl)phenyl)pyrazolo[1,5-a]pyrimidine
(8bai). The reaction was performed according to the general
procedure employing 47.8 mg (0.300 mmol, 1.00 equiv) of
aminopyrazole 6a and 82.0 μL (0.600 mmol, 2.00 equiv) of aldehyde
5b. Purification by silica gel column chromatography (2%−5%
EtOAc/CH2Cl2) afforded 8bai (77.9 mg, 77%) as a yellow solid. mp:
130−132 °C. FTIR (neat): 1619, 1414, 1329,1318, 1122, 1104, 1071,
1015, 810, 766, 752, 691 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.69
(d, J = 7.3 Hz, 1H), 8.46 (s, 1H), 8.24 (d, J = 8.2 Hz, 2H), 8.16−8.08
(m, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.32−7.23
(m, 2H). 13C NMR (101 MHz, CDCl3): δ 154.1, 144.5, 143.5, 140.2,
135.6, 132.1 (q, J = 32.7 Hz), 131.8, 128.8, 127.6, 126.5, 126.3, 125.9
(q, J = 3.8 Hz), 123.9 (q, J = 272.3 Hz), 111.3, 105.1. 19F NMR (376
MHz, CDCl3): δ −62.8. HRMS (ESI): m/z [M + H]+ calcd for
C16H14N5 , 276.1244; found 276.1247.
2-Methyl-3,5-diphenylpyrazolo[1,5-a]pyrimidine (8aci). The re-
action was performed according to the general procedure employing
52.0 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6c and 61.0 μL
(0.600 mmol, 2.00 equiv) of aldehyde 5a. Purification by silica gel
column chromatography (5%−25% EtOAc/hexanes) afforded 8aci
(70.2 mg, 82%) as a yellow solid. mp: 138−140 °C. FTIR (neat):
1609, 1559, 1493, 1422, 816, 767, 700, 689, 594 cm−1. 1H NMR (400
MHz, CDCl3): δ 8.59 (d, J = 7.3 Hz, 1H), 8.16−8.06 (m, 2H), 7.88−
7.81 (m, 2H), 7.54−7.41 (m, 5H), 7.35−7.28 (m, 1H), 7.23 (d, J =
7.4 Hz, 1H), 2.67 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 155.7,
153.0, 145.9, 137.1, 134.4, 132.5, 130.3, 128.8, 128.7, 128.4, 127.2,
126.1, 109.3, 104.7, 14.5. HRMS (ESI): m/z [M + H]+ calcd for
+
C19H16N3 , 286.1339; found 286.1343.
+
C19H13F3N3 , 340.1056; found 340.1053.
2-Ethyl-3-methyl-5-phenylpyrazolo[1,5-a]pyrimidine (8adi). The
reaction was performed according to the general procedure employing
37.6 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6d and 61.0 μL
(0.600 mmol, 2.00 equiv) of aldehyde 5a. Purification by silica gel
column chromatography (5%−20% EtOAc/hexanes) afforded 8adi
(51.1 mg, 72%) as a yellow solid. mp: 77−79 °C. FTIR (neat): 1611,
1515, 1494, 1260, 1086, 1020, 795, 764, 742, 682, 645, 534 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.52 (d, J = 7.3 Hz, 1H), 8.14−8.03 (m,
2H), 7.54−7.40 (m, 3H), 7.09 (d, J = 7.3 Hz, 1H), 2.84 (q, J = 7.6
Hz, 2H), 2.34 (s, 3H), 1.34 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 159.2, 154.3, 146.6, 137.6, 134.3, 130.0, 128.8, 127.0,
103.8, 103.0, 20.8, 13.3, 6.8. HRMS (ESI): m/z [M + H]+ calcd for
5-(4-Methoxyphenyl)-3-phenylpyrazolo[1,5-a]pyrimidine (8cai).
