H A L O G E N A T I O N O F N - A C Y L - ~ - A M I N O K E T O N E S

S. I . Z a v ' y a l o v a n d G . I . E z h o v a UDC 542.944:547.447.5

The bromina t ion of ace tamidoace tone (In) in cone. HC1 in the p r e sence of LiC1 (3 h, 20~ leads to the fo rmat ion of pyruvaldehyde (II) [1]. Such a reac t ion cour se can be explained in the following manner . F i r s t the kinet ieal ly control led bromina t ion (KCB) of (Ia) at the ac t ive methylene group takes place; the thus formed b romide (IIIa) undergoes fu r the r hydrolyt ic c leavage to (II), not succeeding in i somer i z ing to 1 - b r o m o - 3 - a c e t - amidoacetone (IVa), the the rmodynamica l ly control led bromina t ion (TCB) product .

As a continuation of this r e s e a r c h we studied in the p re sen t pape r the TCB of ace tamidoace tone (Ia) and 1 -benzamido-2-bu tanone (Ib) in o r d e r to synthes ize b romide (IVa) and 1 - b e n z a m i d o - 3 - b r o m o - 2 - b u t a n o n e (IVb), and f r o m them polyfunctional al iphatic compounds.

The bromina t ion of amido ketones (Ia) and ( Ib )was run in CHC13 and AcOH in o r d e r to avoid hydro lys i s of b romides (IIIa, b), obtained by KCB, which prevents the r e a r r a n g e m e n t of (IIIa, b) to bromides (IVa, b).

BCH~COCH~NHCOR' ~ [RCH~COCHBrNHCOR'] (Ia, b) - | (Il ia, b)

R=H, R'=CH, (a), § RCHBrCOCH~NHCOB'

R=CHs, R'=C~H5 (b). (IVa, b)

The s t r u c t u r e of b romides (IVa, b) was conf i rmed by the IR and PMR s p e c t r a (see the Exper imenta l sect ion), and a l so by chemica l t r an s fo rm a t i ons .

Bromides (IVa, b) when t rea ted with conc. HCI (24 h, 20 ~ fail to give noticeable amounts of aldehyde (II), which tes t i f ies to the inabili ty of (IVa, b) to i s o m e r i z e to b romides (IIIa, b) under these conditions. De- pending on the c h a r a c t e r of the nucleophilic reagent , b romides (IVa, b) behave di f ferent ly in nucleophilic sub- st i tution reac t ions . A normal reac t ion is observed only in the case of the "soft" base CH3COS-, which reac t s with (IVa, b) to give 1 - a c e t a m i d o - 3 - a c e t y l m e r c a p t o a c e t o n e (Va) and 1 - b e n z a m i d o - 3 - a c e t y l m e r c a p t o - 2 - b u t a n -

one (Vb).

The reac t ion of b romides (IVa, b) with a s t rongly nucleophilic and "hard" base like piper idine is a c c o m - panied by migra t ion of the b romine a tom and the fo rmat ion of 1 -ace tamido-1 -p ipe r id inoace tone (Via) and 1- benzamido - l -p ipe r id ino -2 -bu t anone (VIb). The posit ion of the piper idine moie ty in the (Via, b) molecules en- sues f r o m the PMR s pec t r a l data and the hydro lys i s of (VIb) to ethylglyoxal.

(IVa, b) c~I,COS~ BCHSAcCOCHeNHCOR' (Va, b)

HNCsH,o

, RCH2COCH(NC6H10)NHCOR' (Via,b)

The convers ion of (IVa, b) to (Via, b) p robably includes the initial fo rmat ion of an equi l ibr ium mix ture of b r o - mides (IIIa, b) and (IVa, b) under the influence of piperidine and subsequent reac t ion of the l a t t e r with the more reac t ive b romides (IIIa, b). The h igher e lec t rophi l ic r eac t iv i ty of b romides (IIIa, b) when compared with (IVa, b) is due to the fact that they contain an additional e lec t ronega t ive ni t rogen a tom at the e lect rophi l ic cen te r .

N. D. Zel inski i Insti tute of Organic C h e m i s t r y , Academy of Sciences of the USSR, Moscow. Translated" f r o m Izves t iya Akademii Nauk SSSR, Ser iya Khimicheskaya , No. 11, pp. 2575-2578, November , 1980. Or i - ginal a r t i c l e submit ted Decem ber 14, 1979.

