A new method for the synthesis of pyrazolidines with N-amino acid substitutents

Full text of DOI:10.1007/s10593-008-0055-z

Chemistry of Heterocyclic Compounds, Vol. 44, No. 3, 2008
A NEW METHOD FOR THE SYNTHESIS
OF PYRAZOLIDINES WITH N-AMINO
ACID SUBSTITUTENTS
L. A. Sviridova1, G. A. Golubeva1, A. N. Tavtorkin2, and K. A. Kochetkov2
Keywords: amino acids, pyrazolidines, acylation.
Pyrazolidine derivatives with an amino acid substituent at the ring nitrogen atom are very promising as
fibrinogen receptors antagonists but the method for their synthesis from amino acid hydrazides is extremely
limited [1]. We have found that 1-glycylpyrazolidine 1 may be obtained from 1-acetyl-5-(2-hydroxy-
2-phenylethyl)-3-methyl-2-phenylpyrazolidine (2), which is readily available [2]. A well-known method
involving the action of lithium aluminum hydride under mild conditions usually employed for simple amides and
hydrazides was used to remove the acetyl protective group [3]. The resultant unstable cyclic phenylhydrazine 3
converts to give phenylisothiocarbamoyl derivative 4 in high yield.
Me
Me
OH
Ph
OH
Ph
1. LiAlH4/Et2O
2. KF/H2O
N
N
Ph
Ph
N
N
H
O
Me
3
2
PhNCS
PhCH2OCONHCH2CO2H
OH
Me
Me
OH
Ph
N
N
Ph
Ph
Ph
N
N
Ph
NHCO2CH2Ph
S
N
O
H
1
4
_______
* Dedicated to A. A. Akhrem on the occasion of his ninety-fifth birthday.
__________________________________________________________________________________________
1M. V. Lomonosov Moscow State University, Chemistry Faculty, Moscow 119992, Russia;
e-mail: svirid@org.chem.msu.ru. 2A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy
of Sciences, Moscow 119991, Russia; e-mail: const@ineos.ac.ru. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 474-475, March, 2008. Original article submitted February 6, 2008.
368
0009-3122/08/4403-0368©2008 Springer Science+Business Media, Inc.

We were able to carry out the reaction of 3 with N-benzyloxycarbonylglycine under mild conditions only
by using the Mukaiyama method [4], which permits the preparation of other amino acid derivatives similar to 1.
All the reported methods for the acylation of amino acids did not give positive results.
The IR spectra were taken on a UR-20 spectrometer for vaseline mulls. The 1H NMR spectra were taken
on a Bruker-Avance 600 spectrometer at 600 MHz in CDCl3.
5-(2-Hydroxy-2-phenylethyl)-3-methy-1-phenylthiocarbamoyl-2-phenylpyrazolidine
(4).
Compound 2 (100 mg, 0.31 mmol) was added to saturated solution of LiAlH4 (29 mg, 0.2 ml) in ether (1 mmol)
at 0°C in a dry nitrogen stream and then stirred for 30 min at this temperature. Then, saturated aqueous KF
solution (0.5 ml) was added dropwise. Ether (1 ml) was added and the mixture was stirred at room temperature
for an additional 1 h. The organic layer was separated and the aqueous layer was extracted with ether (3 x 1 ml).
The organic phases were combined, dried over potassium carbonate, and evaporated to give cyclic
phenylhydrazine 3 as an oil.
Phenyl isothiocyanate (0.04 ml, 0.33 mmol) was added to a solution of crude compound 3 in ether
(0.5 ml) and left in an inert atmosphere. The precipitate formed was washed with ether to give 94 mg
1
(73%) compound 4, mp 165-166°C. IR spectrum, ν, cm-1: 3278 (OH), 3390 (NH). H NMR spectrum, δ, ppm
(J, Hz): 1.39 (3H, d, J = 6.4, 3-CH3); 1.75 (1H, m, α-H); 2.02 (1H, m, H-4); 2.22 (1H, m, H'-4); 2.68 (1H, m,
α-H'); 3.82 (1H, d, J = 4.6, OH); 4.23 (1H, m, H-3); 4.95 (1H, m, CHOH); 5.45 (1H, m, H-5); 7.00-7.44 (15H,
m, Ar). Found, %: C 71.94; H 6.46; N 10.05. C25H27N3OS. Calculated, %: C 71.91; H 6.52; N 10.06.
1-(N-Benzyloxycarbonylglycyl)-5-(2-hydroxy-2-phenylethyl)-3-methyl-2-phenylpyrazolidine (1). A
solution of 2-chloro-1-methylpyridinium iodide (79 mg, 0.31 mmol), benzyloxycarbonylglycine (70 mg,
0.33 mmol) and N-methylmorpholine (0.07 ml, 0.62 mmol) in methylene chloride (2 ml) was added to
pyrazolidine 3 (obtained according to the previous procedure from compound 2 (0.31 mmol), and left in an inert
atmosphere for 3 h. The solvent was distilled off and the residue was subjected to chromatography on a silica gel
column with gradient elution from 1:10 to 1:1 ethyl acetate-hexane to give 80 mg (55%) 1 as an oil. IR spectrum,
1
ν, cm-1: 1657 (CO amide), 1722 (CO carbamate), 3347 (NH), 3417 (OH). H NMR spectrum, δ, ppm (J, Hz):
1.30 (3H, d, J = 6.6, 3-CH3); 1.91 (2H, m, α-H, H-4); 2.13 (1H, dd, J = 11.8, J = 7.4, H'-4); 2.54 (1H, m, α-H');
3.84 (1H, dd, J = 18.5, J = 4.4, NCOCH2NH); 4.19 (1H, m, H-3); 4.44 (1H, dd, J = 18.5, J = 5.3, NCOCH'2NH);
4.69 (1H, m, H-5); 4.90 (1H, dd, J = 9.7, J = 3.5, CHOH); 5.16 (1H, d, J = 2.6, CH2C6H5); 5.72 (1H, br. s,
NCOCH2NH); 7.01-7.44 (15H, m, Ar). Found, %: C 70.23; H 6.75; N 8.33. C28H31N3O4. Calculated, %:
C 71.02; H 6.60; N 8.87.
REFERENCES
1.
2.
G. K. Vertelov, Author’s Abstract of Chemical Candidate’s Dissertation, Moscow State University,
Moscow (2004), 20 pp.
L. A. Sviridova, A. N. Tavtorkin, and K. A. Kochetkov, in: Abstracts of the International Conference on
Heterocyclic Chemistry Dedicated to Prof. A. N. Kost on the Occasion of his Ninetieth Birthday [in
Russian], Moscow (2005), p. 279.
3.
4.
S. Hanessian, Tetrahedron Lett., 1549 (1967).
E. Baki, K. Saigo, and T. Mukaiyama, Chem. Ind., 1163 (1975).
369