Improved synthesis of 1H-pyrazole-4-carbaldehyde

Article abstract of DOI:10.1080/00397911.2010.503002

A simple and convenient two-step method for the synthesis of the title compound 1 was developed using N-protected 4-pyrazolilmagnesium bromide 9 as a key intermediate. Laborious procedures for purification or isolation of target compound are not required, therefore, up to 20g of 1 could be obtained in a single run.

Full text of DOI:10.1080/00397911.2010.503002

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Improved Synthesis of 1H-Pyrazole-4-
carbaldehyde
Ilya V. Taydakov a , Sergey S. Krasnoselskiy b & Tatiana Y. Dutova c
a G. S. Petrov Institute of Plastics, Moscow, Russian Federation
b People's Friendship University of Russia, Moscow, Russian
Federation
c State Research Center for Antibiotics, Moscow, Russian Federation
Version of record first published: 14 Jun 2011.
To cite this article: Ilya V. Taydakov, Sergey S. Krasnoselskiy & Tatiana Y. Dutova (2011): Improved
Synthesis of 1H-Pyrazole-4-carbaldehyde, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 41:16, 2430-2434
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Synthetic Communications1, 41: 2430–2434, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.503002
IMPROVED SYNTHESIS OF 1H-PYRAZOLE-
4-CARBALDEHYDE
Ilya V. Taydakov,1 Sergey S. Krasnoselskiy,2 and
Tatiana Y. Dutova3
1G. S. Petrov Institute of Plastics, Moscow, Russian Federation
2People’s Friendship University of Russia, Moscow, Russian Federation
3State Research Center for Antibiotics, Moscow, Russian Federation
GRAPHICAL ABSTRACT
Abstract A simple and convenient two-step method for the synthesis of the title compound 1
was developed using N-protected 4-pyrazolilmagnesium bromide 9 as a key intermediate.
Laborious procedures for purification or isolation of target compound are not required,
therefore, up to 20 g of 1 could be obtained in a single run.
Keywords Aldehyde; formylation; Grignard reagents; iodination; pyrazole
INTRODUCTION
Pyrazole-4-carbaldehyde 1 is a useful intermediate in pyrazole chemistry. It
was applied in syntheses of some enzyme inhibitors,[1] ligands for supramolecular
chemistry,[2] and complexing agents.[3] Unfortunately, a reliable and scalable syn-
thetic procedure of this compound has not being described to date. Recently, com-
pound 1 has been obtained by four different methods (Scheme 1).
All these methods have serious disadvantages. Alcohol 2 is not readily avail-
able, and oxidating argent (activated MnO2)[4] is expensive, as well as t-BuLi,[3]
which is pyrophoric and unstable. Low temperatures have to be maintained during
metallation[3] to prevent lithiation at the C(5) of pyrazole. Compound 4 is not
Received May 18, 2010.
Address correspondence to Ilya V. Taydakov, G. S. Petrov Institute of Plastics, JSC, Perovskiy
Proezd 35, Moscow 111024, Russian Federation. E-mail: taidakov@gmail.com
2430

SYNTHESIS OF PYRAZOLE-4-CARBALDEHYDE
2431
Scheme 1. Possible approaches to 1H-pyrazole-4-carbaldehyde (1).
commercially available,[5] and its preparation[6] is a laborious and hazardous task.
The last method was developed by Baumgarten et al.[2] They used the 1-ethoxyethyl
N-protective group, which can be removed by mild acidic hydrolysis. However, this
method is suitable only for small uploads, as column chromatography for the iso-
lation of all intermediates has to be used and the deprotection step is inconvenient.
This step should be conducted in very diluted solution; otherwise, the target
compound 1 is polymerized to a considerable extent.
Herein, we report a simple and practical method for the multigram preparation
of aldehyde 1 based on Baumgarten’s synthetic strategy. Commercially available
4-iodopyrazole 6 was used as a starting material in this procedure. This compound
also could be easily synthesized by iodination of pyrazole 7 with I2=HIO3 mixture[7]
(Scheme 2). This known method was significantly improved for use in large-scale
preparations.
Compound 6 was transformed to N-protected pyrazole 8 by acid-catalyzed
addition of ethyl vinyl ether.[1] After evaporation of solvent, crude product 8 was
1
pure enough (ca. 90% by H NMR) to use in the next step without purification.
Aldehyde 10 was prepared by the reaction of 8 with EtMgBr, followed by the
addition of dimethylformamide (DMF). Temperature was maintained above þ5 ꢀC
(typically þ5–7 ꢀC) in the course of addition of the EtMgBr solution to prevent
formation of a thick tarry precipitate. If this sticky mass is formed in a considerable
Scheme 2. (i) I2, HIO3, AcOH, H2SO4, 60 ꢀC; (ii) benzene, HCI, 50 ꢀC; (iii) EtMgBr, THF, 5 ꢀC; (iv) DMF,
0 ꢀC; (v) HCl, Et2O, rt.

