A Flexible Strategy for the Regiocontrolled Synthesis of Pyrazolo[1,5-a]pyrazines

Article abstract of DOI:10.1021/acs.joc.7b02128

A four-step protocol for the synthesis of pyrazolo[1,5-a]pyrazines has been developed. Commercially available pyrazoles were alkylated and formylated in a regiocontrolled manner to give pyrazole-5-aldehydes bearing 2,2-dialkoxyethyl substitution on N-1. Efficient conditions for the subsequent deprotection and cyclization of these intermediates allowed access to pyrazolo[1,5-a]pyrazines with multiple substitution patterns. The versatility of the pyrazole-5-aldehyde intermediates was further demonstrated through a deprotection and double-reductive amination sequence to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines.

Full text of DOI:10.1021/acs.joc.7b02128

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Note
A flexible strategy for the regiocontrolled
synthesis of pyrazolo[1,5-a]pyrazines
Peter J. Lindsay-Scott, Natalie G. Charlesworth, and Alexandru Grozavu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02128 • Publication Date (Web): 26 Sep 2017
Downloaded from http://pubs.acs.org on September 26, 2017
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A flexible strategy for the regiocontrolled synthesis of pyrazolo[1,5-
a]pyrazines
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Peter J. LindsayꢀScott,* Natalie G. Charlesworth, Alexandru Grozavu
Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom
Supporting Information Placeholder
ABSTRACT: A 4 step protocol for the synthesis of pyrazolo[1,5ꢀa]pyrazines has been developed. Commercially available pyraꢀ
zoles were alkylated and formylated in a regiocontrolled manner to give pyrazoleꢀ5ꢀaldehydes bearing 2,2ꢀdialkoxyethyl substituꢀ
tion on Nꢀ1. Efficient conditions for the subsequent deprotection and cyclization of these intermediates allowed access to pyrazoꢀ
lo[1,5ꢀa]pyrazines with multiple substitution patterns. The versatility of the pyrazoleꢀ5ꢀaldehyde intermediates was further demonꢀ
strated through a deprotection and doubleꢀreductive amination sequence to give 4,5,6,7ꢀtetrahydropyrazolo[1,5ꢀa]pyrazines.
Nitrogenꢀcontaining heterocycles are ubiquitous in modern
drug discovery.1 Medicinal chemistry teams frequently incorꢀ
porate nitrogen atoms in aromatic and heteroaromatic ring
systems to modulate key physicochemical properties such as
lipophilicity, polarity and hydrogenꢀbonding ability in their
pursuit of new pharmacological agents.2 In recent years, pyraꢀ
zolo[1,5ꢀa]pyrazines have emerged as an important class of
nitrogen heterocycles. They have been investigated in a varieꢀ
ty of biological settings, including as kinase inhibitors (against
JAK,3a GSK3,3b PI3K3c and CHKꢀ13d kinases), dopamine reꢀ
ceptor agonists4, V1b antagonists5 and Orexin receptor antagꢀ
onists.6
lation at high temperature.12 However, despite these advances,
no general method has been reported to date which is capable
of providing flexible access to pyrazolo[1,5ꢀa]pyrazines bearꢀ
ing multiple substitution patterns in high yields.
Scheme 1. Synthetic strategies towards pyrazolo[1,5-
a]pyrazines
Synthetic strategies towards pyrazolo[1,5ꢀa]pyrazines have
largely focused on building up the pyrazole ring from pyrazine
precursors (Scheme 1a). Using this methodology, 3ꢀsubstituted
pyrazolo[1,5ꢀa]pyrazines can be accessed in low yields via the
intermolecular reaction of Nꢀaminopyrazinium salts and alꢀ
kynes,3a whilst the corresponding 6ꢀsubstituted analogues can
be synthesized via intramolecular goldꢀ and silverꢀcatalyzed
variants.7 A Pdꢀmediated tandem CꢀH functionalizationꢀ
cyclization tactic has also been explored by Charette and coꢀ
workers to construct 2ꢀsubstituted pyrazolo[1,5ꢀa]pyrazines.8
These approaches suffer from several drawbacks, including
the use of thermallyꢀhazardous Nꢀamination reagents (e.g. Oꢀ
mesitylenesulfonyl hydroxylamine 1)9 to prepare the requisite
Nꢀaminopyrazinium starting materials and a limited reported
substrate scope. An alternative synthetic approach towards
pyrazolo[1,5ꢀa]pyrazines that has received relatively little
attention from the synthetic community involves building up
the pyrazine ring from pyrazole precursors.6,10 Using this stratꢀ
egy, Karp and coꢀworkers were able to form pyrazolo[1,5ꢀ
a]pyrazine 3 in 64% yield over 2 steps via the desymmetrizaꢀ
tion of pyrazole diester 2 (Scheme 1b).11 The products from
this desymmetrization approach necessarily contain an ester
group in the 2ꢀposition, but this can be excised via decarboxyꢀ
We wondered whether pyrazoles 8 bearing an aldehyde at
the 5ꢀposition and a 2,2ꢀdialkoxyethyl group on Nꢀ1 might
serve as versatile intermediates for the construction of pyrazoꢀ
lo[1,5ꢀa]pyrazines (Scheme 2). In order to investigate this
hypothesis, we required synthetic access to these intermediates
in a regiocontrolled manner. To this end, we investigated the
alkylation of commercially available pyrazole 4 with alkyl
bromide 5 in a range of solvents in order to assess the alkylaꢀ
tion regioselectivity (Scheme 2a). However, the major product
observed in all cases was the undesired regioisomer formed
through alkylation pathway (i) (see the Supporting Inforꢀ
mation). These observations are in accordance with literature
precedent,13 which suggests that the alkylation of 3ꢀ and 3,4ꢀ
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substituted pyrazoles generally leads to mixtures of regioisoꢀ tion of 4ꢀsubstituted pyrazoles 7a-f with LDA at low temperaꢀ
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5
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8
meric products favoring the Nꢀ1 alkylated isomer.
ture followed by addition of DMF allowed access to pyrazoleꢀ
aldehydes 8a-f in a regioselective manner, with formylation
occurring exclusively at the 5ꢀposition (75ꢀ89% yield).16 Deꢀ
spite substitution on the 2,2ꢀdialkoxyethyl group, pyrazoles 8k
and 8l were also formed in high yields. Moreover, subjection
of 3ꢀsubstituted pyrazoles 7h-j to the formylation conditions
delivered the corresponding pyrazoleꢀaldehydes 8h-j as single
regioisomers. However, tꢀBuꢀsubstituted pyrazole 7g failed to
show any conversion of starting material to the desired prodꢀ
uct 8g under the reaction conditions. Interestingly, some elimꢀ
ination of ethanol from the 2,2ꢀdialkoxyethyl group was obꢀ
served during the formylation of esterꢀcontaining substrates 7e
and 7h (see the Experimental section).
Scheme 2. Pyrazole alkylation regioselectivity challenges
and proposed route to pyrazolo[1,5-a]pyrazines 9
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Scheme 3. Alkylation of pyrazoles 6
In order to overcome these regioselectivity issues, we opted
instead to explore an alkylationꢀformylation strategy (Scheme
2b). Encouraged by reports of the selective metalation of Nꢀ1
alkylated pyrazoles at the 5ꢀposition,14 we were intrigued by
the possibility of using a 2,2ꢀdialkoxyethyl group on nitrogen
to both control the regiochemistry of formylation and to serve
as a useful functional handle for further elaboration.15 We
reasoned that the alkylation of either tautomer of 4ꢀsubstituted
pyrazoles 6 (R1 = H) would lead to identical alkylated prodꢀ
ucts 7, which might then undergo regioselective metalation at
the most acidic 5ꢀposition.14 In contrast, the alkylation of 3ꢀ
and 3,4ꢀsubstituted pyrazoles 6 (R1 ≠ H) would be expected to
generate Nꢀ1 alkylated pyrazoles 7 regioselectively, allowing
subsequent metalation at the remaining 5ꢀposition. We hyꢀ
pothesized that the acidꢀmediated deprotection of key interꢀ
mediates 8 and subsequent ring closure with ammonia would
then furnish the target heterocycles 9.
b
aCs2CO3 (3 equiv), 5 (1.25 equiv), MeCN, 82 °C. Yield of pure
c
A range of commercially available pyrazoles 6 were thereꢀ
fore subjected to alkylation with alkyl bromide 5 (Scheme 3).
While 4ꢀsubstituted pyrazoles were alkylated smoothly withꢀ
out any issues of regioselectivity (see 7aꢀg), the alkylation of
pyrazoles bearing substituents in the 3ꢀposition generated mixꢀ
tures of regiosomeric products. Gratifyingly, the desired alkylꢀ
ated isomer was formed predominantly in all cases and the
regioisomeric mixtures were readily separable by column
chromatography.16 The synthesis of pyrazoles 7k and 7l bearꢀ
ing methyl substituents on the alkyl chain required more forcꢀ
ing alkylation conditions.
isolated regioisomer after chromatography. Regioselectivity reꢀ
ported in parentheses was determined by 1H NMR analysis of the
crude reaction mixture. d1ꢀbromoꢀ2,2ꢀdimethoxypropane (1.05
equiv), Cs2CO3 (1.5 equiv), DMSO, 120 °C. e2ꢀbromoꢀ1,1ꢀ
diethoxypropane (2 equiv), Cs2CO3 (6 equiv), DMSO, 120 °C.
Having prepared the key intermediates 8 in a regioconꢀ
trolled fashion, we turned our attention to the acidꢀmediated
acetal deprotection step and subsequent ring closure with amꢀ
monia (Scheme 5). Unfortunately, our initial attempts to effect
this transformation in a oneꢀpot manner with ammonia sources
in the presence of ethanol and acetic acid gave rise to complex
reaction mixtures. However, we were delighted to find that an
alternative 2 step deprotectionꢀcyclization protocol provided
With a range of alkylated pyrazoles 7a-l in hand, we set out
to explore the formylation step (Scheme 4). Thus, deprotonaꢀ
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the target pyrazolo[1,5ꢀa]pyrazines 9 in high yields (Scheme tionꢀcyclization sequence to give pyrazolo[1,5ꢀa]pyrazine 14
1
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3
4
5
6
7
8
5). Thus, acetal deprotection of pyrazoles 8 with aqueous
TFA17 followed by solvent swapping and subsequent cyclizaꢀ
tion with ammonium acetate furnished the desired products 9,
circumventing the need to isolate the dialdehyde intermediꢀ
ates.18
in 80% yield over 2 steps.
