S Y N T H E S I S OF ~ - S U L F U R - C O N T A I N I N G

2 - I M I D A Z O L I N O N E D E R I V A T I V E S

S. I . Z a v ' y a l o v , O. M. R a d u l , a n d V. I . G u n a r

UDC 542.9h547.781

According to [1], vi tamin H (biotin) (I) is formed in the living cell by the cyclizat ion of the sulfur- containing b ioprecursor (II), which contains a semicycl ic double bond:

0 0 0 II II 11

/ \ / \ HN NH ~_ HN NH X_/ X__/

CH2SH CH(CH2hC00H C,,zoH (CH2)sCOOHI S (CH~hCOOH (I~ (II) (tU)

One of the routes for the synthesis of (II) could be the prepara t ion of i ts s t ruc tura l i somer (III), which contains an endocyclie double bond, and the subsequent i somer iza t ion of (III) to (II). In the presen t paper, in o rde r to effect the synthesis of (III), we studied methods for insert ing the sulfur atom into the c~-position of 2-imidazolinone der ivat ives .

The reac t ion of 4(5)-methyl-5(4)-piper idinomethyt-2- imidazol inone (IV) with CS2, mercaptans or with excess CH3COSH in refluxing alcohol, by analogy with the thiylation react ions of other types of Mannich bases [2], respect ive ly gave 4(5)-S-thiocarbopiper ididomethyl- , 4(5)-S-alkylmercaptomethyl- , and 4(5)-S- aee ty lmereaptomethyl -5(4) -methyl -2- imidazol inones (V), (Via, b) and (VII) (Table 1):

A 0 t} HN

R' HN NH

/ "\ CH2 CHa I

S R

R' = CH~ (IV)

: C(=s)%__~ (v);

n-C4H9 (Via), CH~C6H5 (Vlb), COCHa (Vll}

The s t ruc tu re of (V) and (Via) was proved by eountersyntheses : by the react ion of (CH20)x and C5H10 �9 NC(-~S)SH .HNC5Hlo with 4(5)-methyl-2- imidazol inone (VIII), and of n-CaHgSNa with 4(5)-methyl-5(4)- bromomethyl-2- imidazol inone (MB), while the s t ruc ture of (VII) was proved by its convers ion to the known N,N,-diacetyl der ivat ive (by refluxing with (CH3CO)20) [3]:

o 0 II I]

/ \ N H NH-- ' - -* (V) NcOCH3

\CHa CH2/Br \CH3 (VIII)

---, (Via)

The react ion of (IV) with an equimolar amount of CHsCOSH gave a mixture of (VII) and sulfide (iX), the s t ruc tu re of which was proved by elemental analysis, molecular weight determinat ion, desulfurizat ion with Ni to 4 ,5-dimethyl-2- imidazol inone (X), and the NMR spect rum of the te t race ty l der ivat ive (XI):

N. D. Zelinskii inst i tute of Organic Chemistry, Academy of Sciences of the USSR. Trans la ted f rom Izvest iya Akademii Nauk SSSR, Seriya Khimieheskaya, No. 6, pp. 1371-1375, June, 1973. Original a r t ic le submitted September 13, t972.

�9 1973 Consultants Bureau, a division of Plenum Publishing Corporation, 227 l~est 17th Street, New York, N. Y. 10011. All rights reserved. This article cannot be reproduced for any purpose whatsoever without permission of the publisher. A copy of this article is available from the publisher for $15.00.

1 3 3 0

.0

[/\ (VII)--r-- IH~/NH

(,x)

[ / t ].(IV) INi /%_,'" t . / \

(XH) /

H3C \CHa (X)

0

l 1 /\ - - - ~ HaCOCN NCOCI-I~ S

H~C CH~- 2 (XI)

The convers ion of (IV) to (IX) can be depicted as a multistep process , which includes the intermediate steps of forming (VII), the aminolysis of (VII) to 4(5)-methyl-5(4)-mercaptomethyl-2- imidazol inone (XII), and the subsequent react ion of (XII) with (IV). This scheme is in agreement with the ability of (VII) to smoothly change to (IX) when heated with excess piperidine in refluxing alcohol. The use of excess CH 3 "COSH in the react ion with (IV) excludes the formation of free piperidine and prevents the aminolysis of (VII) to (XI::), thus assur ing a high yield of (VII).

The thiylation methods that were worked out on the model example (IV) were also appIied to 4(5)- piperidinomethyI-5(4)-(c~-hydroxy-a-earbethoxyamyl)-2-imidazolinone (XIII), which with C6HsCH2SH and CH3COSH gave sulfur der ivat ives that were related to (III), and specifically the 4(5)-S-benzylmercapto- methyl - and 4(5) -S-ace ty lmercaptomethyl -5(4) - (a -hydroxy-a-carbe thoxyamyl) -2- imidazol inones (XIV) and (XV). The s t ruc ture of the latter is in agreement with the elemental analysis data and the IR speetra (see Table 1) :

o

HN//~NH ~ 1~ HN//~NH

R' / "~W CHe

�9 �9 SR

11 = CH2C6H5 (XIV), COCHa (XV)

It'= CH(OH)(CH2hC00C~It5 (XlII)

EXPERIMENTAL METHOD

Prepara t ion of (V), (Via, b), (VII), (XIV) and (XV). A mixture of (IV) [3] or (XIII) [4] and the sulfur- containing reagent in either alcohol or n-propanol was refluxed for 2-8 h, and the react ion products were isolated in ~;he following manner: evaporat ion and subsequent purification of the residue by prepara t ive TLC [A1203 (III activity), a c e t o n e - w a t e r , 9 :1)] [(V)], recrys ta l l iza t ion [(Via) and (XIV)] or washing the residue with ether [(XV)], and fi l trat ion of the obtained precipi tate [(VIb) and (VII)]. The experimental conditions and cha rac te r i s t i c s of the react ion products are given in Table 1.

