Vilsmeier-Haak formylation of 3,5-dimethylpyrazoles

Article abstract of DOI:10.1134/S1070363206110260

Formylation of N-alkyl-3,5-dimethyl-1H-pyrazoles according to Vilsmeier-Haak led to the formation of the corresponding 4-formyl derivatives. 3,5-Dimethyl-1H-pyrazole having no substituent on the nitrogen atom failed to undergo formylation at the 4 position under analogous conditions. 3,5-Dimethyl-1H-pyrazole-4-carbaldehyde was synthesized by alkaline hydrolysis of methyl β-(4-formyl-3,5-dimethyl-1H-pyrazol-1-yl)propionate and subsequent heating of the acid thus formed.

Full text of DOI:10.1134/S1070363206110260

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 11, pp. 1817 1819.
Original Russian Text O.S. Attaryan, S.K. Antanosyan, G.A. Panosyan, G.V. Asratyan, S.G. Matsoyan, 2006, published in Zhurnal Obshchei Khimii,
2006, Vol. 76, No. 11, pp. 1901 1903.
Pleiades Publishing, Inc., 2006.
Vilsmeier Haak Formylation of 3,5-Dimethylpyrazoles
O. S. Attaryana, S. K. Antanosyana, G. A. Panosyanb,
G. V. Asratyana, and S. G. Matsoyana
a Institute of Organic Chemistry, National Academy of Sciences of Armenia,
ul. Zakariya Sarkavaga 167a, Yerevan, 375091 Armenia
b Molecular Structure Research Center, National Academy of Sciences of Armenia, Yerevan, Armenia
Received April 21, 2006
Abstract Formylation of N-alkyl-3,5-dimethyl-1H-pyrazoles according to Vilsmeier Haak led to the
formation of the corresponding 4-formyl derivatives. 3,5-Dimethyl-1H-pyrazole having no substituent on the
nitrogen atom failed to undergo formylation at the 4 position under analogous conditions. 3,5-Dimethyl-1H-
pyrazole-4-carbaldehyde was synthesized by alkaline hydrolysis of methyl -(4-formyl-3,5-dimethyl-1H-pyra-
zol-1-yl)propionate and subsequent heating of the acid thus formed.
DOI: 10.1134/S1070363206110260
Like 1,3-diazoles, electrophilic substitution in
pyrazole molecules occurs either at the ring carbon
atom or at the pyridine-type nitrogen atom [1 7]. The
regioselectivity of electrophilic substitution strongly
depends on the reaction conditions; however, the
formylation of NH-pyrazole I and 1-alkyl-3,5-di-
methyl-1H-pyrazoles II IV takes different pathways
despite similar reaction conditions. By formylation
of compounds II IV according to Vilsmeier Haak (i.e.,
with phosphoryl chloride in DMF at 90 120 C) we
obtained 60 80% of the corresponding pyrazole-4-
carbaldehydes V VII, while the results of formylation
of 3,5-dimethyl-1H-pyrazole (I) were unsatisfactory.
O
CH3
N
CH3
N
HC
H3C
It is presumed that electrophilic substitution in
molecule I occurs at the nitrogen atom to give am-
monium ion [8 9], which hampers formylation at the
4 position. The formyl group in 3,5-dimethyl-1H-
pyrazole-1-carbaldehyde is extremely labile and is
readily eliminated by the action of basic reagents
(NaOH). We succeeded in synthesizing 3,5-dimethyl-
1H-pyrazole-4-carbaldehyde (XI) according to the
following scheme.
POCl3
DMF
H3C
N
R
N
R
I IV
V VII
I, R = H; II, V, R = CH3; III, VI, R = C2H5; IV, VII,
R = C3H7.
O
O
CH3
CH3
CH3
N
HC
H3C
CH2=CH C
OCH3
POCl3
N
N
H3C
H3C
90 100 C
N
N
N
O
O
CH2CH2C
R
CH2CH2C
OCH3
OCH3
I
VIII
IX
OH
O
O
CH3
CH3
HC
H3C
HC
H3C
O
250 C
+
CH2=CH C
N
N
OH
N
N
O
H
XI
CH2CH2C
X
OH
1817