Scheme 5. Formation of pyrazolo[1,5-a]pyrazines 9
(i) 2:1:1 TFA/
OEt
2-MeTHF/H2O (8 mL/g)
N
N
40 °C, 4 h
N N
OEt
N
Scheme 4. Formylation of alkylated pyrazoles 7
R1
R1
(ii) NH4OAc (3 equiv)
AcOH (3 equiv)
EtOH (8 mL/g)
20 °C, 1 h
O
R2
R2
8a-l
9a l
-
, 1 equiv
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N
N
N
N
N
N
N
N
N
I
Br
9b
F
9a
9c
, 83%
, 82%
, 67%
N
N
N
N
N
N
N
N
N
CF3
9d
O
OEt
O
NMe2
a
9f
, 99%
, 69%
9e
, 92%
N
N
N
N
N N
N
N
N
O
iPr
F3C
EtO
Br
Br
9j
, 88%
b
9i
, 84%
9h
, 78%
N
N
N N
N
N
I
I
9k
, 89%
9l
, 83%
aStarting material contained compound 10 as an impurity. Startꢀ
ing material contained compound 11 as an impurity.
b
Scheme 6. Multigram scale synthesis of 9b and further
synthetic transformations of pyrazole-aldehyde 8a
(a) Multigram scale synthesis of pyrazolo[1,5-a]pyrazine 9b
OEt
OEt
(i)
Br
EtO
N
OEt
(i) TFA
2-MeTHF, H2O
40 °C
Cs2CO3, MeCN
82 °C
N
NH
N
N
N
N
(ii) NH4OAc
AcOH, EtOH
20 °C
(ii) LDA, DMF
THF, 78 °C
Br
O
Br
Br
8b
• 4 synthetic steps
• 1 chromatographic purification
12
, 3.08 g
9b
, 2.65 g
63% yield
12
aMaterial contained compound 10 as an impurity after flash chroꢀ
matography. b2.0 equiv LDA used. cMaterial contained compound
11 as an impurity after flash chromatography.
(from
)
(b) Accessing 4-substituted pyrazolo[1,5-a]pyrazine 14
Next, in order to probe the robustness and scalability of the
synthetic methodology, we subjected bromopyrazole 12 to the
alkylation, formylation, deprotection and cyclization protocols
on multigram scale (Scheme 6a). Thus, pyrazolo[1,5ꢀ
a]pyrazine 9b was furnished in 63% yield over 4 steps, with
only a single chromatographic purification performed at the
end of the synthetic sequence. With access secured to pyrazoꢀ
lo[1,5ꢀa]pyrazines bearing substitution at the 2ꢀ, 3ꢀ, 6ꢀ and 7ꢀ
positions, we then investigated the formation of a 4ꢀsubstituted
analogue (Scheme 6b). Thus, addition of MeMgBr to pyrazole
8a and subsequent oxidation delivered ketone 13 in 70% yield
over 2 steps, which was subjected to the standard deprotecꢀ
OEt
OEt
(i) MeMgBr
THF, Et2O
78 °C to 50 °C
EtO
N
EtO
N
(i) TFA
2-MeTHF, H2O
40 °C
N
N
N
N
N
(ii) TEMPO
PhI(OAc)2
CH2Cl2, 20 °C
(ii) NH4OAc
AcOH, EtOH
20 °C
O
O
, 70%
I
I
I
8a
13
(2 steps)
14
, 80%
(2 steps)
Finally, we explored the synthesis of 4,5,6,7ꢀ
tetrahydropyrazolo[1,5ꢀa]pyrazines from pyrazole 8a (Scheme
7). These structurallyꢀrelated compounds represent an imꢀ
portant class of heterocycles with widespread applications in
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medicinal chemistry.19 A deprotection and doubleꢀreductive
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1-(2,2-Diethoxyethyl)-4-iodo-1H-pyrazole (7a). 4ꢀIodoꢀ
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amination process was therefore developed, giving rise to satꢀ
1Hꢀpyrazole (1.02 g, 5.28 mmol) was subjected to General
Procedure 1. The resultant residue was purified by flash colꢀ
umn chromatography (SiO2, eluting with 0ꢀ20% ethyl aceꢀ
tate/heptane) to give pyrazole 7a (1.54 g, 4.99 mmol, 94%
yield) as a colourless oil. vmax (thin film)/cmꢀ1 2974, 1121,
1055, 941; δH (400 MHz, CDCl3) 7.51 (1H, s), 7.50 (1H, s),
4.72 (1H, t, J 5.5), 4.20 (2H, d, J 5.5), 3.74ꢀ3.66 (2H, m),
3.47ꢀ3.39 (2H, m), 1.16 (6H, t, J 6.9); δC (100 MHz, CDCl3)
144.5, 134.9, 101.2, 63.7, 55.8, 55.4, 15.2; HRMS (ESI) m/z:
[M]+ Calcd for C9H15IN2O2 310.0178; Found 310.0180.
urated analogues 15a-c in yields of 47ꢀ75% over 2 steps.
Scheme 7. A double-reductive amination approach to
4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazines 15
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4-Bromo-1-(2,2-diethoxyethyl)-1H-pyrazole (7b). 4ꢀ
Bromoꢀ1Hꢀpyrazole (0.993 g, 6.76 mmol) was subjected to
General Procedure 1. The resultant residue was purified by
flash column chromatography (SiO2, eluting with 0ꢀ20% ethyl
acetate/heptane) to give pyrazole 7b (1.59 g, 6.06 mmol, 89%
yield) as a colourless oil. vmax (thin film)/cmꢀ1 2976, 1122,
1055, 953; δH (400 MHz, CDCl3) 7.49 (1H, s), 7.46 (1H, s),
4.72 (1H, t, J 5.4), 4.17 (2H, d, J 5.3), 3.74ꢀ3.66 (2H, m),
3.48ꢀ3.40 (2H, m), 1.17 (6H, t, J 6.9); δC (100 MHz, CDCl3)
140.0, 130.6, 101.1, 92.9, 63.7, 55.6, 15.2; HRMS (ESI) m/z:
[M]+ Calcd for C9H15BrN2O2 262.0317; Found 262.0316.
In summary, we have developed a flexible strategy for the
synthesis of pyrazolo[1,5ꢀa]pyrazines. The regioselectivity
challenges, low yields and thermallyꢀhazardous reagents assoꢀ
ciated with existing synthetic methodologies have been sucꢀ
cessfully overcome via a 4 step reaction sequence. Furtherꢀ
more, the pyrazoleꢀ5ꢀaldehyde intermediates were shown to be
amenable to functionalization, allowing access to multiple
substitution patterns and saturated analogues in a highly regioꢀ
controlled manner.
1-(2,2-Diethoxyethyl)-4-fluoro-1H-pyrazole
(7c).
4ꢀ
Fluoroꢀ1Hꢀpyrazole (0.800 g, 9.23 mmol) was subjected to
General Procedure 1. The resultant residue was purified by
flash column chromatography (SiO2, eluting with 0ꢀ20% ethyl
acetate/heptane) to give pyrazole 7c (1.67 g, 8.29 mmol, 89%
yield) as a colourless oil. vmax (thin film)/cmꢀ1 2978, 1580,
1126, 1061, 1020; δH (400 MHz, CDCl3) 7.36 (1H, d, J 4.1),
7.34 (1H, d, J 4.1), 4.71 (1H, t, J 5.3), 4.10 (2H, d, J 5.3),
3.74ꢀ3.66 (2H, m), 3.48ꢀ3.41 (2H, m), 1.18 (6H, t, J 7.0); δC
(100 MHz, CDCl3) 149.5 (d, J 245.0), 126.4 (d, J 13.9), 116.6
(d, J 27.9), 101.3, 63.7, 55.9, 15.2; δF (1H decoupled, 376
MHz, CDCl3) −177.5; HRMS (ESI) m/z: [M]+ Calcd for
C9H15FN2O2 202.1118; Found 202.1110.
EXPERIMENTAL SECTION
All reactions were carried out under an atmosphere of N2
and commercially available reagents were used as received.
Thin layer chromatography (TLC) was performed on commerꢀ
cially available preꢀcoated TLC plates (0.25 mm silica gel
with fluorescent indicator UV254) and visualisation was
achieved by either the quenching of UV fluorescence or with a
1
KMnO4 stain. H, 13C and 19F NMR spectra were recorded on
1-(2,2-Diethoxyethyl)-4-(trifluoromethyl)-1H-pyrazole
(7d). 4ꢀ(Trifluoromethyl)ꢀ1Hꢀpyrazole (0.570 g, 4.19 mmol)
was subjected to General Procedure 1. The resultant residue
was purified by flash column chromatography (SiO2, eluting
with 0ꢀ20% ethyl acetate/heptane) to give pyrazole 7d (0.987
g, 3.91 mmol, 93% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2980, 1238, 1115, 1057, 968; δH (400 MHz, CDCl3)
7.75 (1H, s), 7.70 (1H, s), 4.75 (1H, t, J 5.4), 4.22 (2H, d, J
5.3), 3.76ꢀ3.68 (2H, m), 3.48ꢀ3.40 (2H, m), 1.16 (6H, t, J 7.1);
δC (100 MHz, CDCl3) 137.1, 130.0 (q, J 3.7), 122.6 (q, J
266.3), 113.6 (q, J 38.2), 101.0, 63.9, 55.4, 15.1; δF (1H deꢀ
coupled, 376 MHz, CDCl3) −56.4; HRMS (ESI) m/z: [M]+
Calcd for C10H15F3N2O2 252.1086; Found 252.1075.
a Bruker AVꢀHD 400 spectrometer and Bruker Avance III 500
spectrometer. Signal positions were recorded in δ ppm with
the abbreviations s, br. s, d, t, q, quint, dd and m denoting sinꢀ
glet, broad singlet, doublet, triplet, quartet, quintet, doublet of
1
doublets and multiplet respectively. All H NMR chemical
shifts were referenced to SiMe4 as an internal standard (0.00
ppm). All 13C NMR chemical shifts in CDCl3 were referenced
to the residual solvent peak at 77.00 ppm. All 19F NMR chemꢀ
ical shifts were referenced to CFCl3 (0.00 ppm). All coupling
constants, J, are quoted in Hz. Infraꢀred spectra were recorded
on a Shimadzu IRAffinity 1 FTꢀIR spectrometer. Melting
points were obtained using a DSC 1 STARe system. Highꢀ
resolution electrospray ionization (ESIꢀTOF) mass spectra
were obtained with an Agilent Technologies 6230 series timeꢀ
ofꢀflight mass spectrometer.