Reaction of (VIII) with (CH20)x and C5H10NC(=S)SH "HNCsH10. With s t i r r ing, to 4.25 g of piperidine in 40 ml of alcohol was added 3.8 g of CS 2 in 25 ml of alcohol, after which the mixture was kept for 0.5 h, and then a finely pulverized mixture of 1.5 g of (CH20)x and 4.9 g of (VIII) [5] was added graduaily. The mix- ture was refluxed for 8 h, cooled, and the precipi tate was f i l tered. We obtained 8.2 g (60%) of (V).

Countersyntheses of (Via). To 0.185 g of n-C4HgSH and 0.08 g of NaOH in 10 ml of aieohoi was added a solution oF 0.55 g of (MB) [3] in 15 ml of alcohol, after which the mixture was kept at ~20 ~ for 48 h, fil- tered, and the f i l t rate was evaporated. The res idue was rec rys ta l l i zed in success ion f rom a 1 : 1 EA - h e p t a n e mixture and a 5 : 1 E A - a l c o h o l mixture. We obtained 0.28 g (70%) of (Via).

N-Acetylat ion of (VII). A mixture of 0.18 g of (VII) and 5 ml of (CH3CO)20 was refluxed for 3 h, the f i l t rate was evaporated, and the residue was rec rys ta l l i zed f rom n-heptane. We obtained 0.07 g (27%) of the N, N ' -d iace ty l derivative, mp 78-80 ~ [3].

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Preparation of (IX). A mixture of 0.37 g of (VII) and 0.3 ml of piperidine in 25 ml of alcohol was re- fluxed for 3h, and the precipitate was filtered and washed in succession with hot alcohol, dilute HCI solution (I : I), water, alcohol and ether. We obtained 0.21 g (83%) of (IX), decomposition point above 280 ~ Found: C 46.93; H 5.48; S 13.09%. Ci0HIaO2N4S. Calculated: C 47.10; H 5.50; S 12.50%. When (VIII) was heated with excess skeletal Ni in refluxing alcohol (I0 h) we isolated (X), with decomposition point above 290 ~ (from water) [5].

Tetraacetyl Derivative (IX)-(XI). A mixture of 1 g of (IX) and 35 ml of (CH3CO)20 was refluxed until all of the precipitate had dissolved (6 h), after which the solution was evaporated and the residue was treated with ethyl acetate. We obtained 0.88 g (53%) of (XI), mp 119-120 ~ (from 4 : 1 benzene-heptane), Rf 0.61 (Sikffol, 1:1 benzene-ethyl acetate). Infrared spectrum (KBr, p, era-i): 1750, 1730, 1720 (C=O). NMR s p e c t r u m ~ (5, ppm): 2.23 (2-CH~, he re and subsequent ly a singlet), 2.51 (2-CH3CO), 2,55 (2-CH3CO), 3.95 (2-CH2S). Found: C 50.93; H 5.12; N 13.07; S 7.44~; mol . wt. 420 (Rast) . C18H2206N4S. Calculated: H 5.24; N 13.26; S 7.95%; tool. wt. 422. Compound (VIII) was isola ted in 89% yield when (XI) was heated with excess p iper id ine in refluxing alcohol (3 h).

C O N C L U S I O N S

1. A method was developed for the synthes is of oz-sulfur-containing de r iva t ives of 2- imidazol inone by the r eac t i en of 4 (5 ) -p ipe r id ino-methy l -2 - imidazo l inones with mercap tans , carbon disulfide and thioacetic acid.

2. 4 !5 ) -Methy l -5 (4 ) -S -ace ty lmercap tomethy l -2 - imidazo l inone was conver ted to b i s [4(5) -methyl -2- imidazoi in~nyl-5(4)-methyl] sulfide trader the influence of p iper id ine .

1.

2. 3.

4.

5.

LITERATURE CITED

A. Lezius, E. Ringelmann, and F. Lynen, Biochim. Z., 336, 510 (1963). N. I<reutzkamp, H. Y. Oei, and H. Peschel , Arch . Pha rm. , 304, 649 (1971). N. A. Rodionova, M. P. Unanyan, G. V. Kondra t ' eva , S. I. Zav 'ya lov , and V. V. Filippov, Izv. Akad. Nauk SSSR, Se t . Khim., 1970, 660. S. I . Zav 'ya lov , O. M. Radul, and N. A. Rodionova, Izv. Akad. Nauk SSSR, Se t . Khim., 1972, 2025. S. I. Zav 'ya lov , M. P. Unanyan, G. V. Kondra t ' eva , and V. I. Filippov, Izv. Akad. Nauk SSSR, Set . Khim., 1967, 1792.

*The NMR spec t rum was taken on a DA-60-I1 ins t rument in pyridine, using HMDS as the internal s tan- dard .

1333