Synthesis of derivatives of pyrazole with chiral substituents at the nitrogen atom

Full text of DOI:10.1007/s10593-008-0003-y

Chemistry of Heterocyclic Compounds, Vol. 44, No. 1, 2008
LETTERS TO THE EDITOR
SYNTHESIS OF DERIVATIVES
OF PYRAZOLE WITH CHIRAL
SUBSTITUENTS AT THE
NITROGEN ATOM
A. V. Kurkin, A. A. Utkina, and M. A. Yurovskaya
Keywords: azadicarboxylate, pyrazole, L-proline, enantioselective α-amination.
The stereoselective creation of C–N bonds with the use of simple and accessible reagents is one of the
most important problems of organic chemistry. Among the substances synthesized annually with the objective of
discovering medicinal substances, all have a large number of chiral structures, while at the same time there is a
tendency to develop enantiomeric purity, but not racemic substances. This tendency applies in full measure to
pyrazole derivatives, the biological activity of which is well known [1, 2]. In this work we have used for the first
time for the synthesis of pyrazoles with chiral substituents at the nitrogen atom the recently described [3]
reaction of directed stereoselective α-amination of aldehydes using azadicarboxylates as the source of nitrogen,
catalyzed by L-proline. This reaction leads to the formation of optically active α-hydrazino aldehydes which are
suitable chiral synthons, among others for the construction of the pyrazole ring. The observed stereochemistry
may be explained by the initial formation of an enamine from proline and the aldehyde with subsequent
coordination to the azadicarboxylate via hydrogen bonds (intermediate A).
O
N
O
H
H
OR1
R
N
O
O
N
A
R1
O
The stereoselective formation of the C–N bond facilitates the anti position of the substituent R relative to
the carboxyl group of proline and the formation energetically favorable six-membered transition state.
__________________________________________________________________________________________
M. V. Lomonosov Moscow State University, Moscow 119992, Russia; e-mail:
kurkin@direction.chem.msu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, 127-130,
January, 2008. Original article submitted December 4, 2007.
106
0009-3122/08/4401-0106©2008 Springer Science+Business Media, Inc.

An original method for the introduction of an asymmetric carbon into the pyrazole ring was developed
based on this reaction.
1. L-proline (10% mol)
MeCN
N
N
CO2Bu-t
t-BuO2C
Ph(CH2)2CHO
+
2. NaBH4, EtOH
2
1
O
OBu-t
O
OBu-t
PhCH2Cl
NaH
N
O
N
O
HO
Ph
NH
PhCH2O
NH
DMF–THF, 1:1
Ph
OBu-t
OBu-t
3 (96%)
4 (50%)
OMe
OMe
OMe
N
N
MeO
Ph
O
Ph
5
H
dioxane, 6 N HCl
6 (70%)
∆
For example, interaction of di-tert-butyl azadicarboxylate (2), catalyzed by L-proline, with 3-phenyl-
propanal (1) at 0°C in acetonitrile with subsequent reduction with NaBH4 in situ led to the formation of di-tert-
butyl 1-[1-benzyl-2-hydroxy)ethyl]hydrazine-1,2-dicarboxylate (3). Reduction of the aldehyde group is
necessary to prevent racemization in subsequent cyclization to pyrazole in acid medium.
A series of consecutive reactions: introduction of the benzyl protecting group at the hydroxy group,
removal of the tert-butoxy protecting groups in acid medium, and, finally, cyclization in situ with the tetramethyl
acetal of malonaldehyde led to the formation of the desired 1-[1-benzyl-2-benzyloxy)ethyl]pyrazole (6) in 70%
yield and an enantiomeric purity of >99% (according to HPLC on a column with a chiral stationary phase).
1
13
The H and C NMR spectra were recorded on a Bruker AMX-400 spectrometer (400 and 100 MHz
respectively) with TMS as internal standard. Specific rotations were measured on a Jasco DIP-360 (589 nm)
polarimeter. Chromatospectral studies were carried out with Carlo Erba/Kratos Fractovap Series 4200, Hewlett
Packard Ultra-1 column, 25 m×mm, 0.33 µ thick layer, helium carrier gas (1 ml/min), split of flow 1:10,
evaporation temperature 280°C, temperature gradient from 150 to 280°C ( 5 C/min). Control of the course of
reactions and purity of products was carried out by TLC on Silufol UV-254 plates and gas chromatography with
detector by mass spectrometry. Enantiometric purity of substrates by HPLC using a chiral stationary phase:
Chiralpak AD-RH 4.6x250 mm, 5 µ, eluent hexane-2-propanol 75:25, 1.0 ml/min, temperature 20°C.
Di-tert-butyl 1-[(1-Benzyl-2-hydroxy)ethyl]hydrazine-1,2-dicarboxylate (3). L-Proline (0.06 g,
0.5 mmol) was added to a solution of di-tert-butyl azadicarboxylate (2) (1.15 g, 5 mmol) in acetonitrile (50 ml),
the mixture was cooled to 0°C, and 3-phenylpropanal 1 (0.99 ml, 7.5 mmol) was added dropwise. The reaction
mixture was stirred at 0°C for 2 h and then for 1 h at room temperature. After this the solution was decolorized,
cooled to 0°C again, ethanol (50 ml) and NaBH4 (0.19 g, 5 mmol) were added, and the mixture was stirred for
5-10 min at 0°C. The reaction mixture was washed with 50% aqueous NH4Cl and extracted with ethyl acetate.
107