The reaction was performed according to the general procedure
employing 47.8 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6a
and 73.0 μL (0.600 mmol, 2.00 equiv) of aldehyde 5c. Purification by
silica gel column chromatography (2%−5% EtOAc/CH2Cl2) afforded
8cai (66.4 mg, 73%) as a yellow solid. mp: 136−138 °C. FTIR (neat):
1604, 1563, 1412, 1251, 1180, 1023, 845, 789, 767, 694, 547 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.60 (d, J = 7.4 Hz, 1H), 8.41 (s, 1H),
8.21−8.06 (m, 4H), 7.46 (t, J = 7.8 Hz, 2H), 7.31−7.17 (m, 2H),
7.02 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H). 13C NMR (101 MHz, CDCl3):
δ 161.7, 155.5, 144.7, 143.0, 135.1, 132.3, 129.5, 128.9, 128.7, 126.1,
126.0, 114.3, 110.2, 104.8, 55.4. HRMS (ESI): m/z [M + H]+ calcd
for C19H16N3O+, 302.1288; found 302.1300.
+
C15H16N3 , 238.1339; found 238.1338.
5-Phenylpyrazolo[1,5-a]pyrimidine (8aei). The reaction was
performed according to the general procedure employing 25.0 mg
(0.300 mmol, 1.00 equiv) of aminopyrazole 6e and 61.0 μL (0.600
mmol, 2.00 equiv) of aldehyde 5a, with slight modification in reaction
concentration (0.100 M, 3.00 mL of dioxane). Purification by silica
gel column chromatography (5%−20% EtOAc/hexanes) afforded
5-(3-Bromophenyl)-3-phenylpyrazolo[1,5-a]pyrimidine (8dai).
The reaction was performed according to the general procedure
employing 47.8 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6a
and 70.0 μL (0.600 mmol, 2.00 equiv) of aldehyde 5d. Purification by
silica gel column chromatography (2%−5% EtOAc/CH2Cl2) afforded
8dai (91.4 mg, 87%) as a yellow solid. mp: 115−117 °C. FTIR
(neat): 1610, 1558, 1492, 1406, 1260, 1194, 780, 762, 686, 548, 535
cm−1. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J = 7.4 Hz, 1H), 8.45
(s, 1H), 8.28 (t, J = 1.8 Hz, 1H), 8.17−8.10 (m, 2H), 8.08 (dt, J = 7.6,
1.2 Hz, 1H), 7.61 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.48 (t, J = 7.8 Hz,
2H), 7.39 (t, J = 7.9 Hz, 1H), 7.32−7.21 (m, 2H). 13C NMR (101
MHz, CDCl3): δ 154.2, 144.5, 143.4, 139.0, 135.5, 133.4, 131.9,
1
8aei (17.5 mg, 30%) as a yellow solid. H and 13C NMR spectra
matched with previously reported literature.17 1H NMR (600 MHz,
CDCl3): δ 8.69 (d, J = 7.3 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 8.09−
8.05 (m, 2H), 7.55−7.45 (m, 3H), 7.26 (d, J = 7.4 Hz, 1H), 6.71 (d, J
= 2.2 Hz, 1H). 13C NMR (151 MHz, CDCl3): δ 156.2, 148.5, 145.6,
137.1, 135.1, 130.5, 129.0, 127.2, 105.5, 97.0.
K
DOI: 10.1021/acs.joc.8b02606
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The Journal of Organic Chemistry
Article
+
2-(tert-Butyl)-5-phenylpyrazolo[1,5-a]pyrimidine (8afi). The re-
action was performed according to the general procedure employing
41.8 mg (0.300 mmol, 1.00 equiv) of aminopyrazole 6f and 61.0 μL
(0.600 mmol, 2.00 equiv) of aldehyde 5a, with slight modification in
reaction concentration (0.100 M, 3.00 mL of dioxane). Purification by
silica gel column chromatography (10%−30% Et2O/hexanes)
afforded 8afi (45.7 mg, 61%) as a tan solid. mp: 88−90 °C. FTIR
HRMS (ESI): m/z [M + H]+ calcd for C15H14N3O2 , 268.1081;
found 268.1078.