2432
I. V. TAYDAKOV, S. S. KRASNOSELSKIY, AND T. Y. DUTOVA
amount, the stirrer would be blocked or even broken. Reaction of 9 with DMF is
slightly exotermic. A cooling ice–NaCl bath should be use to keep the temperature
at 0 ꢀC. A crude product obtained after usual workup of the reaction mixtiure
1
contains approx. 80% of 10 (determined by H NMR), but no further purification
was needed.
Special attention was paid to the final deprotection stage. Evaluative experi-
ments showed that compound 1 was polymerized in solutions at elevated tempera-
ture in the presence of an acid. Also, we have established that the transformation
process of 10 to 1 was relatively fast even at room temperature, and prolonged heat-
ing with the excess of acid was not required as claimed by Baumgarten et al.[2] When
HCl is used, compound 1 is stable and insoluble in Et2O hydrochloride, whereas
starting compound 10 dissolves in this solvent. All these data led us to develop a very
simple procedure for simultaneous deprotection and purification of 1 by titration of
solution of 10 in anhydrous Et2O with the HCl solution. The polymer impurities are
precipitated (as a tar) by the first portions of titrant, and after that pure 1 as a crys-
talline hydrochloride was precipitated from the clear solution by the excess of HCl.
Free 1 can be regenerated from the salt by the treatment with saturated aqueous
KHCO3 solution.
In conclusion, we have developed a simple, scalable, and reliable synthetic
approach to 1H-pyrazole-4-carbaldehyde (1). The title compound was obtained from
pyrazole in good overall yield without purification of any intermediate compounds.
EXPERIMENTAL
Reagents and solvents (synthetic grade) were purchased from Merck
(Germany) and Acros Organics (Belgium). Analytical thin-layer chromatography
(TLC) was performed on precoated Merck silica-gel 60 F256 plates, and preparative
TLC was performed on thick unbonded layers of the same sorbent made in-house.
1H and 13C NMR spectra were recorded in CDCl3 or dimethylsulfoxide
(DMSO-d6) on a Bruker AC-300 spectrometer operated at 300 MHz and 75 MHz
respectively at 25 ꢀC. All 1H chemical shifts are reported in parts per million
(ppm) relative to tetramethylsilane (TMS, 0.00 ppm); 13C shifts are reported in
ppm relative to CDCl3 or DMSO-d6. Mass spectra were recorded on a Finnigan
INCOS-50 instrument (EI, 70 eV, direct insertion). Melting points were determined
in capillary tubes on MRM-1HV (Shorpp, Germany) and uncorrected.
4-Iodo-1H-pyrazole (6)
Pyrazole (300 g, 4.41 mol) was dissolved in a mixture of 1200 mL AcOH and
173 mL of 30% aqueous H2SO4 (0.6 mol). Solution was heated to 60 ꢀC, and iodine
(450 g, 1.77 mol) and HIO3 ꢁ 2H2O (190 g, 0.89 mol) were added in small portions
with stirring. Each portion of I2 was followed by a portion of HIO3 ꢁ 2H2O, which
causes disappearance of the brown color of the solution. Total time of addition
was 2 h, and after that the reaction mixture was additionally stirred for 2 h at
60–65 ꢀC and then cooled to room temperature. The solvent was removed under
reduced pressure; after that, K2CO3 (15% solution) was added to adjust the pH to
7–8. The white solid was extracted with EtOAc (3 ꢂ 500 mL). Combined organic