Ethyl 1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate
(7e). Ethyl 1Hꢀpyrazoleꢀ4ꢀcarboxylate (1.12 g, 7.98 mmol)
was subjected to General Procedure 1. The resultant residue
was purified by flash column chromatography (SiO2, eluting
with 0ꢀ20% ethyl acetate/heptane) to give pyrazole 7e (1.90 g,
7.43 mmol, 93% yield) as a colourless oil. vmax (thin film)/cmꢀ1
2978, 1715, 1554, 1225, 1113, 1059, 1026; δH (400 MHz,
CDCl3) 7.95 (1H, s), 7.91 (1H, s), 4.78 (1H, t, J 5.3), 4.29 (2H,
q, J 7.2), 4.20 (2H, d, J 5.3), 3.75ꢀ3.67 (2H, m), 3.48ꢀ3.41
(2H, m), 1.35 (3H, t, J 7.2), 1.16 (6H, t, J 6.9); δC (100 MHz,
CDCl3) 163.0, 141.2, 133.9, 115.1, 100.9, 63.7, 60.1, 55.3,
15.1, 14.3; HRMS (ESI) m/z: [M]+ Calcd for C12H20N2O4
256.1423; Found 256.1420.
General Procedure 1 for alkylation of pyrazoles. To a
stirred solution of the pyrazole 6 (1 equiv.) in acetonitrile (8
mL/g) at room temperature was added cesium carbonate (1.5
equiv.) in one portion, followed by a solution of 2ꢀbromoꢀ1,1ꢀ
diethoxyꢀethane 5 (1.05 equiv.) in acetonitrile (2 mL/g) dropꢀ
wise. The reaction mixture was stirred in an 82 °C heating
block for 16 hours, then was cooled to room temperature and
filtered through celite, washing with ethyl acetate (20 mL/g).
The filtrate was concentrated to give a residue which was puriꢀ
fied as specified.
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(ESI) m/z: [M]+ Calcd for C12H21BrN2O2 304.0786; Found
1-(2,2-Diethoxyethyl)-N,N-dimethyl-1H-pyrazole-4-
1
2
3
4
5
6
7
8
carboxamide (7f). N,NꢀDimethylꢀ1Hꢀpyrazoleꢀ4ꢀcarboxamide
(0.485 g, 3.49 mmol) was subjected to General Procedure 1.
The resultant residue was purified by flash column chromatogꢀ
raphy (SiO2, eluting with 0ꢀ10% methanol/ethyl acetate) to
give pyrazole 7f (0.779 g, 3.05 mmol, 87% yield) as a colourꢀ
less oil. vmax (thin film)/cmꢀ1 2976, 1609, 1551, 1123, 1057; δH
(400 MHz, CDCl3) 7.81 (1H, s), 7.74 (1H, s), 4.78 (1H, t, J
5.3), 4.20 (2H, d, J 5.3), 3.75ꢀ3.67 (2H, m), 3.49ꢀ3.41 (2H, m),
3.19 (3H, br. s), 3.10 (3H, br. s), 1.16 (6H, t, J 6.9); δC (100
MHz, CDCl3) 164.4, 139.8, 132.7, 117.3, 100.9, 63.5, 55.0,
38.8, 35.8, 15.1; HRMS (ESI) m/z: [M]+ Calcd for C12H21N3O3
255.1583; Found 255.1577.
304.0775.
4-Bromo-1-(2,2-diethoxyethyl)-3-(trifluoromethyl)-1H-
pyrazole (7j). 4ꢀBromoꢀ3ꢀ(trifluoromethyl)ꢀ1Hꢀpyrazole
(0.505 g, 2.35 mmol) was subjected to General Procedure 1.
1
The resultant residue (>19:1 r.r. as determined by H NMR
analysis on the crude material) was purified by flash column
chromatography (SiO2, eluting with 0ꢀ20% methyl tertꢀbutyl
ether/heptane) to give pyrazole 7j (0.644 g, 1.95 mmol, 82%
yield) as a colourless oil. vmax (thin film)/cmꢀ1 2980, 1231,
1123, 1059, 1003; δH (400 MHz, CDCl3) 7.57 (1H, s), 4.73
(1H, t, J 5.4), 4.21 (2H, d, J 5.3), 3.77ꢀ3.69 (2H, m), 3.51ꢀ3.44
(2H, m), 1.18 (6H, t, J 6.9); δC (125 MHz, CDCl3) 140.4 (q, J
37.2), 133.4, 120.6 (q, J 268.9), 100.7, 91.3, 64.0, 56.0, 15.2;
δF (1H decoupled, 376 MHz, CDCl3) −62.0; HRMS (ESI) m/z:
[M]+ Calcd for C10H14BrF3N2O2 330.0191; Found 330.0175.
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4-(tert-Butyl)-1-(2,2-diethoxyethyl)-1H-pyrazole (7g). To
a stirred solution of 4ꢀtertꢀbutylꢀ1Hꢀpyrazole (0.504 g, 4.05
mmol) in acetonitrile (4.03 mL) at room temperature was addꢀ
ed cesium carbonate (1.99 g, 6.09 mmol) in one portion, folꢀ
lowed by a solution of 2ꢀbromoꢀ1,1ꢀdiethoxyethane (0.661
mL, 4.26 mmol) in acetonitrile (1.01 mL) dropwise. The reacꢀ
tion mixture was stirred in an 82 °C heating block for 16
hours. To the mixture was added cesium carbonate (1.99 g,
6.09 mmol) in one portion, followed by a solution of 2ꢀbromoꢀ
1,1ꢀdiethoxyethane (0.126 mL, 0.811 mmol) in acetonitrile
(0.50 mL) dropwise. The reaction mixture was stirred in an 82
°C heating block for 2 hours, then was cooled to room temperꢀ
ature and filtered through celite, washing with ethyl acetate
(100 mL). The filtrate was concentrated to give a residue
which was purified by flash column chromatography (SiO2,
eluting with 0ꢀ20% ethyl acetate/heptane) to give pyrazole 7g
(0.721 g, 3.00 mmol, 73% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2960, 1126, 1059, 989; δH (400 MHz, CDCl3) 7.38
(1H, s), 7.25 (1H, s), 4.72 (1H, t, J 5.5), 4.13 (2H, d, J 5.5),
3.72ꢀ3.65 (2H, m), 3.40ꢀ3.33 (2H, m), 1.25 (9H, s), 1.14 (6H,
t, J 7.0); δC (100 MHz, CDCl3) 136.9, 133.1, 126.8, 101.8,
63.8, 55.1, 31.8, 29.3, 15.2; HRMS (ESI) m/z: [M]+ Calcd for
C13H24N2O2 240.1838; Found 240.1828.
1-(2,2-Dimethoxypropyl)-4-iodo-1H-pyrazole (7k). To a
stirred solution of 4ꢀiodoꢀ1Hꢀpyrazole (0.513 g, 2.65 mmol) in
dimethyl sulfoxide (4.11 mL) at room temperature was added
cesium carbonate (1.30 g, 3.97 mmol) in one portion, followed
by a solution of 1ꢀbromoꢀ2,2ꢀdimethoxypropane (0.376 mL,
2.78 mmol) in dimethyl sulfoxide (1.03 mL) dropwise. The
reaction mixture was stirred in a 120 °C heating block for 16
hours, then was cooled to room temperature and filtered
through celite, washing with ethyl acetate (80 mL). The filtrate
was concentrated, then was diluted with water (30 mL), sat.
aq. sodium chloride solution (10 mL) and methyl tertꢀbutyl
ether (30 mL) and the layers were separated. The aqueous
layer was extracted with methyl tertꢀbutyl ether (50 mL), then
the combined organics were dried over Na2SO4 and concenꢀ
trated to give a residue, which was purified by flash column
chromatography (SiO2, eluting with 0ꢀ20% ethyl aceꢀ
tate/heptane) to give pyrazole 7k (0.645 g, 2.18 mmol, 82%
yield) as a pale yellow oil. vmax (thin film)/cmꢀ1 2957, 1175,
1043, 986, 941; δH (400 MHz, CDCl3) 7.50 (1H,s), 7.49 (1H,
s), 4.24 (2H, s), 3.29 (6H, s), 1.16 (3H, s); δC (100 MHz,
CDCl3) 144.0, 134.5, 100.0, 56.6, 56.5, 48.7, 19.7; HRMS
(ESI) m/z: [M]+ Calcd for C8H13IN2O2 296.0022; Found
296.0024.
Ethyl 1-(2,2-diethoxyethyl)-1H-pyrazole-3-carboxylate
(7h). Ethyl 1Hꢀpyrazoleꢀ3ꢀcarboxylate (1.00 g, 7.17 mmol)
was subjected to General Procedure 1. The resultant residue
(3:1 r.r. as determined by 1H NMR analysis on the crude mateꢀ
rial) was purified by flash column chromatography (SiO2, elutꢀ
ing with 0ꢀ20% ethyl acetate/heptane) to give pyrazole 7h
(1.11 g, 4.33 mmol, 60% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2978, 1715, 1229, 1119, 1055, 1024; δH (400 MHz,
CDCl3) 7.50 (1H, d, J 2.0), 6.79 (1H, d, J 2.2), 4.79 (1H, t, J
5.4), 4.41 (2H, q, J 7.0), 4.28 (2H, d, J 5.5), 3.74ꢀ3.67 (2H,
m), 3.46ꢀ3.38 (2H, m), 1.40 (3H, t, J 7.1), 1.15 (6H, t, J 7.0);
δC (100 MHz, CDCl3) 162.3, 143.9, 132.1, 108.7, 101.3, 64.0,
60.9, 55.7, 15.2, 14.4; HRMS (ESI) m/z: [M]+ Calcd for
C12H20N2O4 256.1423; Found 256.1416.