1818
Methyl
ATTARYAN et al.
-(3,5-dimethyl-1H-pyrazol-1-yl)propio-
(1H, CHO). Found, %: C 63.16; H 7.89; N 18.42.
C8H12N2O. Calculated, %: C 62.91; H 7.64; N 18.17.
nate (VIII) was obtained in 88% yield by addition of
methyl acrylate to compound I on heating to 90
100 C. Formylation of VIII with POCl3 DMF gave
methyl -(4-formyl-3,5-dimethyl-1H-pyrazol-1-yl)-
propionate (IX) which was subjected to alkaline hyd-
rolysis. By subsequent acidification we isolated acid
X, and heating of the latter at 250 C (3 mm Hg) gave
4-formylpyrazole XI in 65% yield.
3,5-Dimethyl-1-propyl-1H-pyrazole-4-carbal-
dehyde (VII). Yield 28.6 g (86%), bp 125 C (5 mm
Hg), n2D0 = 1.5124, d240 = 1.0656. IR spectrum, , cm :
1
1
1510 (ring). H NMR spectrum (DMSO-d6), , ppm,
(J, Hz): 0.92 t (3H, CH3, J = 7.4), 1.81 m (2H, CH2,
J = 7.3), 2.33 s (3H, CH3), 2.48 s (3H, CH3), 3.93 t
(2H, NCH2, J = 7.1), 9.81 s (1H, CHO). Found, %: C
62.94; H 7.64; N 18.17. C8H12N2O. Calculated, %: C
63.16; H 7.89; N 18.42.
The IR spectrum of XI contained absorption bands
at 1600 cm due to stretching vibrations of the al-
dehyde carbonyl and 1520 cm due to vibrations of
the pyrazole ring. Absorption bands at 3200
3300 cm were asigned to stretching vibrations of
the NH group. In the H NMR spectrum of XI, the
NH signal appeared in a weak field ( 12.50 ppm),
and the aldehyde proton gave a signal at 9.15 ppm.
1
1
Methyl -(3,5-dimethyl-1H-pyrazol-1-yl)pro-
pionate (VIII). A mixture of 9.6 g (0.1 mol) of 3,5-
dimethyl-1H-pyrazole (I), 10 ml of methyl acrylate,
and 0.1 g of hydroquinone was heated for 8 h at 90 C
under reflux. Excess methyl acrylate was removed,
and the residue was distilled under reduced pressure.
1
1
Yield 16 g (87.9%), bp 98 101 C (1 mm Hg), nD20
=
EXPERIMENTAL
1.4802, d240 = 1.0674. IR spectrum, , cm : 1510
1
1
1
(ring), 1700 (CHO). H NMR spectrum (DMSO-d6),
The H NMR spectra were recorded on a Varian
, ppm, (J, Hz): 2.33 s (3H, CH3), 2.55 s (3H, CH3),
2.88 t (2H, CH2, J = 6.6), 3.64 s (3H, OCH3), 4.20 t
(2H, NCH2, J = 6.6). Found, %: C 59.12; H 7.44; N
15.16. C9H14N2O2. Calculated, %: C 59.34; H 7.69;
N 15.38.
Mercury-300 instrument (300 MHz). The IR spectra
were obtained on a Specord 75-IR spectrometer from
samples prepared as thin films. GLC analysis was
performed on an LKhM-8MD chromatograph equip-
ped with a 1.5-m 3-mm column packed with 10% of
Carbowax-20 M on Inerton AW-HMDS (0.20
Methyl -(4-formyl-3,5-dimethyl-1H-pyrazol-1-
yl)propionate (IX). Yield 21.4 g (68%), bp 168 C
(1 mm Hg), n2D0 = 1.5164, d240 = 1.2374. IR spectrum,
, cm : 1510 (ring). H NMR spectrum (DMSO-d6),
, ppm (J, Hz): 2.33 s (3H, CH3) 2.55 s (3H, CH3),
2.88 t (2H, CH2, J = 6.6), 3.64 s (3H, OCH3), 4.20 t
(2H, NCH2, J = 6.6), 9.81 s (1H, CHO). Found, %: C
56.89; H 6.42; N 13.11. C10H14N2O3. Calculated, %:
C 57.14; H 6.67; N 13.33.
1
0.25 mm); carrier gas helium, flow rate 50 ml min .
General procedure for formylation of pyrazoles
I IV and VIII. A mixture of 0.1 mol of compound
I IV or VIII and 0.6 mol of dimethylformamide was
heated to 90 C under stirring, and 0.2 mol of phos-
phoryl chloride was added over a period of 1 h under
stirring, maintaining the temperature below 120 C.
The mixture was then cooled with ice water, neutrali-
zed with an aqueous solution of sodium hydroxide,
and extracted with chloroform, the extract was dried
over magnesium sulfate, the solvent was distilled off,
and the residue was distilled under reduced pressure.
1
1
-(4-Formyl-3,5-dimethyl-1H-pyrazol-1-yl)pro-
pionic acid (X). A mixture of 21.4 g of methyl -(4-
formyl-3,5-dimethyl-1H-pyrazol-1-yl)propionate (IX),
8 g of sodium hydroxide, and 50 ml of water was stir-
red for 3 h at room temperature. It was then extracted
with diethyl ether, the aqueous phase was neutralized
with hydrochloric acid, and the precipitate was filtered
off. Yield 16.4 g (82%), white crystals (from water),
1,3,5-Trimethyl-1H-pyrazol-4-carbaldehyde (V).
Yield 10 g (59%), bp 130 C (5 mm Hg), mp 80 83 C
1
1
(from CCl4). IR spectrum, , cm : 1510 (ring). H
NMR spectrum (DMSO-d6 CCl4, 1:3), , ppm :
2.33 s (3H, CH3), 2.49 s (3H, CH3), 3.70 s (3H,
NCH3), 9.80 s (1H, CHO). Found, %: C 60.62; H
7.02; N 20.02. C7H10N2O. Calculated, %: C 60.87; H
7.25; N 20.29.
1
mp 119 121 C. IR spectrum, , cm : 1510 (ring),
1710 (C=O), 3300 3500 (O H). H NMR spectrum
1
(DMSO-d6), , ppm, (J, Hz): 2.34 s (3H, CH3) 2.54 s
(3H, CH3), 2.78 t (2H, CH2, J = 6.7), 4.16 t (2H,
NCH2, J = 6.7), 9.81 s (1H, CHO), 12.15 br.s (1H,
COOH). Found, %: C 54.88; H 5.90; N 14.03.
C9H12N2O3. Calculated, %: C 55.10; H 6.12; N 14.28.
1-Ethyl-3,5-dimethyl-1H-pyrazole-4-carbalde-
hyde (VI). Yield 11.8 g (65%), bp 122 C (5 mm Hg),
n2D0 = 1.5176, d240 = 1.0670. IR spectrum, , cm :
1
1
1510 (ring). H NMR spectrum (DMSO-d6), , ppm
(J, Hz): 1.38 t (3H, CH3, J = 7.2), 2.34 s (3H, CH3),
2.49 s (3H, CH3), 4.03 q (2H, CH2, J = 7.2), 9.81 s
3,5-Dimethyl-1H-pyrazole-4-carbaldehyde (XI).
-(4-Formyl-3,5-dimethyl-1H-pyrazol-1-yl)propionic
acid (X), 6.2 g, was placed in a vacuum distillation
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 11 2006