General Procedure for Two-Step, One-Pot Annulations
Using Trimethyl Orthoformate 5q as the Aldehyde (0.3
mmol scale). Aminopyrazole 6a (0.300 mmol, 1.00 equiv, 47.8
mg) and PivOH (1.20 mmol, 4.00 equiv, 123 mg) were added to a
flame-dried 2−5 mL Biotage microwave vial (No. 351521) charged
with a stir bar on the benchtop. The vial was capped with a Teflon-
lined cap and flushed with nitrogen for ∼2 min. Under positive
nitrogen pressure, the solution of trimethyl orthoformate 5q (0.33
mL, 3.0 mmol, 10 equiv) in dioxane (0.100 M, 3.00 mL) was quickly
added. The reaction mixture was then heated with a Biotage Initiator+
(No. 356007), which employs an external IR sensor and a closed
reaction vessel. The resultant mixture was stirred in the microwave
reactor for 30 min at 150 °C, using the following settings (absorption
level, low; vial type, 2−5 mL; prestirring, 0; initial power, 0; dynamic
deflector optimization, ON; pressure: OFF; power, OFF; fixed hold
time, ON; stir rate, 600). After cooling to rt, the cap was opened, and
[Cp*Rh(MeCN)3](SbF6)2 (10 mol %, 0.030 mmol, 25 mg), KOAc
(0.30 mmol, 1.0 equiv, 29 mg) and sulfoxonium ylide 7a (0.450
mmol, 1.50 equiv, 137 mg) or formyl sulfoxonium ylide 7i (0.330
mmol, 1.10 equiv, 39.7 mg) were added. The vial was capped with a
Teflon-lined cap, flushed with nitrogen for ∼2 min, and then heated
in the microwave reactor for 1 h at 150 °C using the above settings.
After cooling to rt, the crude mixture was transferred to a separatory
funnel with CH2Cl2 (50 mL). PivOH was removed by extracting with
saturated NaHCO3 (100 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic extracts were dried (anhydrous Na2SO4) and
concentrated under reduced pressure. The product was purified by
silica gel column chromatography.
1
(neat): 1609, 1544, 1415, 1358, 1242, 793, 765, 739, 689 cm−1. H
NMR (400 MHz, CDCl3): δ 8.61 (d, J = 7.3 Hz, 1H), 8.09−7.97 (m,
2H), 7.54−7.42 (m, 3H), 7.15 (d, J = 7.3 Hz, 1H), 6.54 (s, 1H), 1.42
(s, 9H). 13C NMR (101 MHz, CDCl3): δ 168.8, 155.7, 148.9, 137.4,
134.7, 130.2, 128.9, 127.1, 104.5, 93.2, 32.8, 30.4. HRMS (ESI): m/z
+
[M + H]+ calcd for C16H18N3 , 252.1495; found 252.1485.
General Procedure for Two-Step, One-Pot Annulations
Using Ethyl Glyoxylate 5p as the Aldehyde (0.3 mmol
scale). Aminopyrazole 6a (0.300 mmol, 1.00 equiv, 47.8 mg),
PivOH (1.20 mmol, 4.00 equiv, 123 mg), and 3 Å molecular sieves
(∼300 mg) were added to a flame-dried 2−5 mL Biotage microwave
vial (No. 351521) that was charged with a stir bar on the benchtop.
The vial was capped with a Teflon-lined cap and flushed with nitrogen
for ∼2 min. Under positive nitrogen pressure, the solution of ethyl
glyoxylate 5p (65.4 μL of a 50% (v/v) in toluene, 0.330 mmol, 1.10
equiv) in dioxane (0.100 M, 3.00 mL) was quickly added. The
reaction mixture was then heated with a Biotage Initiator+ (No.
356007), which employs an external IR sensor and a closed reaction
vessel. The resultant mixture was stirred in the microwave reactor for
30 min at 150 °C using the following settings (absorption level, low;
vial type, 2−5 mL; prestirring, 0; initial power, 0; dynamic deflector
optimization, ON; pressure: OFF; power, OFF; fixed hold time, ON;
stir rate, 600). After cooling to rt, the cap was opened, and
[Cp*Rh(MeCN)3](SbF6)2 (10 mol %, 0.030 mmol, 25 mg), KOAc
(0.30 mmol, 1.0 equiv, 29 mg) and sulfoxonium ylide 7a (0.450
mmol, 1.50 equiv, 137 mg) or formyl sulfoxonium ylide 7i (0.330
mmol, 1.10 equiv, 39.7 mg) were added. The vial was capped with a
Teflon-lined cap, flushed with nitrogen for ∼2 min and then heated in
the microwave reactor for 1 h at 150 °C using the above settings.