1-(1,1-Diethoxypropan-2-yl)-4-iodo-1H-pyrazole (7l). To
a stirred solution of 4ꢀiodoꢀ1Hꢀpyrazole (0.545 g, 2.81 mmol)
in dimethyl sulfoxide (4.36 mL) at room temperature was addꢀ
ed cesium carbonate (5.52 g, 16.9 mmol) in one portion, folꢀ
lowed by a solution of 2ꢀbromoꢀ1,1ꢀdiethoxyꢀpropane (0.991
mL, 5.62 mmol) in dimethyl sulfoxide (1.09 mL) dropwise.
The reaction mixture was stirred in a 120 °C heating block for
16 hours, then was cooled to room temperature and filtered
through celite, washing with ethyl acetate (100 mL). The filꢀ
trate was concentrated then was diluted with water (30 mL),
sat. aq. sodium chloride solution (10 mL) and methyl tertꢀ
butyl ether (30 mL) and the layers were separated. The aqueꢀ
ous layer was extracted with methyl tertꢀbutyl ether (30 mL),
then the combined organics were dried over Na2SO4 and conꢀ
centrated to give a residue, which was purified by flash colꢀ
umn chromatography (SiO2, eluting with 10ꢀ15% ethyl aceꢀ
tate/heptane) to give pyrazole 7l (0.631 g, 1.95 mmol, 69%
yield) as a colourless oil. vmax (thin film)/cmꢀ1 2976, 1115,
1105, 1059, 939; δH (400 MHz, CDCl3) 7.52 (1H, s), 7.51 (1H,
s), 4.56 (1H, d, J 4.5), 4.35 (1H, quint, J 6.6), 3.74ꢀ3.66 (1H,
m), 3.65ꢀ3.57 (1H, m), 3.44ꢀ3.37 (1H, m), 3.32ꢀ3.24 (1H, m),
1.54 (3H, d, J 7.2), 1.17 (3H, t, J 7.0), 1.08 (3H, t, J 7.0); δC
(100 MHz, CDCl3) 143.9, 133.6, 104.2, 64.5, 64.2, 60.9, 55.3,
4-Bromo-1-(2,2-diethoxyethyl)-3-isopropyl-1H-pyrazole
(7i). 4ꢀBromoꢀ3ꢀisopropylꢀ1Hꢀpyrazole (0.409 g, 2.16 mmol)
was subjected to General Procedure 1. The resultant residue
(7:1 r.r. as determined by 1H NMR analysis on the crude mateꢀ
rial) was purified by flash column chromatography (SiO2, elutꢀ
ing with 0ꢀ30% methyl tertꢀbutyl ether/heptane) to give pyraꢀ
zole 7i (0.492 g, 1.61 mmol, 74% yield) as a colourless oil.
vmax (thin film)/cmꢀ1 2970, 1125, 1059, 1028; δH (400 MHz,
CDCl3) 7.40 (1H, s), 4.72 (1H, t, J 5.6), 4.11 (2H, d, J 5.5),
3.73ꢀ3.66 (2H, m), 3.46ꢀ3.38 (2H, m), 3.03 (1H, septet, J 6.8),
1.28 (6H, d, J 6.8), 1.15 (6H, t, J 7.0); δC (100 MHz, CDCl3)
155.7, 131.1, 101.2, 91.7, 63.7, 55.3, 26.7, 21.6, 15.2; HRMS
ACS Paragon Plus Environment

The Journal of Organic Chemistry
15.2, 15.1, 14.7; HRMS (ESI) m/z: [M]+ Calcd for
Page 6 of 11
subjected to General Procedure 2. The resultant residue was
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5
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7
8
C10H17IN2O2 324.0335; Found 324.0328.
purified by flash column chromatography (SiO2, eluting with
0ꢀ20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8d
(0.779 g, 2.78 mmol, 78% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2980, 1703, 1254, 1215, 1126, 1069; δH (400 MHz,
CDCl3) 10.05 (1H, s), 7.79 (1H, s), 4.83 (1H, t, J 5.6), 4.71
(2H, d, J 5.7), 3.75ꢀ3.68 (2H, m), 3.51ꢀ3.43 (2H, m), 1.13 (6H,
t, J 7.1); δC (125MHz, CDCl3) 178.7, 137.2 (q, J 3.6), 136.3
(q, J 3.6), 122.0 (q, J 268.0), 118.3 (q, J 39.1), 100.3, 63.0,
54.1, 15.1; δF (1H decoupled, 376 MHz, CDCl3) −54.5; HRMS
(ESI) m/z: [M]+ Calcd for C11H15F3N2O3 280.1035; Found
280.1063.
General Procedure 2 for formylation of pyrazole deriva-
tives. To a flask was added tetrahydrofuran (6 mL/g) and
diisopropylamine (1.6 equiv.) at room temperature and the
mixture was stirred in a dryꢀice/acetone bath. To the mixture
was added nꢀbutyl lithium solution (2.5 M in hexanes, 1.5
equiv.) dropwise and the mixture was stirred in a dryꢀ
ice/acetone bath for 30 minutes. To the reaction mixture was
added a solution of the pyrazole 7 (1 equiv.) in tetrahydrofuran
(2 mL/g) dropwise and the mixture was stirred in a dryꢀ
ice/acetone bath for 30 minutes. To the reaction mixture was
added a solution of N,Nꢀdimethylformamide (1.8 equiv.) in
tetrahydrofuran (2 mL/g) dropwise and the reaction mixture
was stirred in a dryꢀice/acetone bath for 1 hour. To the reacꢀ
tion mixture was added 2ꢀpropanol (2.5 equiv.) dropwise and
the reaction mixture was transferred to an ice/water bath. To
the reaction mixture was added sat. aq. ammonium chloride
solution (20 mL/g) over 5 minutes and water (5 mL/g). The
mixture was extracted with methyl tertꢀbutyl ether (2 x 50
mL/g) and the combined organics were dried over sodium
sulfate and concentrated to give a residue which was purified
as specified.
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Ethyl
1-(2,2-diethoxyethyl)-5-formyl-1H-pyrazole-4-
carboxylate (8e). Pyrazole 7e (1.83 g, 7.13 mmol) was subꢀ
jected to General Procedure 2. The resultant residue was puriꢀ
fied by flash column chromatography (SiO2, eluting with 0ꢀ
20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8e (1.52
g, 5.55 mmol, 77% yield corrected for 4:1 mixture of 8e:10) as
a pale yellow oil. Data listed for major product. vmax (thin
film)/cmꢀ1 2978, 1717, 1688, 1209, 1049; δH (400 MHz,
CDCl3) 10.50 (1H, s), 7.95 (1H, s), 4.85 (1H, t, J 4.3), 4.72
(2H, d, J 4.3), 4.37 (2H, q, J 7.2), 3.73ꢀ3.66 (2H, m), 3.51ꢀ
3.44 (2H, m), 1.39 (3H, t, J 6.9), 1.13 (6H, t, J 6.6); δC (100
MHz, CDCl3) 182.4, 162.2, 140.9, 138.7, 119.2, 100.3, 62.5,
61.1, 54.0, 15.1, 14.2; HRMS (ESI) m/z: [M]+ Calcd for
C13H20N2O5 284.1372; Found 284.1365.
1-(2,2-Diethoxyethyl)-4-iodo-1H-pyrazole-5-
carbaldehyde (8a). Pyrazole 7a (0.516 g, 1.66 mmol) was
subjected to General Procedure 2. The resultant residue was
purified by flash column chromatography (SiO2, eluting with
0ꢀ20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8a
(0.427 g, 1.26 mmol, 75% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2974, 1684, 1125, 1057, 982; δH (400 MHz, CDCl3)
9.81 (1H, s), 7.61 (1H, s), 4.81 (1H, t, J 5.7), 4.68 (2H, d, J
5.7), 3.74ꢀ3.66 (2H, m), 3.51ꢀ3.43 (2H, m), 1.13 (6H, t, J 7.0);
δC (100 MHz, CDCl3) 180.6, 144.8, 136.3, 100.3, 68.7, 62.7,
53.7, 15.1; HRMS (ESI) m/z: [M]+ Calcd for C10H15IN2O3
338.0127; Found 338.0118.
1-(2,2-Diethoxyethyl)-5-formyl-N,N-dimethyl-1H-
pyrazole-4-carboxamide (8f). To a flask was added tetrahyꢀ
drofuran (2.45 mL) and diisopropylamine (0.472 mL, 3.36
mmol) at room temperature and the mixture was stirred in a
dryꢀice/acetone bath. To the mixture was added nꢀbutyl lithiꢀ
um solution (2.5 M in hexanes, 1.28 mL, 3.20 mmol) dropwise
and the mixture was stirred in a dryꢀice/acetone bath for 30
minutes. To the reaction mixture was added a solution of pyꢀ
razole 7f (408 mg, 1.60 mmol) in tetrahydrofuran (0.816 mL)
dropwise and the mixture was stirred in a dryꢀice/acetone bath
for 30 minutes. To the reaction mixture was added a solution
of N,Nꢀdimethylformamide (0.223 mL, 2.88 mmol) in tetrahyꢀ
drofuran (0.816 mL) dropwise and the reaction mixture was
stirred in a dryꢀice/acetone bath for 1 hour. To the reaction
mixture was added 2ꢀpropanol (0.305 mL, 4.00 mmol) dropꢀ
wise and the reaction mixture was transferred to an ice/water
bath. To the reaction mixture was added sat. aq. ammonium
chloride solution (20 mL) over 5 minutes and water (5 mL).
The mixture was extracted with 2ꢀmethyltetrahydrofuran (3 x
30 mL) and then with 9:1 ethyl acetate/2ꢀpropanol (3 x 30 mL)
and the combined organics were dried over sodium sulfate and
concentrated to give a residue which was purified by flash
column chromatography (SiO2, eluting with 50ꢀ80% ethyl
acetate/heptane) to give pyrazoleꢀaldehyde 8f (0.356 g, 1.26
mmol, 78% yield) as a pale yellow oil. vmax (thin film)/cmꢀ1
2976, 1688, 1624, 1396, 1126, 1057; δH (400 MHz, CDCl3)
10.09 (1H, s), 7.62 (1H, s), 4.84 (1H, t, J 5.5), 4.67 (2H, d, J
5.5), 3.75ꢀ3.68 (2H, m), 3.52ꢀ3.45 (2H, m), 3.12 (6H, s), 1.14
(6H, t, J 6.8); δC (100 MHz, CDCl3) 181.1, 163.4, 137.8,
137.6, 123.3, 100.4, 62.8, 53.8, 39.2, 35.4, 15.1; HRMS (ESI)
m/z: [M]+ Calcd for C13H21N3O4 283.1532; Found 283.1537.
