SYNTHESES OF ~-FUNCTIONALLY SUBSTITUTED 2-1MIDAZOLINONES

S. I. Zav'yalov, L. B. Kochanova, and N. E. Knyaz'kova

UDC 542.91:547.781

The a-hydroxy and a-mercapto derivatives of dehydrodesthiobiotin of type (I) and (II) have interest as potential biological and chemical precursors of vitamin H (biotin) [i]~

O

A. HN NH X=0H (I), SH (II)

I I

CH~X (CH~)sC00H In order to find efficient methods for the synthesis of (I) and (II) and study the pos-

sibility of their further transformation to biotin, in the present paper we studied on simple model examples the conditions for inserting various functional groups in the e-position of substituted 2-imidazolinones.

As is known [i, 2], the simplest method for obtaining 4(5)-aminoalkyl-2-imidazolinones is the Mannich reaction with C-monosubstituted 2-imidazolinones, which proceeds in hot meth- anol. It was shown by us that the Mannich base, and specifically 4(5)-methyl-5(4)-piperidino- methyl-2-imidazolinone (Ill), is formed at a fast rate when 4(5)-methyl-2-imidazolinone (IV) is reacted with paraform and piperidine in the presence of AcOH in aqueous solution:

0 0 0

A A H H - ' HN NH AcS'H Ar H

aMe Me CH2NCsHIo Me CH~SAe

[ Ac~O I DB~ (Ill) (V) POCI3 [

0 0 0

Ac~NAc H~J~NH AcN~NAc I =1 l=l\ I=k

Me Me CHO a Me Me

(VII) (XIII) (VIII)

0 0 O O

(IX) (XI) (XII) (X)

N-Monoacetylation and replacement of the nitrogen function by the thioacetoxyl function were observed when (III) is reacted with a mixture of Ac20 and AcSH at 20~ with the forma- tion of l-acetyl-4-acetylmercaptomethyl-5-methyl-2-imidazolinone (V). PMR spectrum of (V) (6, ppm): 1.88 s (CHsO=C), 2.02 s (CHsCOS), 2.38 s (CH3CON), 3.98 s (CH2). In harmony with [3], it must be assumed that the sterically less hindered N ~ nitrogen atom is acetylated.

Exchange of the nitrogen function in (III) by the sulfur function evidently facilitates the ease of forming the internally stabilized intermediate carbcation (VI):

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow. Translated from IzvestiyaAkademii Nauk SSSR, Seriya Khimicheskaya, No. ii, pp. 2629-2632, November, 1979. Original article submitted May 23, 1979.

0568-5230/79/28!i-2445507.50 �9 1980 Plenum Publishing Corporation 2445

i (III) > H~i~~ NH > (V)

(w)

Sulfur functions can also be inserted in the a-position by the chlorination of the N ~, N3-diacetyl derivatives of the 4 (5)-methyl- and 4,5-dimethyl-2-imidazolinones (VII) and (VIII) using SO2C12 and subsequent treatment of the intermediate chlorides (IX) and (X) with AcSK in acetone. As a result of these transformations we respectively isolated the 1,3- diacetyl-5-acetylmercaptomethyl- and i, 3-diacetyl-4,5-diaeetylmercaptomethyl-2-imidazolinones (XI) and (XII), which were previously obtained by starting with the ~-bromination products of diacetyl derivatives (VII) and (VIII) [4].

Attempts to a-chlorinate the N-unsubstituted 2-imidazolinone (IV) proved unsuccessful. The use of the Vilsmeier reagent (DMF/POCI3 or DME/SO2CIz) makes it possible to insert the oxygen function in the (IV) molecule: the reaction of (IV) with Vilsmeier reagent at 20 ~ gave 4-methyl-5-formyl-2-imidazolinone (XIII), which was isolated and characterized as the 2,4-dinitrophenylhydrazone (yield -40%). The reaction of (IV) with DMF/SOCI2 or DMF/PCI~ went less smoothly.

EXPERIMENTAL

The UV spectra were taken in alcohol on a Specord UV-VIS instrument, the IR spectra were taken as a KBr pellet on a UR-20 instrument, and the PMR spectra were taken in CF3COOH on a DA-60-1L instrument (internal standard = HMDS). The TLC was run on Silufol UV-254 (detection with iodine vapors and in UV light).

4(5)-Methyl-5(4)-piperidinomethyl-2-imidazolinone (III). To 0.25 g of (IV) [5] and 0.08 g of paraform in I0 ml of water were added 0.5 ml of piperidine and 2 drops of AcOH. The mixture was heated for 20 min at 90 ~ (here and subsequently the bath temperature), and the precipitate was filtered, washed with water, and dried in the air to give 0.41 g (83%) of (III), which decomposes above 290 ~ [i]. Rf 0.75 (i-C3HTOH:NH~OH:H20, 7:1:2). PMR spec- trum (6, ppm): 1.67 s (CH2CH2CH2), 1.98s (CH3C~-C), 2.70 s (CH2NCH2), 3.38 s (NCH2~).

l-Acetyl-4-acetylmercaptomethyl-5-methyl-2-imidazolinone (V). A mixture of 0.5 g of (III) and 1.5 ml of AcSH in i0 ml of Ac20 was stirred for I h at 20 ~ kept for 5 days at 20 ~ , and evaporated in vacuo. The residue was treated with water, and the precipitate was filtered and dried in the air to give 0.2 g (42%) of (V), mp 196-198 ~ , Rf 0.75 [2:1 ethyl acetate (EA)--acetone]. Infrared spectrum (~, cm-X): 1690, 1710, 1720. Found: C 47.35; H 5.61; N 12.25; S 13.70%. CgHI2N202S. Calculated: C 47.37; H 5.26; N 12.28; S 14.03%.