SYNTHESIS OF PYRAZOLE-4-CARBALDEHYDE
2433
solutions were washed with brine, dried over MgSO4, and evaporated to dryness.
The crystalline solid was washed with a small amount of CCl4 and dried in the
air, affording 736.5 g (86%) of 6 as a light creamy powder.
1
Mp 107.0–107.5 ꢀC (lit.[2] 107–108 ꢀC). H NMR (CDCl3, 25 ꢀC): d 9.49 (br.s,
13
1H, NH), 7.6 (s, 2H, CH); C NMR (DMSO-d6, 25 ꢀC): d 133.8, 56.5; MS (EI)
m=z: 194 (Mþ, 100%), 127 (Iþ, 18%), 67 (Mþ ꢃ I, 20.7%).
1-(1-Ethoxyethyl)-4-iodo-1H-pyrazole (8)
Into a 4-iodo-1H-pyrazole (6) solution (80 g, 406 mmol) in 300 mL of benzene,
50 mL of 30% HCl (in Et2O) and 50 mL (37.5 g, 502 mmol, 1.27 eq) of ethyl vinyl
ether were added. The resulting mixture was stirred under nitrogene at 50 ꢀC for
3 h. Then it was cooled and left at room temperature overnight. The organic phase
was extracted with 50 mL of saturated KHCO3 solution, washed with brine, and
dried over MgSO4. The solvent was evaporated under reduced pressure (bath tem-
perature 40 ꢀC), and the resulting light yellow oil was used in the next step without
purification. Yield 106 g (98%). Analytical sample was purified by preparative TLC
(Rf ¼ 0.73, CH2Cl2–hexane 2:1 v=v).
1H NMR (CDCl3, 25 ꢀC): d 7.6 (s, 1H, CH), 7.5 (s, 1H, CH); 5.45 (q, 1H,
J ¼ 6.1 Hz, CH), 3.3 (m, 2H, CH2), 1.6 (d, 3H, J ¼ 6.1 Hz, CH3), 1.1 (t, 3H,
13
J ¼ 6.9 Hz, CH3); C NMR (CDCl3, 25 ꢀC): d 144, 130.6, 88, 64.5, 57.5, 22, 14.6;
MS (EI) m=z: 266 (Mþ, 13%), 222 (17%), 194 (33%), 144 (17%), 73 (83%), 45 (100%).
1H-Pyrazole-4-carbaldehyde Hydrochloride (1)
Grignard reagent (1.4 M approx.) was prepared in usual manner from 9.5 g Mg
(390 mmol) and 29 mL (42.5 g, 390 mmol) EtBr in 250 mL of dry THF. To a
mechanically stirred solution of 8 (80 g, 300 mmol) in 250 mL of dry THF solution
of EtMgBr was added dropwise at þ5–7 ꢀC under an argon atmosphere. A jacketed
dropping funnel was used, and warm water was passed through the jacket to prevent
crystallization of the Grignard solution. Then the funnel was rinsed with 70 mL of
tetrahydrofuran (THF), and the reaction mixture was additionally stirred for 1 h.
A tarry matter which can present in the mixture dissolved within this period of time.
The clear dark solution was cooled again to 0 ꢀC, and the solution of 34.8 mL DMF
(32.9 g, 450 mmol) in 30 mL of THF was added slowly. The resulting solution was
left at room temperature overnight (a white crystalline precipitate was formed); then
it was cooled to 0 ꢀC and decomposed by the careful addition of 100 mL of saturated
NH4Cl solution. After that, water (80 mL) was added to dissolve completely the
inorganic salts. The organic phase was separated, and the water phase was extracted
by Et2O (3 ꢂ 200 mL). Combined phases were washed with brine, dried subsequently
over NaSO4 (to remove most of the water) and MgSO4, and evaporated in vacuo.
The oily residue (42 g) was redissolved in 250 mL of Et2O, and 5 g of anhydrous
MgSO4 were added to the turbid solution. Then it was filtered through the Celite
pad (5 mm). The clear solution was transferred to a beaker, and HCl (saturated
solution in anhydrous Et2O, approx. 27–30% by weight) was slowly added with con-
tinious stirring. After the first portions of the solution (usually 10–15 mL) were
added, a dark yellow tar was formed. The further addition of HCl solution led to

2434
I. V. TAYDAKOV, S. S. KRASNOSELSKIY, AND T. Y. DUTOVA
the formation of a white crystalline precipitate. At this moment, the addition was
interrupted, the mixture was stirred for 15 min, a clear solution was decanted from
the residue, and the rest of the HCl solution (130 mL) was added in three portions.
The progress of the reaction was monitored by TLC (CH2Cl2–EtOAc 4:1 v=v,
compound 10 Rf ¼ 0.58, compound 1 Rf ¼ 0.05), and generally 1–2 h was needed
to transform 10 to 1 completely at 50- to 100-g scale. The light yellow solid was fil-
tered, washed with anhydrous Et2O, and dried in the air to a constant weight. Yield
21 g (53%). Hydrochloride is stable at room temperature and convenient to handle.
Exact composition: C5H5NO ꢁ 0.92HCl (by argentometry). Anal. calcd. for
C5H5NO ꢁ HCl: C, 45.65; H, 4.60; Cl, 26.95. Found: C, 45.78; H, 5.22; Cl, 25.44.
1
Mp 181–183 ꢀC (decomp., in sealed tube). H NMR (DMSO-d6, 25 ꢀC): d 9.8
(s, 1H, CHO), 8.6 (br. s, 2H, NH þ HCl), 8.1 (s, 2H, CH); 13C NMR (DMSO-d6,
25 ꢀC): d 185.1, 136.5, 123.6; MS (EI) m=z: 96 (Mþ, 84%), 95 (Mþ ꢃ H, 100%), 68
(22%), 39 (44%).
ACKNOWLEDGMENT
We are grateful to ArtChem GmbH (Campus Berlin-Buch, Germany) for the
support of this work.
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