4-Bromo-1-(2,2-diethoxyethyl)-1H-pyrazole-5-
carbaldehyde (8b). Pyrazole 7b (1.59 g, 6.07 mmol) was
subjected to General Procedure 2. The resultant residue was
purified by flash column chromatography (SiO2, eluting with
0ꢀ20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8b
(1.53 g, 5.27 mmol, 86% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2976, 1686, 1126, 1059, 976; δH (400 MHz, CDCl3)
9.90 (1H, s), 7.56 (1H, s), 4.82 (1H, t, J 5.6), 4.65 (2H, d, J
5.5), 3.74ꢀ3.66 (2H, m), 3.52ꢀ3.44 (2H, m), 1.14 (6H, t, J 7.0);
δC (100 MHz, CDCl3) 179.3, 139.9, 134.9, 103.6, 100.3, 62.6,
53.9, 15.1; HRMS (ESI) m/z: [M]+ Calcd for C10H15BrN2O3
290.0266; Found 290.0256.
1-(2,2-Diethoxyethyl)-4-fluoro-1H-pyrazole-5-
carbaldehyde (8c). Pyrazole 7c (1.61 g, 7.98 mmol) was subꢀ
jected to General Procedure 2. The resultant residue was puriꢀ
fied by flash column chromatography (SiO2, eluting with 0ꢀ
20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8c (1.63
g, 7.11 mmol, 89% yield) as a pale yellow oil. vmax (thin
film)/cmꢀ1 2978, 1690, 1126, 1063; δH (400 MHz, CDCl3) 9.89
(1H, s), 7.41 (1H, d, J 3.9), 4.80 (1H, t, J 5.6), 4.56 (2H, d, J
5.7), 3.74ꢀ3.66 (2H, m), 3.51ꢀ3.44 (2H, m), 1.14 (6H, t, J 7.0);
δC (100 MHz, CDCl3); 177.0 (d, J 2.9), 153.9 (d, J 266.3),
125.7 (d, J 11.7), 125.6 (d, J 16.9), 100.3, 62.7, 54.4, 15.1; δF
(1H decoupled, 376 MHz, CDCl3) −167.7; HRMS (ESI) m/z:
[M]+ Calcd for C10H15FN2O3 230.1067; Found 230.1062.
Ethyl
1-(2,2-diethoxyethyl)-5-formyl-1H-pyrazole-3-
carboxylate (8h). Pyrazole 7h (1.11 g, 4.33 mmol) was subꢀ
jected to General Procedure 2. The resultant residue was puriꢀ
fied by flash column chromatography (SiO2, eluting with 0ꢀ
20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8h
1-(2,2-Diethoxyethyl)-4-(trifluoromethyl)-1H-pyrazole-5-
carbaldehyde (8d). Pyrazole 7d (0.898 g, 3.56 mmol) was
ACS Paragon Plus Environment

Page 7 of 11
The Journal of Organic Chemistry
(0.549 g, 1.96 mmol, 45% yield corrected for 13:1 mixture of (2 mL/g) and 2ꢀmethyltetrahydrofuran (2 mL/g) at room temꢀ
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4
5
6
7
8
8h:11) as a white solid. Data listed for major product. m.p. 39ꢀ
42 °C; vmax (thin film)/cmꢀ1 2978, 1722, 1692, 1213, 1123,
1057; δH (400 MHz, CDCl3) 9.93 (1H, s), 7.41 (1H, s), 4.86
(1H, t, J 5.6), 4.74 (2H, d, J 5.3), 4.44 (2H, q, J 7.1), 3.75ꢀ3.68
(2H, m), 3.49ꢀ3.41 (2H, m), 1.41 (3H, t, J 7.2), 1.12 (6H, t, J
7.0); δC (100 MHz, CDCl3) 179.5, 161.2, 143.3, 141.0, 115.3,
100.6, 63.2, 61.3, 53.8, 15.0, 14.2; HRMS (ESI) m/z: [M]+
Calcd for C13H20N2O5 284.1372; Found 284.1376.
perature. The reaction mixture was stirred in a 40 °C heating
block for 3 hours, then was cooled to room temperature and
concentrated to give a residue, which was concentrated from
toluene (3 x 5 mL/g). The resultant residue was combined with
ethanol (8 mL/g), acetic acid (3 equiv.) and ammonium acetate
(3 equiv.) and the mixture was stirred at room temperature for
1 hour. The reaction mixture was concentrated and then water
(20 mL/g) and 2ꢀmethyltetrahydrofuran (20 mL/g) were addꢀ
ed. The mixture was stirred at room temperature and solid
potassium carbonate was added portionwise until the aqueous
layer reached pH 8, then the layers were separated and the
aqueous layer was extracted with 2ꢀmethyltetrahydrofuran (20
mL/g). The combined organics were dried over sodium sulfate
and concentrated to give a residue which was purified as specꢀ
ified.
4-Bromo-1-(2,2-diethoxyethyl)-3-isopropyl-1H-pyrazole-
5-carbaldehyde (8i). Pyrazole 7i (0.415 g, 1.36 mmol) was
subjected to General Procedure 2. The resultant residue was
purified by flash column chromatography (SiO2, eluting with
20ꢀ50% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8i
(0.212 g, 0.636 mmol, 46% yield) as a colourless oil. vmax (thin
film)/cmꢀ1 2972, 1686, 1119, 1061, 1030; δH (400 MHz,
CDCl3) 9.85 (1H, s), 4.81 (1H, t, J 5.6), 4.59 (2H, d, J 5.7),
3.74ꢀ3.67 (2H, m), 3.49ꢀ3.41 (2H, m), 3.07 (1H, septet, J 7.0),
1.31 (6H, d, J 7.0), 1.12 (6H, t, J 7.0); δC (100 MHz, CDCl3)
179.7, 155.7, 135.1, 102.4, 100.3, 62.4, 53.5, 26.5, 21.4, 15.1;
HRMS (ESI) m/z: [M]+ Calcd for C13H21BrN2O3 332.0736;
Found 332.0729.
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3-Iodopyrazolo[1,5-a]pyrazine (9a). Pyrazoleꢀaldehyde 8a
(0.337 g, 1.00 mmol) was subjected to General Procedure 3.
The resultant residue was purified by flash column chromatogꢀ
raphy (SiO2, eluting with 20ꢀ50% ethyl acetate/heptane) to
give pyrazolo[1,5ꢀa]pyrazine 9a (0.205 g, 0.837 mmol, 83%
yield) as a white solid. m.p. 114ꢀ116 °C; vmax (thin film)/cmꢀ1
3105, 1506, 1339, 1287, 1227; δH (400 MHz, CDCl3) 8.97
(1H, s), 8.36 (1H, d, J 4.9), 8.05 (1H, s), 7.93 (1H, d, J 4.9); δC
(100 MHz, CDCl3) 146.7, 144.6, 136.1, 130.0, 121.9, 50.0;
HRMS (ESI) m/z: [M]+ Calcd for C6H4IN3 244.9450; Found
244.9448.
4-Bromo-1-(2,2-diethoxyethyl)-3-(trifluoromethyl)-1H-
pyrazole-5-carbaldehyde (8j). Pyrazole 7j (0.592 g, 1.79
mmol) was subjected to General Procedure 2. The resultant
residue was purified by flash column chromatography (SiO2,
eluting with 0ꢀ20% ethyl acetate/heptane) to give pyrazoleꢀ
aldehyde 8j (0.491 g, 1.37 mmol, 76% yield) as a pale yellow
oil. vmax (thin film)/cmꢀ1 2980, 1695, 1225, 1130, 1059, 1009;
δH (400 MHz, CDCl3) 9.92 (1H, s), 4.84 (1H, t, J 5.7), 4.69
(2H, d, J 5.7), 3.75ꢀ3.67 (2H, m), 3.52ꢀ3.45 (2H, m), 1.13 (6H,
t, J 7.0); δC (126 MHz, CDCl3) 179.1, 140.3 (q, J 37.2), 136.7,
120.0 (q, J 269.8), 100.9, 98.8, 62.8, 54.2, 15.0; δF (1H decouꢀ
pled, 376 MHz, CDCl3) −62.2; HRMS (ESI) m/z: [M]+ Calcd
for C11H14BrF3N2O3 358.0140; Found 358.0120.
3-Bromopyrazolo[1,5-a]pyrazine (9b). Method A: Pyraꢀ
zoleꢀaldehyde 8b (0.538 g, 1.85 mmol) was subjected to Genꢀ
eral Procedure 3. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 20ꢀ50% ethyl
acetate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9b (0.301 g,
1.52 mmol, 82% yield) as a pale yellow solid. Method B: 4ꢀ
Bromoꢀ1Hꢀpyrazole (3.08 g, 21.0 mmol) was subjected to
General Procedure 1. The resultant residue was taken forward
without any further purification and subjected to General Proꢀ
cedure 2, assuming 100% yield for the first step. The resultant
residue was taken forward without any further purification and
subjected to General Procedure 3, assuming 100% yield for
the second step. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 20ꢀ50% ethyl
acetate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9b (2.65 g,
13.4 mmol, 63% overall yield from 4ꢀbromoꢀ1Hꢀpyrazole) as
a pale yellow solid. m.p. 103ꢀ106 °C; vmax (thin film)/cmꢀ1
3015, 1514, 1425, 1346, 1310, 1294, 1269, 1225; δH (400
MHz, CDCl3) 9.04 (1H, s), 8.34 (1H, d, J 4.9), 8.01 (1H, s),
7.93 (1H, d, J 5.1); δH (400 MHz, (CD3)2SO) 9.13 (1H, s),
8.85 (1H, d, J 4.5), 8.36 (1H, s), 8.02 (1H, d, J 4.5); δC (100
MHz, CDCl3) 143.6, 142.1, 133.6, 129.9, 121.8, 86.5; HRMS
(ESI) m/z: [M]+ Calcd for C6H4BrN3 196.9589; Found
196.9578. Data were consistent with those previously reported
in the literature.20
1-(2,2-Dimethoxypropyl)-4-iodo-1H-pyrazole-5-
carbaldehyde (8k). Pyrazole 7k (0.573 g, 1.94 mmol) was
subjected to General Procedure 2. The resultant residue was
purified by flash column chromatography (SiO2, eluting with
0ꢀ20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8k
(0.535 g, 1.65 mmol, 85% yield) as a pale yellow solid. m.p.