After cooling to rt, the crude mixture was transferred to a separatory
funnel with CH2Cl2 (50 mL). PivOH was removed by extracting with
saturated NaHCO3 (100 mL). The organic layer was separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 50 mL). The
combined organic extracts were dried (anhydrous Na2SO4) and
concentrated under reduced pressure. The product was purified by
silica gel column chromatography.
tert-Butyl 4-(5-methoxy-3-phenylpyrazolo[1,5-a]pyrimidin-7-yl)-
piperidine-1-carboxylate (8qaa). The reaction was performed
according to the general procedure employing 137 mg (0.450
mmol, 1.50 equiv) of sulfoxonium ylide 7a. Purification by silica gel
column chromatography (10%−20% EtOAc/hexanes) afforded 8qaa
(95.4 mg, 78%) as a white solid. mp: 135−137 °C. FTIR (neat):
1684, 1629, 1545, 1426, 1392, 1229, 1167, 1120, 945, 865, 762, 692
cm−1. H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 8.06−7.97 (m,
1
2H), 7.41 (t, J = 7.7 Hz, 2H), 7.24−7.16 (m, 1H), 6.17 (s, 1H),
4.41−4.17 (m, 2H), 4.06 (s, 3H), 3.62 (tt, J = 12.1, 3.4 Hz, 1H),
3.05−2.83 (m, 2H), 2.19−2.08 (m, 2H), 1.69−1.54 (m, 2H), 1.47 (s,
9H). 13C NMR (101 MHz, CDCl3): δ 162.2, 154.7, 153.9, 143.7,
141.8, 132.5, 128.6, 125.6, 108.4, 95.9, 79.7, 53.9, 43.7, 36.4, 29.4,
Ethyl 7-(1-(tert-butoxycarbonyl)piperidin-4-yl)-3-
phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (8paa). The reac-
tion was performed according to the general procedure employing
137 mg (0.450 mmol, 1.50 equiv) of sulfoxonium ylide 7a.
Purification by silica gel column chromatography (10%−30%
EtOAc/hexanes) afforded 8paa (111 mg, 82%) as a yellow solid.
mp: 140−142 °C. FTIR (neat): 1717, 1691, 1668, 1427, 1239, 1171,
+
28.4. HRMS (ESI): m/z [M + H]+ calcd for C23H29N4O3 , 409.2234;
found 409.2236.
5-Methoxy-3-phenylpyrazolo[1,5-a]pyrimidine (8qai). The reac-
tion was performed according to the general procedure employing
39.7 mg (0.330 mmol, 1.10 equiv) of formyl sulfoxonium ylide 7i.
Purification by silica gel column chromatography (10%−20% EtOAc/
hexanes) afforded 8qai (24.3 mg, 36%) as a yellow solid. mp: 84−86
°C. FTIR (neat): 1633, 1535, 1434, 1405, 1285, 1184, 1019, 946,
793, 757, 686, 512 cm−1. 1H NMR (600 MHz, CDCl3): δ 8.40 (d, J =
7.4 Hz, 1H), 8.30 (s, 1H), 8.06−7.97 (m, 2H), 7.42 (t, J = 7.6 Hz,
2H), 7.26−7.18 (m, 1H), 6.35 (d, J = 7.4 Hz, 1H), 4.08 (s, 3H). 13C
NMR (151 MHz, CDCl3): δ 161.8, 143.3, 142.8, 137.0, 132.3, 128.6,
125.7, 125.6, 108.3, 100.2, 54.1. HRMS (ESI): m/z [M + H]+ calcd
for C13H12N3O+, 226.0975; found 226.0973.