1830 0568-5230/80/2911-1830507.50 �9 1981 Plenum Publishing Corpora t ion

=~(~ ~ HNCsHIo

Br (Ivy, b)

Br+ (Via, b) <HNC~H~____~0 (Ilia,b) ~-----"~-~

H_NC~H,0

U 1

R CH=CCH2NHCOR'

I RCHs C~CHNHCOR ~

The react ion of (IVa, b) with AcONa, AcOAg, o r PhCHaCOOAg in CHaCN or DMF (20 ~ gives complex, inseparable mixtures of products. Attempts to replace Br 2 by SO2C12 for the halogenation of (In) in o rde r to obtain chloride (VII) or (VIII) led to an unexpected result . In the PMR spec t rum (CF3COOH) of the chloride formed here appear the singlet signals of two CH 3 groups with 6 2.51 and 2.62 ppm and one CH2 group with 6 4.55 ppm, which a re shifted downfield by 0.5-0.6 ppm when compared with the corresponding signals of the s tar t ing ketone (In). These spec t ra l data indicate that (Ia) is chlorinated at the N atom to give N-ch loroace t - amidoacetone (IX).

CHsCOCHC1NHAC C1CH2COCH2NHAc (VII) (VIII)

SO,C12 �9 (Ia) " 7. CH~COCH~NC1Ac

(IX)

Chloride (IX) also has other properties that are characteristic for N-chloroamides: It decomposes in conc. HCI with the liberation of Cl 2 [2] and its IR spectrum has the band of the N-chloroamido group (1700 cm -I) [3]. The possibility of the N-chlorination of (In) by SO2CI 2 is also in agreement with the resuR of re-

acting benzamide with SO2CI 2 at 20 ~ which leads to the known N-chlorobenzamide, previously obtained by treating benzamide with chlorine [4]. When heated with water, (IX) does not give noticeable amounts of al-

dehyde (II).

0 �9 o

(xi) (x)

However, chloride (IX) can successfu l ly replace (II) for obtaining 7-methylpter in iX) f rom 2 ,5 , 6 - t r i a m i n o - 4 - hydroxypyrimidine (XI).

EXPERIMENTAL

The UV spectra were taken on a Specord UV-VIS instrument, the rR spectra were taken as KBr pellets on a UR-20 instrument, and the PMR spectra were taken on a DA-601L instrument, using HMDS as the inter- nal standard. The TLC was run on Silufol UV-254.

Bromination of Acetamidoacetone (In). A mixture of 0.5 g of (In) [5], 0.28 ml of Br 2, and 0.02 g of LiCI in 3 ml of CHCI 3 was stirred for 36 h at 20~ and then the CHCI 3 solution was decanted from the obtained oil. The latter was washed with CHCI 3 and kept in vacuo for 12 h. We obtained 0.83 g (98%) of oily l-bromo-3- acetamidoacetone (IVa). Infrared spectrum (v, em-1): 1660 (CON), 1735 (CO). PMR spectrum (CF3COOH, 6, ppm): 2.24 s (CH3CON), 3.62 s (CH2N), 4.20 m (CH2Br }.

Similar results were obtained when (la) was brominated in AcOH.

Reaction of 1-Bromo-3-acetamidoaeetone (IVa) with AcSK. With cooling in ice and stirring, to a solu- tion of 0.82 g of (IVa) in 5 ml of acetone was added a solution of AcSK (from 0.92 ml of AcSH and 0.49 g of KOH in 2 ml of H20). The reaction mixture was stirred for 3 h at 20 ~ after which it was evaporated in vacuo, and the residue was treated with aqueous NaHCO 3 solution to pH 7.5 and then extracted with ethyl acetate (EA). The extract was dried over MgSO 4, evaporated, and the residue was subjected to low-temperature crystalliza- tion from ether to give 0.38 g (47%) of l-acetamido-3-acetylmereaptoaeetone (Va), mp 67-68 ~ Rf 0.36 (1:2 EA-benzene). Infrared spectrum (v, cm-1): 1665 iCON), 1690 (COS), 1720 (CO). PMR spectrum iCDCI3, 5,

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ppm): 1.95 s (CH3CON) , 2.28 s (CHaCOS), 3.68 s (COCH2S), 4.16 d (COCH2NH, J = 5 Hz). Found: C 44.43; H 5.99; N 7.49; S 16.80%. CTHllO3NS. Calculated: C 44.44; H 5.82; N 7.40; S 16.93%.