76ꢀ79 °C; vmax (thin film)/cmꢀ1 2992, 1686, 1045; δH (400
MHz, CDCl3) 9.81 (1H, s), 7.63 (1H, s), 4.74 (2H, s), 3.28
(6H, s), 1.17 (3H, s); δC (100 MHz, CDCl3) 180.7, 145.0,
136.6, 100.3, 69.1, 54.3, 48.7, 19.9; HRMS (ESI) m/z: [M]+
Calcd for C9H13IN2O3 323.9971; Found 323.9964.
1-(1,1-Diethoxypropan-2-yl)-4-iodo-1H-pyrazole-5-
carbaldehyde (8l). Pyrazole 7l (0.509 g, 1.57 mmol) was subꢀ
jected to General Procedure 2. The resultant residue was puriꢀ
fied by flash column chromatography (SiO2, eluting with 0ꢀ
20% ethyl acetate/heptane) to give pyrazoleꢀaldehyde 8l
(0.490 g, 1.39 mmol, 88% yield) as a pale yellow oil. vmax
(thin film)/cmꢀ1 2976, 1688, 1113, 1061, 1015, 957; δH (400
MHz, CDCl3) 9.82 (1H, s), 7.62 (1H, s), 5.47 (1H, quint, J
7.0), 4.69 (1H, d, J 7.2), 3.75ꢀ3.68 (1H, m), 3.59ꢀ3.49 (2H, m),
3.29ꢀ3.21 (1H, m), 1.55 (3H, d, J 6.8), 1.22 (3H, t, J 7.0), 0.94
(3H, t, J 7.0); δC (100 MHz, CDCl3) 180.8, 144.6, 136.4,
104.2, 68.6, 63.5, 62.7, 57.9, 15.9, 15.2, 15.1; HRMS (ESI)
m/z: [M]+ Calcd for C11H17IN2O3 352.0284; Found 352.0274.
3-Fluoropyrazolo[1,5-a]pyrazine (9c). Pyrazoleꢀaldehyde
8c (1.44 g, 6.24 mmol) was subjected to General Procedure 3.
The resultant residue was purified by flash column chromatogꢀ
raphy (SiO2, eluting with 20ꢀ50% ethyl acetate/heptane) to
give pyrazolo[1,5ꢀa]pyrazine 9c (0.574 g, 4.18 mmol, 67%
yield) as a white solid. m.p. 65ꢀ68 °C; vmax (thin film)/cmꢀ1
3101, 1622, 1558, 1481, 1362, 1105; δH (400 MHz, CDCl3)
9.07 (1H, s), 8.21 (1H, d, J 3.9), 7.87 (1H, d, J 3.5), 7.83 (1H,
d, J 4.9); δC (100 MHz, CDCl3) 142.3 (d, J 5.9), 141.2 (d, J
251.6), 129.2, 127.6 (d, J 11.7), 123.2 (d, J 27.9), 121.3; δF
General Procedure 3 for deprotection and cyclization of
pyrazole derivatives. To a flask was added the pyrazoleꢀ5ꢀ
carbaldehyde 8 (1 equiv.), trifluoroacetic acid (4 mL/g), water
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The Journal of Organic Chemistry
Page 8 of 11
(1H decoupled, 376 MHz, CDCl3) −178.2; HRMS (ESI) m/z:
CDCl3) 8.93 (1H, s), 8.27 (1H, d, J 4.3), 7.85 (1H, d, J 4.7),
[M]+ Calcd for C6H4FN3 137.0389; Found 137.0391.
3.32 (1H, septet, J 7.0), 1.40 (6H, d, J 7.0); δC (100 MHz,
CDCl3) 159.0, 143.0, 134.2, 129.3, 121.6, 84.8, 27.0, 21.6;
HRMS (ESI) m/z: [M]+ Calcd for C9H10BrN3 239.0058; Found
239.0048.
1
2
3
4
5
6
7
8
3-(Trifluoromethyl)pyrazolo[1,5-a]pyrazine(9d).
Pyraꢀ
zoleꢀaldehyde 8d (0.637 g, 2.27 mmol) was subjected to Genꢀ
eral Procedure 3. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 20ꢀ50% ethyl
acetate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9d (0.294 g,
1.57 mmol, 69% yield) as a white solid. m.p. 68ꢀ71 °C; vmax
(thin film)/cmꢀ1 3134, 1545, 1362, 1217, 1117, 1007; δH (400
MHz, CDCl3) 9.25 (1H, s), 8.46 (1H, d, J 4.7), 8.26 (1H, s),
8.09 (1H, d, J 4.3); δC (125 MHz, CDCl3) 143.6, 140.3 (q, J
3.0), 132.9, 131.0, 122.5 (q, J 268.0), 121.9, 104.6 (q, J 40.9);
δF (1H decoupled, 376 MHz, CDCl3) −55.2; HRMS (ESI) m/z:
[M]+ Calcd for C7H4F3N3 187.0357; Found 187.0355.
3-Bromo-2-(trifluoromethyl)pyrazolo[1,5-a]pyrazine
(9j). Pyrazoleꢀaldehyde 8j (0.427 g, 1.19 mmol) was subjected
to General Procedure 3. The resultant residue was purified by
flash column chromatography (SiO2, eluting with 20ꢀ50%
ethyl acetate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9j
(0.279 g, 1.05 mmol, 88% yield) as an offꢀwhite solid. m.p.
72ꢀ75 °C; vmax (thin film)/cmꢀ1 3094, 1207, 1182, 1136, 1024;
δH (400 MHz, CDCl3) 9.14 (1H, s), 8.38 (1H, dd, J 4.9, 1.4),
8.10 (1H, d, J 4.9); δC (125 MHz, CDCl3) 144.7, 142.2 (q, J
37.2), 134.9, 132.0, 121.7, 120.4 (q, J 270.7), 85.0; δF (1H
decoupled, 376 MHz, CDCl3) −61.5; HRMS (ESI) m/z: [M]+
Calcd for C7H3BrF3N3 264.9462; Found 264.9455.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl pyrazolo[1,5-a]pyrazine-3-carboxylate (9e). Pyraꢀ
zoleꢀaldeyhde 8e (1.42 g, 5.19 mmol corrected for 4:1 mixture
of 8e:10) was subjected to General Procedure 3. The resultant
residue was purified by flash column chromatography (SiO2,
eluting with 20ꢀ50% ethyl acetate/heptane) to give pyrazoꢀ
lo[1,5ꢀa]pyrazine 9e (0.919 g, 4.81 mmol, 92% yield) as a
yellow solid. m.p. 85ꢀ87 °C; vmax (thin film)/cmꢀ1 3100, 1697,
1487, 1352, 1285, 1233, 1057, 743; δH (400 MHz, CDCl3)
9.61 (1H, s), 8.48 (1H, s), 8.45 (1H, dd, J 4.7, 1.4), 8.09 (1H,
d, J 4.5), 4.44 (2H, q, J 7.0), 1.45 (3H, t, J 7.1); δH (400 MHz,
(CD3)2SO) 9.49 (1H, s), 8.99 (1H, d, J 4.9), 8.62 (1H, s), 8.20
(1H, d, J 4.7), 4.37 (2H, q, J 7.1), 1.37 (3H, t, J 7.2); δC (100
MHz, CDCl3) 162.3, 145.6, 144.7, 135.1, 131.3, 122.1, 106.2,
60.7, 14.4; HRMS (ESI) m/z: [M]+ Calcd for C9H9N3O2
191.0695; Found 191.0695. Data were consistent with those
previously reported in the literature.20
3-Iodo-6-methylpyrazolo[1,5-a]pyrazine (9k). Pyrazoleꢀ
aldehyde 8k (0.482 g, 1.49 mmol) was subjected to General
Procedure 3. The resultant residue was purified by flash colꢀ
umn chromatography (SiO2, eluting with 20ꢀ50% ethyl aceꢀ
tate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9k (0.345 g,
1.33 mmol, 89% yield) as an offꢀwhite solid. m.p. 117ꢀ120 °C;
vmax (thin film)/cmꢀ1 3103, 1520, 1420, 1321, 1277; δH (400
MHz, CDCl3) 8.87 (1H, s), 8.19 (1H, s), 7.97 (1H, s), 2.57
(3H, s); δC (100 MHz, CDCl3) 146.2, 143.4, 139.2, 134.7,
119.0, 49.2, 20.7; HRMS (ESI) m/z: [M]+ Calcd for C7H6IN3
258.9606; Found 258.9604.
3-Iodo-7-methylpyrazolo[1,5-a]pyrazine (9l). Pyrazoleꢀ
aldehyde 8l (0.423 g, 1.20 mmol) was subjected to General
Procedure 3. The resultant residue was purified by flash colꢀ
umn chromatography (SiO2, eluting with 20ꢀ50% ethyl aceꢀ
tate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9l (0.259 g, 1.00
mmol, 83% yield) as a white solid. m.p. 107ꢀ110 °C; vmax (thin
film)/cmꢀ1 3084, 1526, 1321, 1300, 1092; δH (400 MHz,
CDCl3) 8.88 (1H, s), 8.08 (1H, s), 7.81 (1H, s), 2.74 (3H, s);
δC (100 MHz, CDCl3) 146.3, 142.2, 136.0, 131.9, 128.9, 50.0,
14.2; HRMS (ESI) m/z: [M]+ Calcd for C7H6IN3 258.9606;
Found 258.9605.