Procedure for Three-Component Reaction of Aminopyr-
azole 6a, Aldehyde 5n, and β-Keto Sulfoxonium Ylide 7a (1
mmol scale). Aminopyrazole 6a (1.00 mmol, 1.00 equiv, 159 mg),
aldehyde 5n (2.00 mmol, 2.00 equiv, 220 mg), [Cp*Rh(MeCN)3]-
(SbF6)2 (5 mol %, 0.0500 mmol, 41.7 mg), PivOH (4.00 mmol, 4.00
equiv, 409 mg), KOAc (1.00 mmol, 1.00 equiv, 98.1 mg), 3 Å
molecular sieves (∼1 g), sulfoxonium ylide 7a (1.50 mmol, 1.50
equiv, 455 mg), and dioxane (0.400 M, 2.50 mL) were added to a
flame-dried 2−5 mL Biotage microwave vial (No. 351521) charged
with a stir bar on the benchtop. The vial was capped with a Teflon-
lined cap, flushed with nitrogen for ∼5 min, and then heated with a
Biotage Initiator+ (No. 356007), which employs an external IR sensor
1
866, 765, 728, 693 cm−1. H NMR (400 MHz, CDCl3): δ 8.51 (s,
1H), 8.12−8.06 (m, 2H), 7.45 (t, J = 7.7 Hz, 2H), 7.39 (s, 1H),
7.31−7.25 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 4.43−4.21 (m, 2H),
3.76 (tt, J = 12.1, 3.4 Hz, 1H), 3.06−2.88 (m, 2H), 2.23−2.15 (m,
2H), 1.80−1.66 (m, 2H), 1.48 (s, 9H), 1.46 (t, J = 7.1 Hz, 3H). 13C
NMR (101 MHz, CDCl3): δ 164.2, 154.6, 152.8, 146.5, 144.2, 142.9,
131.4, 128.8, 126.8, 126.6, 113.2, 103.7, 79.8, 62.4, 43.9, 36.7, 29.0,
+
28.4, 14.2. HRMS (ESI): m/z [M + H]+ calcd for C25H31N4O4 ,
451.2340; found 451.2339.
Ethyl 3-phenylpyrazolo[1,5-a]pyrimidine-5-carboxylate (8pai).
The reaction was performed according to the general procedure
employing 39.7 mg (0.330 mmol, 1.10 equiv) of formyl sulfoxonium
ylide 7i. Purification by silica gel column chromatography (10%−30%
EtOAc/hexanes) afforded 8pai (64.6 mg, 81%) as a yellow solid. mp:
120−122 °C. FTIR (neat): 1724, 1297, 1138, 1015, 761, 685, 602,
556 cm−1. 1H NMR (400 MHz, CDCl3): δ 8.74 (d, J = 7.3 Hz, 1H),
8.52 (s, 1H), 8.13−8.01 (m, 2H), 7.53 (d, J = 7.3 Hz, 1H), 7.45 (t, J =
7.8 Hz, 2H), 7.33−7.25 (m, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.46 (t, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 163.7, 146.5, 143.8,
143.7, 135.5, 131.1, 128.9, 126.9, 126.5, 113.3, 107.5, 62.5, 14.2.
L
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and a closed reaction vessel. The resultant mixture was stirred in the
microwave reactor for 1 h at 150 °C using the following settings
(absorption level, low; vial type, 2−5 mL; prestirring, 0; initial power,
0; dynamic deflector optimization, ON; pressure: OFF; power, OFF;
fixed hold time, ON; stir rate, 600). After cooling to rt, the crude
mixture was transferred to a separatory funnel with CH2Cl2 (150 mL).
PivOH was removed by extraction with saturated NaHCO3 (300
mL). The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 150 mL). The combined organic extracts
were washed with saturated NaHSO3 (10 wt %, 300 mL) to remove
the remaining aldehyde.16 The organic layer was dried (anhydrous
Na2SO4) and concentrated under reduced pressure. Purification by
silica gel column chromatography (5%−30% EtOAc/CH2Cl2)
Catalyzed Annulations through Activation and Cleavage of C−H
Bonds. Angew. Chem., Int. Ed. 2016, 55, 11000−11019. (e) Yoshino,
T.; Matsunaga, S. (Pentamethylcyclopentadienyl)cobalt(III)-Cata-
lyzed C−H Bond Functionalization: From Discovery to Unique
Reactivity and Selectivity. Adv. Synth. Catal. 2017, 359, 1245−1262.
(f) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Transition-Metal-
Catalyzed C−H Bond Addition to Carbonyls, Imines, and Related
Polarized π Bonds. Chem. Rev. 2017, 117, 9163−9227.
(5) Hoang, G. L.; Soholm Halskov, K.; Ellman, J. A. Synthesis of
Azolo[1,3,5]triazines via Rhodium(III)-Catalyzed Annulation of N-
Azolo Imines and Dioxazolones. J. Org. Chem. 2018, 83, 9522−9529.