Reaction of 1 -Bromo-3-ace tamidoaee tone (IVa) with Piperidine, With s t i r r ing and cooling with solid CO 2, to 1.66 g of bromide (IVa) was added 12 ml of piperidine, af ter which the mixture was kept for 12 h at 20 ~ evaporated in vacuo, the residue was t reated with benzene, the piperidine hydrobromide was fi l tered, the fi l trate was evaporated, and the residue was chromatographed on A1203 (II activity). Elution with benzene gave 0.5 g (30%) of 1 -ace tamido- l -p iper id inoace tone (Via), mp 112-113 ~ (after low- tempera ture r e c r y s t a l l i z a - tion f rom ether), Rf 0.51 (1:1 E A - a c e t o n e ) . Infrared spec t rum (v, cm-1): 1650 (CON), 1720 (C=O). PMR spec t rum (CC14, 5, ppm), 1.43 m (CH2CH2CH2), 1.83 s (CH3CON) , 2.22 s (CH3CO) , 2.16-2.66 (CH2NCH2) , 51)5 d (NCHN, J = 8 Hz). Found: C 60.43; H 9.12; N 14.03%. C10HIsN202. Calculated: C 60.56; H 9.14; N 14.13%.

Bromination of 1-Benzamido-2-butanone (17o). A mixture of 0.5 g of (Ib) [1], 0.19 ml of Br2, and 0.02 g of LiC1 in 5 ml of AcOH was kept for 36 h at 20 ~ af ter which it was diluted with 15 ml of water , NaHCO 3 was added to pH 7, and the mixture was extracted with benzene. The extract was dried over MgSO 4 and evaporated in vacuo to give 0.64 g (91%) of 1 -benzamido-3-bromo-2-bu tanone (IVb) as an oil, Rf 0.32 (2:1 benzene -EA) . Infrared spec t rum (v, cm-1): 1650 (CON), 1730 (CO). PMR spec t rum (CDC13, 5, ppm): 1.62 d (CH3, J = 7 Hz), 4.26-4.69 (COCH2N, CHBr), 7.05-7.46 ( m - a n d p-protons of a romat ic ring), 7.55-7.88 (o-protons of a romat ic ring).

Reaction of Bromide (IVa) with AcSNa, With s t i r r ing , to a solution of 1.34 g of bromide (IVb) in 17 ml of acetone was gradually added a solution of AcSNa (from 1 ml of AcSH and 0.8 g of NaHCO3 in 3 ml of water) , af ter which the mixture was kept for 12 h at 20 ~ evaporated in vacuo, the residue was t rea ted with NaHCOa in water to pH 7, extracted with EA, the extract was dried over MgSO4, evaporated, and the residue was c h r o m a - tographed on SiO2 (100/160 mesh). Etution with a 1:1 b e n z e n e - E A mixture gave 0.75 g (57%) of 1 -benzamido- 3-ace ty lmercapto-2-butanone (Vb) as an oil, Rf 0.51 (acetone). Infrared spec t rum (v, em-1): 1650 (CON); 1690 (CH3COS), 1725 (C =O). PMR spec t rum (CDC13, 6, ppm): 1.40 d (CH3, J = 6 Hz), 2.24 s (CH3COS), 4.18- 4.78 (COCH2N, COHS), 7.18-7.56 (m- and p-protons of a romat ic ring), 7.64-8.02 (o-protons of a romat ic ring).