N,N-Dimethylpyrazolo[1,5-a]pyrazine-3-carboxamide
(9f). Pyrazoleꢀaldeyhde 8f (0.365 g, 1.29 mmol) was subjected
to General Procedure 3. The resultant residue was purified by
flash column chromatography (SiO2, eluting with 0ꢀ10%
methanol/ethyl acetate) to give pyrazolo[1,5ꢀa]pyrazine 9f
(0.244 g, 1.28 mmol, 99% yield) as a white solid. m.p. 123ꢀ
126 °C; vmax (thin film)/cmꢀ1 3115, 1628, 1611, 1526, 1410,
1042; δH (400 MHz, CDCl3) 9.55 (1H, s), 8.40 (1H, d, J 4.5),
8.18 (1H, s), 8.03 (1H, d, J 4.7), 3.26 (6H, br. s); δC (100
MHz, CDCl3) 163.6, 146.3, 141.4, 136.0, 130.9, 121.5, 108.9,
39.0, 35.9; HRMS (ESI) m/z: [M]+ Calcd for C9H10N4O
190.0855; Found 190.0871.
(±)-1-(1-(2,2-Diethoxyethyl)-4-iodo-1H-pyrazol-5-
yl)ethan-1-ol (16). To a flask was added pyrazoleꢀaldehyde 8a
(0.612 g, 1.81 mmol) and tetrahydrofuran (6.12 mL) at room
temperature and the mixture was stirred in a dryꢀice/acetone
bath. To the reaction mixture was added methylmagnesium
bromide solution (3.0 M in diethyl ether, 1.81 mL, 5.43 mmol)
dropwise and the mixture was stirred in a dryꢀice/acetone bath
for 1 hour. The reaction mixture was transferred to a −50 °C
cooling bath and stirred for 30 minutes, then 2ꢀpropanol
(0.346 mL, 4.52 mmol) was added dropwise and the reaction
mixture was transferred to an ice/water bath. To the reaction
mixture was added sat. aq. ammonium chloride solution (20
mL) over 5 minutes and water (5 mL). The mixture was exꢀ
tracted with methyl tertꢀbutyl ether (2 x 30 mL) and the comꢀ
bined organics were dried over sodium sulfate and concentratꢀ
ed to give a residue which was purified by flash column chroꢀ
matography (SiO2, eluting with 20ꢀ50% ethyl acetate/heptane)
to give pyrazole 16 (0.494 g, 1.40 mmol, 77% yield) as a colꢀ
ourless oil. vmax (thin film)/cmꢀ1 3356, 2976, 1373, 1115, 1061;
δH (400 MHz, CDCl3) 7.45 (1H, s), 5.18ꢀ5.10 (1H, m), 4.79
(1H, t, J 5.2), 4.60 (1H, dd, J 14.0, 7.0), 4.35 (1H, dd, J 13.7,
4.1), 3.78ꢀ3.67 (2H, m), 3.59ꢀ3.49 (2H, m), 3.36ꢀ3.28 (1H, m),
1.54 (3H, d, J 6.4), 1.19 (3H, t, J 6.9), 1.08 (3H, t, J 6.9); δC
Ethyl pyrazolo[1,5-a]pyrazine-2-carboxylate (9h). Pyraꢀ
zoleꢀaldeyhde 8h (0.449 g, 1.60 mmol corrected for 13:1 mixꢀ
ture of 8h:11) was subjected to General Procedure 3. The reꢀ
sultant residue was purified by flash column chromatography
(SiO2, eluting with 20ꢀ50% ethyl acetate/heptane) to give pyꢀ
razolo[1,5ꢀa]pyrazine 9h (0.240 g, 1.25 mmol, 78% yield) as
an offꢀwhite solid. m.p. 111ꢀ113 °C; vmax (thin film)/cmꢀ1
3105, 1209, 1105, 1016; δH (400 MHz, CDCl3) 9.15 (1H, s),
8.45 (1H, d, J 4.5), 8.00 (1H, d, J 4.7), 7.36 (1H, s), 4.51 (2H,
q, J 7.1), 1.46 (3H, t, J 7.0); δC (100 MHz, CDCl3) 161.9,
146.0, 145.3, 136.2, 131.2, 121.9, 102.0, 61.7, 14.3; HRMS
(ESI) m/z: [M]+ Calcd for C9H9N3O2 191.0695; Found
191.0695.
3-Bromo-2-isopropylpyrazolo[1,5-a]pyrazine (9i). Pyraꢀ
zoleꢀaldeyhde 8i (0.168 g, 0.503 mmol) was subjected to Genꢀ
eral Procedure 3. The resultant residue was purified by flash
column chromatography (SiO2, eluting with 20ꢀ50% ethyl
acetate/heptane) to give pyrazolo[1,5ꢀa]pyrazine 9i (0.102 g,
0.423 mmol, 84% yield) as a yellow solid. m.p. 45ꢀ49 °C; vmax
(thin film)/cmꢀ1 2968, 1512, 1489, 1314, 1271; δH (400 MHz,
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Page 9 of 11
The Journal of Organic Chemistry
(100 MHz, CDCl3) 145.5, 144.5, 101.8, 65.0, 63.7, 63.6, 56.9,
lowed by sodium triacetoxyborohydride (3.0 equiv.). The mixꢀ
53.3, 22.8, 15.2, 15.0; HRMS (ESI) m/z: [M]+ Calcd for
ture was stirred at room temperature for 2 hours, then was
transferred to an ice/water bath and sat. aq. sodium bicarꢀ
bonate solution (20 mL/g) was added. The layers were sepaꢀ
rated and the aqueous layer was extracted with ethyl acetate
(20 mL/g). The combined organics were dried over sodium
sulfate and concentrated to give a residue which was purified
as specified.
1
2
3
4
5
6
7
8
C11H19IN2O3 354.0440; Found 354.0434.
1-(1-(2,2-Diethoxyethyl)-4-iodo-1H-pyrazol-5-yl)ethan-1-
one (13). To a flask was added pyrazole 16 (0.417 g, 1.18
mmol) and dichloromethane (4.17 mL) at room temperature
and the mixture was stirred in an ice/water bath. To the mixꢀ
ture was added iodobenzene diacetate (773 mg, 2.35 mmol)
and (2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxyl (0.0184 g, 0.118
mmol) and the mixture was stirred at room temperature for 2
hours. To the reaction mixture was added sat. aq. sodium thioꢀ
sulfate solution (5mL) and the mixture was stirred at room
temperature for 30 minutes, then water (10 mL) was added.
The mixture was extracted with dichloromethane (3 x 10 mL)
and the combined organics were dried over sodium sulfate and
concentrated to give a residue which was purified by flash
column chromatography (SiO2, eluting with 0ꢀ20% ethyl aceꢀ
tate/heptane) to give pyrazole 13 (0.377 g, 1.07 mmol, 91%
yield) as a colourless oil. vmax (thin film)/cmꢀ1 2976, 1678,
1244, 1125, 1061; δH (400 MHz, CDCl3) 7.57 (1H, s), 4.74
(1H, t, J 5.3), 4.64 (2H, d, J 5.3), 3.71ꢀ3.64 (2H, m), 3.49ꢀ3.41
(2H, m), 2.76 (3H, s), 1.13 (6H, t, J 7.1); δC (100 MHz,
CDCl3) 190.4, 145.5, 141.1, 100.7, 62.7, 62.7, 54.5, 31.6,
15.1; HRMS (ESI) m/z: [M]+ Calcd for C11H17IN2O3 352.0284;
Found 352.0284.
3-Iodo-5-(4-methoxybenzyl)-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrazine (15a). Pyrazoleꢀaldehyde
8a (0.507 g, 1.50 mmol) was subjected to General Procedure
4. The resultant residue was purified by flash column chromaꢀ
tography (SiO2, eluting with 20ꢀ50% ethyl acetate/heptane) to
give tetrahydropyrazolo[1,5ꢀa]pyrazine 15a (0.264 g, 0.715
mmol, 47% yield) as a red solid. m.p. 90ꢀ95 °C; vmax (thin
film)/cmꢀ1 2930, 1510, 1348, 1244, 1173, 1032; δH (400 MHz,
CDCl3) 7.47 (1H, s), 7.27 (2H, d, J 8.5), 6.89 (2H, d, J 8.4),
4.15 (2H, t, J 5.3), 3.82 (3H, s), 3.69 (2H, s), 3.57 (2H, s), 2.88
(2H, t, J 5.3); δC (100 MHz, CDCl3) 159.1, 143.4, 138.8,
130.1, 129.1, 113.9, 61.1, 55.3, 53.6, 50.3, 49.3, 47.8; HRMS
(ESI) m/z: [M]+ Calcd for C14H16IN3O 369.0338; Found
369.0334.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
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54
55
56
57
58
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60
5-(tert-Butyl)-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrazine (15b). Pyrazoleꢀaldehyde 8a (0.510 g, 1.51 mmol)
was subjected to General Procedure 4. The resultant residue
was purified by flash column chromatography (SiO2, eluting
with 20ꢀ50% ethyl acetate/heptane) to give tetrahydropyrazoꢀ
lo[1,5ꢀa]pyrazine 15b (0.350 g, 1.15 mmol, 75% yield) as a
yellow solid. m.p. 66ꢀ70 °C; vmax (thin film)/cmꢀ1 2968, 1350,
1204, 1179, 933; δH (400 MHz, CDCl3) 7.46 (1H, s), 4.15 (2H,
t, J 5.2), 3.68 (2H, s), 2.96 (2H, t, J 5.2), 1.19 (9H, s); δC (100
MHz, CDCl3) 143.3, 139.4, 54.2, 53.7, 49.0, 43.9, 43.8, 25.9;
HRMS (ESI) m/z: [M]+ Calcd for C10H16IN3 305.0389; Found
305.0387.