The organic phase was dried with MgSO4 and the solvent was removed in vacuum to give a white crystalline
1
substance (2.64 g, 96%), mp 110-111°C (acetonitrile). H NMR spectrum, δ, ppm: 1.28 and 1.36 (9H in total,
both s, C(CH3)3); 1.52 (9H, s, C(CH3)3); 2.48-2.79 (2H, m, CH2Ph); 3.41-3.68 (2H, m, CH2OH); 4.49-4.92 (1H,
13
m, CHN); 5.95 and 6.07 (1H in total, both s, NH); 7.08-7.39 (5H, m, Ph). C NMR spectrum, δ, ppm: 28.01
(6C, (CH3)3C); 35.88 (CH2Ph); 51.25 (CH); 62.21 (CH2OH): 82.12 (2C, C(CH3)3); 126.67 (C, CH); 129.07 (2C,
CH); 130.86 (2C, CH); 135.02 (C); 164.23 (C=O); 167.15 (C=O). [α]21 +34.3 (CHCl3, c 0.05). Found, %:
D
C 62.39; H 8.15; N 7.58. C19H30N2O5. Calculated, %: C 62.27; H 8.25; N 7.64.
Di-tert-butyl 1-[1-benzyl-2-(benzyloxy)ethyl]hydrazine-1,2-dicarboxylate (4). NaH (0.3 g, 12.6 mmol)
was added with stirring to solution of compound 3 (2.64 g, 7.2 mmol) in 1:1 THF-DMF (40 ml), stirring was
continued for 30 min, then benzyl chloride (0.91 ml, 7.9 mmol) was added dropwise. When addition of benzyl
chloride was completed, the mixture was heated to 80°C and kept at this temperature for 6-8 h (TLC
monitoring). The solvent was removed in vacuum, methanol (5 ml) was added to the residue, the solution was
diluted with water and extracted with CH2Cl2 (2×300 ml). The extract was dried over MgSO4 and the solvent
1
removed in vacuum to give a light-yellow oil (1.6 g, 50%). H NMR spectrum, δ, ppm: 1.30-1.48 (18H, m,
C(CH3)3); 2.46-2.60 (2H, m, CH2Ph); 3.28-3.25 (4H, m, CH2OCH2Ph); 4.98-5.12 (1H, m, CHN); 6.75 and 6.87
(1H in total, both s, NH); 7.17-7.48 (10H, m, C6H5). Found, %: C 67.89; H 7.82; N 5.98. C26H36N2O5. Calculated,
%: C 68.40; H 7.95; N 6.14.
1-[(1-Benzyl-2-benzyloxy)ethyl]-1H-pyrazole (6). Tetramethylacetal of malonic dialdehyde 5 (0.03 ml,
0.16 mmol) was added to a solution of compound 4 (0.07 g, 0.16 mmol) in 6 N HCl (20 ml) and the mixture was
stirred at room temperature, until evolution of gas had ceased, and then for further 2-4 h at 70-80°C. The
reaction mixture was poured into cold water and extracted with CH2Cl2 (3×50 ml). The organic layer was
separated, washed with water, dried over Na2SO4, the solvent was removed in vacuum, and the residue
chromatographed on a silica gel column with 15:1 petroleum ether–ethyl acetate as eluent. A thick dark-brown
oil was isolated (0.032 g, 70%). 1H NMR spectrum, δ, ppm, J (Hz): 3.13-3.18 (2H, m, CHCH2Ph); 3.27 and 3.37
(2H, m and m, CHCH2O); 4.39 (1H, m, CH); 5.10 (2H, s, OCH2Ph); 6.05 (1H, br. s, H-4pyrazole); 6.89 (2H, dd,
J = 7.6, J = 2.4, C6H5); 7.04 (1H, d, J = 2.4, H-3pyrazole); 7.15 (3H, m, C6H5); 7.32 (5H, m, C6H5); 7.54 (1H, m,
H-5pyrazole). [α]21 +3.8 (CHCl3, c 0.055), ee >99% (according to HPLC on a column with a chiral stationary
D
phase).
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