React ion of Bromide (IVb) with Piperidine. With s t i r r ing and cooling with solid CO2, to 0.51 g of bromide (IVb) was gradually added 8 ml of piperidine, af ter which the mixture was kept for 12 h at 20 ~ evaporated in vacuo, the residue was t reated with benzene, the piperidine hydrobromide was f i l tered, the fi l trate was evap- o ra ted , and the residue was chromatographed on SiO~ (100/160 mesh). Elution with ~ 1:5 E A - h e n z e n e mix-

t u r e gave 0.26 g (50%) of 1 -benzamido- l -p iper id ino-2-bu tanone (VIb), mp 120-121 ~ (after low- tempera ture crysta l l iza t ion f rom ether) , Rf 0.47 (2:1 EA-benzene ) . Infrared spec t rum (v, cm-1): 1645 (CON), 1725 (C =O). PMR spec t rum (CDC13, 5, ppm): 1.00 t (CH 3, J = 7 Hz), 1.42 b r . s (CH2CH2CH2), 2.03-3.02 (CH2NCH2, CH2CO), 5.20 d (NCHN, J = 7 Hz). 7.06-7.45 (m- and p-protons of a romat ic ring), 7.59-7.95 (o-protons of a romat ic ring). Found: C 69.72; H 8.10; N 10.04%. C16H22N202. Calculated: C 70.07; H 8.05; N 10.02%.

Hydrolytic Cleavage of (VIb), A solution of 0.18 g of ketone (VIb) in 4 ml of 1:1 HC1 solution was heated for 2 h at 90-100 ~ af ter which the mixture was cooled to 20 ~ the benzoic acid precipitate was fi l tered, the fi l trate was diluted with 5 ml of water , neutral ized with Na2CO a, and a solution of NtI4OH (from 0.18 g of NH 2- OH-HCI and 0.11 g of KOH in 3 ml of water) was added. The react ion mixture was heated for 1.5 h at 100 ~ cooled, and excess Ni(OAc)2.4H20 was added. The red precipi tate of the Ni complex of ethylglyoxal dioxime was filtered and dried in the air . Yield 0.05 g. In its IR spec t rum the obtained Ni comple~ coincided with the

authentic specimen [1].

Chlorination of Aeetamidoacetone (In). To 0.5 g of ketone (In) was added 0.42 ml of SO2C12 and on con- clusion of b r i sk react ion the mixture was s t i r red for 1 h at 20 ~ and the volatile impuri t ies were evaporated in vacuo. We obtained 0.63 g (97%) of N-chloroacetamidoacetone (I~) as an oil. Infrared spec t rum (v, cm-1): 1700 (CHaCONC1), 1735 (C=O) . PMR spec t rum (CF3COOH, 5, ppm): 2.52 s (CHaCONC1), 2.62 s (CHACO), 4.55

s (CH2).

Acetamidoacetone (Ia), PMR spec t rum (CF3COOH, 5, ppm): 1.92 s (CH3CO), 2.12 s (CH3CO), 4.03 s (CH2). The l iberation of C12 was observed when (IX) is kept with conc. HC1 for 2 h at 20 ~

Chlorination of Benzamide . A mixture of 0.5 g of benzamide and 2.2 g of SO2C12 was s t i r red for 48 h at 20 ~ af ter which it was poured into ice water , kept for 100 h at 20 ~ and the precipi tate was filtered and dried in the air . We obtained 0.15 g (23%) of N-chlorobenzamide, mp 115-117 ~ Rf 0.34 (2:5 EA-benzene ) . The mixed melt ing point of the obtained N-chlorobenzamide with an authentic specimen [4] was not depressed and

they both had the same Rf.

1832

Condensation of N-Chloroace tamidoace tone (IX) with 2 , 5 , 6 - T r i a m i n o - 4 - h y d r o x y p y r i m i d i n e (XI). With s t i r r i ng , to a mix tu re of 0.63 g of (IX) and 0.5 g of sulfate (XI) in 8 ml of wa te r was gradual ly added 2.5 ml of Et3N and the mix tu re was s t i r r e d for ano ther 12 h at 20 ~ To the reac t ion mix tu re was added 10% KOH solu- t ion until all of the p rec ip i t a te had d i s so lved , a f t e r which the solution was heated fo r 10 min at 100 ~ acidified with AcOH to pH 6-6.5 , and the p rec ip i t a te was f i l te red , washed in success ion with wa te r , acetone, and e the r , and dr ied at 100 ~ in vacuo. We obtained 0.31 g (84%) of 7 -me thy lp t e r in (X), decomposi t ion point > 360 ~ Rf 0.47 ( i - P r O H - H 2 0 - N H 4 O H , 7:2:3, f luorescen t spot in UV light). In its Rf, UV, IR, and PMR s p e c t r a the ob- tained 7 -me thy lp t e r in coincided with an authentic spec imen [6].