3-Iodo-4-methylpyrazolo[1,5-a]pyrazine (14). To a flask
was added pyrazole 13 (329 mg, 0.934 mmol), trifluoroacetic
acid
(1.32
mL),
water
(0.658
mL)
and
2ꢀ
methyltetrahydrofuran (0.658 mL) at room temperature. The
reaction mixture was stirred in a 40 °C heating block for 3
hours, then was cooled to room temperature and concentrated
to give a residue, which was concentrated from toluene (3 x 5
mL). The resultant residue was combined with ethanol (2.08
mL), acetic acid (0.164 mL, 2.80 mmol) and ammonium aceꢀ
tate (0.216 g, 2.80 mmol) and the mixture was stirred at room
temperature for 1 hour. The reaction mixture was concentrated
and then water (20 mL) and 2ꢀmethyltetrahydrofuran (20 mL)
were added. The mixture was stirred at room temperature and
solid potassium carbonate was added portionwise until the
aqueous layer reached pH 8. The layers were then separated
and the aqueous layer was extracted with 2ꢀ
methyltetrahydrofuran (20 mL). The combined organics were
dried over sodium sulfate, and concentrated to give a residue
which was purified by flash column chromatography (SiO2,
eluting with 20ꢀ50% ethyl acetate/heptane) to give pyrazoꢀ
lo[1,5ꢀa]pyrazine 14 (0.195 g, 0.754 mmol, 80% yield) as a
yellow solid. m.p. 137ꢀ139 °C; vmax (thin film)/cmꢀ1 3082,
1487, 1377, 1325; δH (400 MHz, CDCl3) 8.30 (1H, d, J 4.7),
8.00 (1H, s), 7.73 (1H, d, J 4.7), 3.07 (3H, s); δC (100 MHz,
CDCl3) 154.0, 147.8, 134.6, 128.9, 121.2, 49.1, 23.6; HRMS
(ESI) m/z: [M]+ Calcd for C7H6IN3 258.9606; Found 258.9601.
5-Cyclopropyl-3-iodo-4,5,6,7-tetrahydropyrazolo[1,5-
a]pyrazine (15c). Pyrazoleꢀaldehyde 8a (0.506 g, 1.50 mmol)
was subjected to General Procedure 4. The resultant residue
was purified by flash column chromatography (SiO2, eluting
with 20ꢀ50% ethyl acetate/heptane) to give tetrahydropyrazoꢀ
lo[1,5ꢀa]pyrazine 15c (0.234 g, 0.808 mmol, 53% yield) as a
pink oil. vmax (thin film)/cmꢀ1 2926, 1346, 1229, 970;δH (400
MHz, CDCl3) 7.47 (1H, s), 4.16 (2H, t, J 5.5), 3.71 (2H, s),
3.10 (2H, t, J 5.5), 1.95ꢀ1.90 (1H, m), 0.62ꢀ0.58 (2H, m), 0.55ꢀ
0.52 (2H, m); δC (100 MHz, CDCl3) 143.3, 138.7, 53.5, 50.3,
50.2, 47.7, 37.5, 6.5; HRMS (ESI) m/z: [M]+ Calcd for
C9H12IN3 289.0076; Found 289.0071.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
NMR spectra (PDF).
General Procedure 4 for deprotection and reductive
amination of pyrazole derivatives. To a flask was added the
pyrazoleꢀaldehyde 8a (1 equiv.), trifluoroacetic acid (4 mL/g),
water (2 mL/g) and 2ꢀmethyltetrahydrofuran (2 mL/g) at room
temperature. The reaction mixture was stirred in a 40 °C heatꢀ
ing block for 3 hours, then was cooled to room temperature
and concentrated to give a residue, which was concentrated
from toluene (3 x 5 mL/g). The resultant residue was comꢀ
bined with ethyl acetate (13 mL/g) at room temperature. The
mixture was stirred in an ice/water bath and a solution of
amine (1.2 equiv.) in ethyl acetate (12 mL/g) was added, folꢀ
AUTHOR INFORMATION
Corresponding Author
*Email: lindsayꢀscott_peter@lilly.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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15. For examples of 2,2ꢀdialkoxyethylꢀsubstituted pyrazoles as
We thank Christopher Reutter (Eli Lilly) for his assistance with
high resolution mass spectrometry samples. We thank Nicholas A.
Magnus (Eli Lilly) and Andrew Faller (Eli Lilly) for useful disꢀ
cussions during the preparation of this manuscript.
heterocycle precursors, see: Seneci, P.; Nicola, M.; Inglesi,
M.; Vanotti, E.; Resnati, G. Synth. Commun. 1999, 29, 311.
16. The regioselectivity during the alkylation and formylation
steps was confirmed by 1H NMR NOESY correlations.
17. 2ꢀMeTHF was selected as a coꢀsolvent during the deprotecꢀ
tion of 8 due to its stability towards aqueous acid, see: Ayꢀ
cock, D. F. Org. Process Res. Dev. 2007, 11, 156.
18. For an example of dialdehydes with limited stability, see: Lu,
Y.; Kim, I. S.; Hassan, A.; Del Valle, D. J.; Krische, M. J.
Angew. Chem. Int. Ed. 2009, 48, 5018.
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REFERENCES
1. Gomtsyan, A. Chem. Heterocycl. Compd. (New York, NY,
U.S.) 2012, 48, 7.
2. Pennington, L. D.; Moustakas, D. T., J. Med. Chem. 2017, 60,
3552.
9
3. (a) Bach Taña, J.; Pages Santacana, L. M.; Taltavull Moll, J.;
Eastwood, P. R.; Gonzalez Rodrigues, J.; Giulio Matassa, V.
Pyrazole derivatives as JAK inhibitors. WO 2011101161,
2011. (b) Siegel, S.; Wilman, A.; Roehrig, S.; Svenstrup, N.;
Gnoth, M. J.; Heitmeier, S.; Rester, U.; Tersteegen, A.; Gerꢀ
isch, M. Imidazoꢀ, pyrazolopyrazines and imidazotriazines
and their use. Patent Appl. 20110053929, 2011. (c) Pastor
Fernandez, J.; Martinez Gonzales, S.; Rodriguez Hergueta,
A.; Ramos Lima, F. J.; Alvarez Eecobar, R. M.; Higueras
Hernandez, A. I. New bicyclic compounds as PI3ꢀK and
MTOR inhibitors. WO 2011141713, 2011. (d) Ninkovic, S.;
Braganza, J. F.; Collins, M. R.; Kath, J. C.; Li, H.; Richter, D.
T. 6 Substituted 2ꢀheterocyclyamino pyrazine compounds as
CHKꢀ1 inhibitors. WO 2010016005, 2010.
4. Gray, D. L. F.; Davoren, J. E.; Dounay, A. B.; Efremov, I. V.;
Mente, S. R.; Subramanyam, C. Heteroaromatic compounds
and their use as dopamine D1 ligands. WO 2015166370,
2015.
5. Di Fabio, R.; Terreni, S.; Tarsi, L.; Pozzan, A.; Gentile, G.;
Tonelli, F. Pyrazolo[1,5ꢀa]pyrazine derivatives as antagonists
of V1B receptors. WO 2009130232, 2009.
19. Blackburn, C.; Barrett, C.; Brunson, M.; Chin, J.; England,
D.; Garcia, K.; Gigstad, K.; Gould, A.; Gutierrez, J.; Hoar, K.;
Rowland, R. S.; Tsu, C.; Ringeling, J.; Wager, K.; Xu, H.
Bioorg. Med. Chem. Lett. 2014, 24, 5450.
20. Eastwood, P. R.; Gonzalez Rodriguez, J.; Gomez Castillo, E.;
Bach Taña, J. Heteroaryl imidazolone derivatives as JAK inꢀ
hibitors. WO 2011157397, 2011.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6. Liverton, N.; Kuduk, S. D.; Beshore, D. C.; Meng, N.; Luo,
Y. Fused heteroaryl derivatives as orexin receptor antagonists.
WO 2016101119, 2016.
7. Braganza, J. F.; Bernier, L.; Botrous, I.; Collins, M. R.; Li, B.;
McAlpine, I.; Ninkovic, S.; Ren, S.; Sach, N.; TranꢀDubé, M.;
Zeng, Q.; Zheng, B. Tetrahedron Lett. 2015, 56, 5757.
8. Mousseau, J. J.; Bull, J. A.; Ladd, C. L.; Fortier, A.; Sustac
Roman, D.; Charette, A. B. J. Org. Chem. 2011, 76, 8243.
9. Mendiola, J.; Rincon, J. A.; Mateos, C.; Soriano, J. F.; De
Frutos, O.; Niemeier, J. K.; Davis, E. M. Org. Process Res.
Dev. 2009, 13, 263.
10. Zvonok, A. M.; Kuz'menok, N. M.; Stanishevskii, L. S.
Chem. Heterocycl. Compd. (New York, NY, U.S.) 1989, 25,
1164.
11. Woll, M. G.; Qi, H.; Turpoff, A.; Zhang, N.; Zhang, X.; Chen,
G.; Li, C.; Huang, S.; Yang, T.; Moon, Y.ꢀC.; Lee, C.ꢀS.;
Choi, S.; Almstead, N. G.; Naryshkin, N. A.; Dakka, A.;
Narasimhan, J.; Gabbeta, V.; Welch, E.; Zhao, X.; Risher, N.;
Sheedy, J.; Weetall, M.; Karp, G. M. J. Med. Chem. 2016, 59,
6070.
12. Allen, S.; Boys, M. L.; Chicarelli, M. J.; Fell, J. B.; Fischer, J.
P.; Gaudino, J.; Hicken, E. J.; Hinklin, R. J.; Kraser, C. F.;
Laird, E.; Robinson, J. E.; Tang, T. P.; Burgess, L. E.; Rieger,
R. A.; Pheneger, J.; Satoh, Y.; Leftheris, K.; Raheja, R. K.;
Bennett, B. L. 4,6ꢀSubstitutedꢀpyrazolo[1,5ꢀa]pyrazines as jaꢀ
nus kinase inhibitors. WO 2016090285, 2016.
13. For the alkylation of pyrazole
4 with SEMꢀCl (2ꢀ
(chloromethoxy)ethyl)trimethylsilane), see: (a) Lin, R.; Chiu,
G.; Yu, Y.; Connolly, P. J.; Li, S.; Lu, Y.; Adams, M.;
FuentesꢀPesquera, A. R.; Emanuel, S. L.; Greenberger, L. M.
Bioorg. Med. Chem. Lett. 2007, 17, 4557. (b) Lee, Y.ꢀK.;
Parks, D. J.; Lu, T.; Thieu, T. V.; Markotan, T.; Pan, W.;
McComsey, D. F.; Milkiewicz, K. L.; Crysler, C. S.; Ninan,
N.; Abad, M. C.; Giardino, E. C.; Maryanoff, B. E.; Damiano,
B. P.; Player, M. R. J. Med. Chem. 2008, 51, 282.
14. Despotopoulou, C.; Klier, L.; Knochel, P. Org. Lett. 2009, 11,
3326.
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