(6) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C−H
Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017,
117, 9247−9301 and references cited therein .
1
afforded 8naa (351 mg, 77%) as a light yellow solid. H and 13C
NMR spectra matched with 8naa obtained from small scale (0.3
mmol).
(7) Shaaban, S.; Abdel-Wahab, B. F. Groebke−Blackburn−
́
Bienayme Multicomponent Reaction: Emerging Chemistry for Drug
Discovery. Mol. Diversity 2016, 20, 233−254 and references cited
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02606.
■
therein .
S
(8) For leading references on sulfoxonium ylides as carbene
precursors, see: (a) Baldwin, J. E.; Adlington, R. M.; Godfrey, C. R.
A.; Gollins, D. W.; Vaughan, J. G. J. A Novel Entry to Carbenoid
Species via β-Ketosulfoxonium Ylides. J. Chem. Soc., Chem. Commun.
1993, 1434−1435. (b) Mangion, I. K.; Nwamba, I. K.; Shevlin, M.;
Huffman, M. A. Iridium-Catalyzed X−H Insertions of Sulfoxonium
Ylides. Org. Lett. 2009, 11, 3566−3569. (c) Burtoloso, A. C. B.; Dias,
R. M. P.; Leonarczyk, I. A. Sulfoxonium and Sulfonium Ylides as
Diazocarbonyl Equivalents in Metal-Catalyzed Insertion Reactions.
Eur. J. Org. Chem. 2013, 2013, 5005−5016. (d) Neuhaus, J. D.; Oost,
R.; Merad, J.; Maulide, N. Sulfur-Based Ylides in Transition-Metal-
Catalysed Processes. Top. Curr. Chem. 2018, 376, 15.
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
■
ORCID
Gia L. Hoang: 0000-0003-2332-1854
Jonathan A. Ellman: 0000-0001-9320-5512
(9) For leading references on the application of sulfoxonium ylides
in Rh(III)-catalyzed C−H functionalization, see: (a) Xu, Y.; Zhou, X.;
Zheng, G.; Li, X. Sulfoxonium Ylides as a Carbene Precursor in
Rh(III)-Catalyzed C−H Acylmethylation of Arenes. Org. Lett. 2017,
19, 5256−5259. (b) Barday, M.; Janot, C.; Halcovitch, N. R.; Muir, J.;
Aïssa, C. Cross-Coupling of α-Carbonyl Sulfoxonium Ylides with C−
H Bonds. Angew. Chem., Int. Ed. 2017, 56, 13117−13121. (c) Wu, X.;
Xiong, H.; Sun, S.; Cheng, J. Rhodium-Catalyzed Relay Carbenoid
Functionalization of Aromatic C−H Bonds toward Fused Hetero-
arenes. Org. Lett. 2018, 20, 1396−1399. (d) Zheng, G.; Tian, M.; Xu,
Y.; Chen, X.; Li, X. Rhodium(III)-Catalyzed Annulative Coupling
Between Arenes and Sulfoxonium Ylides via C−H Activation. Org.
Chem. Front. 2018, 5, 998−1002. (e) Xu, Y.; Zheng, G.; Yang, X.; Li,
X. Rhodium(III)-Catalyzed Chemodivergent Annulations Between N-
Methoxybenzamides and Sulfoxonium Ylides via C−H Activation.
Chem. Commun. 2018, 54, 670−673. (f) Hoang, G. L.; Ellman, J. A.
Rhodium(III)-Catalyzed C−H Functionalization of C-alkenyl Azoles
with Sulfoxonium Ylides for the Synthesis of Bridgehead N-fused
[5,6]-Bicyclic Heterocycles. Tetrahedron 2018, 74, 3318−3324.
(g) Oh, H.; Han, S.; Pandey, A. K.; Han, S. H.; Mishra, N. K.;
Kim, S.; Chun, R.; Kim, H. S.; Park, J.; Kim, I. S. Synthesis of (2H)-
Indazoles through Rh(III)-Catalyzed Annulation Reaction of
Azobenzenes with Sulfoxonium Ylides. J. Org. Chem. 2018, 83,
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the NIH (No. R35GM122473, to
J.A.E).
■
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