Ace tamidoace tone (Ia) i t se l f does not r eac t with sulfate (XI) under the above indicated conditions.

C O N C L U S I O N S

1. The bromina t ion of ace tamidoace tone and 1 -benzamido-2-bu tanone in CHC13 o r AcOH re spec t ive ly gives 1 - b r o m o - 3 - a c e t a m i d o a c e t o n e and 1 - b e n z a m i d o - 3 - b r o m o - 2 - b u t a n o n e .

2. The reac t ion of 1 - b r o m o - 3 - a c e t a m i d o a c e t o n e and 1 - b e n z a m i d o - 3 - b r o m o - 2 - b u t a n o n e with thioacet ic acid sa l t s r e s p e c t i v e l y gives 1 - a c e t a m i d o - 3 - a c e t y l m e r c a p t o a c e t o n e and 1 - b e n z a m i d o - 3 - a c e t y l m e r c a p t o - 2 - butanone, while reaction with piperidine gives l-acetamido-l-piperidinoacetone and l-benzamido-l-piperidino- 2 -butanone.

ide.

1. 2. 3. 4. 5.

6.

3. N-Chloroace tamidoace tone was obtained by the chlor inat ion of ace tamidoace tone with sulfuryl ch lo r -

L I T E R A T U R E C I T E D

S. I. Zav 'ya lov and G. I. Ezhova, Izv. Akad. Nauk SSSR, Set . K h i m . , 1044 (1979). A. W. Hofmann, B e t . , 15, 410 (1882). K. Nakanishi , In f ra red Absorpt ion Spec t roscopy , Holden-Day. R. L. Datta and T. Gosh, J . Am. Chem. Soc . , 35, 1044 (1913). S. I. Zav 'ya lov , M. P. Unanyan, G. V. Kondra t ' eva , and V. V. Fil ippov, Izv. Akad. Nauk SSSR, Ser. K h i m . , 1792 (1967). S. I. Zav 'ya lov and T. K. Budkova, Izv. Akad. Nauk SSSR, Ser. K h i m . , 1323 {1979).

E L E C T R O P H I L I C C Y C L I Z A T I O N O F 2 - G E R A N Y L T H I O P H E N E

A N D I T S 5 - C A R B O X Y D E R I V A T I V E *

A. V . S e m e n o v s k i i $ a n d N. M. E m e l ' y a n o v UDC66.095.252:547.733

The e lec t rophi l ic cycl iza t ion of 1 , 5 - p o l y e n e s , containing e i the r an olefinic or ace ty lenic f r agment ( t e r - minator) in the homoal ly l ic posi t ion to the t e r m i n a l mult iple bond, is accompanied by the fo rmat ion of a f ive - m e m b e r e d r ing, which is used to build hydrindan and perhydrocyclopentanophenanthrene skeletons [2-4]. Re - cent ly , it was shown that the thiophene r ing can be used in an analogous cycl izat ion, which leads to the f o r m a - tion of cyclohexano[b]thiophene de r iva t ives [5, 6]. In o r d e r to have acces s to compounds of the hydrindan s e r i e s and, in the final ana lys i s , to perhydrocyc lopentanophenanthrenes we studied the e lec t rophi l ic cycl izat ion of the p rev ious ly unknown 2-geranyl th iophene (Ia) and the cor responding 5-carboxyl lc acid (Ib), containing the thienyl group as the t e r m i n a t o r in the al lyl ic posi t ion to the t e rmina l double bond, which were obtained in r e - spec t i vey fe ld s of 90 and 80% by the following scheme:

(Ia) (Ib) *See [1] for p r e l i m i n a r y communica t ion .

Deceased .

N. D. Zel inski i Inst i tute of Organic C h e m i s t r y , Academy of Sciences of the USSR, Moscow. Trans la ted f r o m Izves t iya Akademii Nauk SSSR, Ser iya Khimicheskaya , No. 11, pp. 2578-2583, November , 1980. Or ig i - nal a r t i c l e submit ted J a n u a r y 4, 1980.

0568-5230/80/2911-1833507.50 �9 1981 Plenum Publishing Corpora t ion 1833