1,3-Diacetyl-5-acetylmercaptomethyl-2-imidazolinone (XI). To 0.36 g of (VII) [4] was added 0.3 g of S02CIz, and the mixture was stirred for 4 h at 20 ~ and then dissolved in 6 ml of acetone. TO the stirred solution were added AcSK solution (from 0.5 ml of AcSH and 0.3 g of KOH in i ml of water) and 0.5 g of NaHC03, after which the mixture was kept for 12 h at 20 ~ , evaporated in vacuo, and the residue was treated with water. The precipitate was fil- tered and recrystallized from ether at --50 to--60 ~ We obtained 0.18 g (35%) of (XI)~ mp 73-74 ~ Rf 0.60 (4:1 benzene--EA). The mixed melting point of the obtained thioacetate (XI) with an authentic specimen was not depressed.

1,3-Diacetyl-4,5-diacetylmercaptomethyl-2-imidazolinone (XII). To 0.2 g of (VIII) [4] was added 0.3 g of S02C12, after which the mixture was stirred for 4 h at 20 ~ and then dis- solved in 6 ml of acetone. With stirring, to this solution were added aqueous AcSK solution (from 0.5 ml of AcSH and 0.3 g of KOH in I ml of water) and 0.5 g of NaHC03, and the mixture was kept for 12 h at 20 ~ . After the above indicated workup we obtained 0.12 g (35%) of (XII), mp 108-110 ~ , Rf 0.87 (i:i benzene--EA~. PMR spectrum (~, ppm): 2.22 s (2CH3COS), 2.54 s (2CH~CON), 4.38 s (2CH2S). The mixed melting point of the obtained thioacetate (XII). with an authentic specimen was not depressed.

2,4-Dinitrophenylhydrazone of 4-Methyl-5-formyl-2-imidazolinone (XIII). With stirring and cooling in ice, to 0.5 ml of DMF were added 0.4 g of POCI3 (or SO2CI~) and then 0.2 g of pulverized (IV). The mixture was stirred for i h at 20 ~ , diluted with 3 ml of water,

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treated with Na2C03 to pH 7.5-8, heated for 5-10 min at 90 ~ , cooled to 20 ~ , and acidified with dilute HCI solution to pH 2-3. To the obtained solution was added an excess of alco- holic 2,4-dinitrophenylhydrazine solution, which contained several drops of conc. HCI, and the mixture was refluxed for 10-15 min, after which the precipitate was filtered, washed with hot alcohol, and dried in the air to give 0.25 g (36%) of the (XIII) 2,4-dinitrophenyl- hydrazone, which decomposes above 250 ~ . Ultraviolet spectrum: %max 410 nm. Found: C 42.20; H 3.30; N 26.52%. C11HIoN6Os. I/2 H20. Calculated: C 41.91; H 3.49; N 26.66%.

2,4-Dinitrophenylhydrazone of ethyl ester of ~-ketodehydrodesthiobiotin [6]: mp 223- 225~ %max 415 nm. PMR spectrum: (6, ppm): 1.08 t (CH3CH20), 1.70 m (CH=CH2), 2.28 s (CHiC=C), 2.38 m (CH2COOC2Hs), 2.64 m (CH2C----N), 4.06 q (CHzO), 8.66 t, 9.52 d, 9.94 s (aro- matic ring)~

CONCLUSIONS

i. The Mannich and Vilsmeier reactions with 4(5)-methyl-2-imidazolinone proceed with involvement of the C5(4) carbon atom.

2. The reaction of 4(5)-methyl-5(4)-piperidinomethyl-2-imidazolinone with a mixture of thioacetic acid and acetic anhydride gives l-acetyl-4-acetylmercaptomethyl-5-methyl-2 - imidazolinone.

3. The chlorination of the Ni,N3-diacetyl derivatives of the 4(5)-methyl- and 4,5-di- methyl-2-imidazolinones with sulfuryl chloride gives the ~-chloro derivatives, which when treated with potassium thioacetate are converted to the corresponding thioacetates.

LITERATURE CITED

I. N.A. Rodionova, M. P. Unanyan, G. V. Kondrat'eva, S. I. Zav'yalov, and V. V. Filippov, Izv. Akad. Nauk SSSR, Ser. Khim., 1970, 660.

2. S.I. Zav'yalov, O. M. Radul, V. I. Gunar, and N. A. Rodionova, Izv. Akado Nauk SSSR, Ser. Khim., 1972, 2335.

3. S.I. Zav'yalov, L. L. Zheleznaya, and A. B. Pavlova, Izv. Akad. Nauk SSSR~ Ser. Khim.~ 1973, 1416.

4. R. Duschinsky and L. A. Dolan, J. Am. Chem. Soc., 70, 657 (1948). 5. S.I. Zav'yalov, M. P. Unanyan, G. V. Kondrat'eva, and V. V. Filippov, Izv. Akad.

Nauk SSSR, Ser. Khim., 3967, 1792. 6. R. Duschinsky and L. A. Dolan, J. Am. Chem. Soc., 67, 2081 (1945).

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