VILSMEIER HAAK FORMYLATION OF 3,5-DIMETHYLPYRAZOLES
1819
setup and was distilled at a bath temperature of 250 C
(3 mm Hg). The distillate was neutralized with potas-
sium carbonate and extracted with chloroform. The
extract was dried over MgSO4 and evaporated, and
the residue crystallized. Yield 62%, mp 112 C (from
4. Shvardberg, M.S., Demneva, A.A., Sagdeev, R.Z., and
Kotlyarskii, I.A., Izv. Akad. Nauk SSSR, Otd. Khim.
Nauk, 1969, no. 4, p. 2546.
5. Attaryan, O.S., Eliazyan, G.A., Asratyan, G.V., Pano-
syan, G.A., Darbinyan, E.G., and Matsoyan, S.G., Arm.
Khim. Zh., 1986, vol. 39, no. 8, p. 511.
1
benzene). IR spectrum, , cm : 1550 (ring), 1670
(CHO). 1H NMR spectrum (DMSO-d6), , ppm:
2.40 s (6H, CH3), 9.83 s (1H, CHO), 12.50 br.s (1H,
NH). Found, %: C 57.84; H 6.23; N 22.36. C6H8N2O.
Calculated, %: C 58.06; H 6.45; N 22.58.
6. Attaryan, O.S., Gavalyan, V.B., Eliazyan, G.A., Asra-
tyan, G.V., and Darbinyan, E.G., Arm. Khim. Zh., 1988,
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Panosyan, G.A., Kinoyan, F.S., Asratyan, G.V., and
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p. 95.
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