••

Indian 10urnal of Chemistry Vol. 38B, August 1999; pp. 909-913

Retro-aza Michael ring opening of cis-2,6-diaryl-4-piperidones with selenium dioxide

V Vijayabaskar, S Perumal*, S Muthusubramanian & S Sivasubramanian School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India

Received 18 February 1999; accepted (revised) 3 May 1999

The reaction of cis-2,6-diaryl-4-piperidones with selenium dioxide in ethanol/acetic acid afford diarylideneacelones! hydroxydiarylideneacetones in good yields via relro-aza-Michael ring opening.

We have been interested in the synthesis of nitrogen heterocycles and their transformation into valuable synthons 1.2. Selenium dioxide is a versatile reagent which introduces a carbonyl at a-position to a carbonyl or a hyroxyl at a-position to an alkene or alkyne, besides effecting a host of other transformationsJ-7. Hence this reagent was chosen for obtaining hetero-a-diketones from cis-2,6-diary l-4-piperidones. These diketones wou ld be valuable synthons in the construction of novel heterocycles . However, this reaction afforded good yields of diarylideneacetones via retro-aza-Michael ring opening reaction. This study is the first example of retro-aza-Michael ring opening brought about by selenium dioxide and the results are discussed in this paper.

Results and Discussion Reaction of piperidones with selenium dioxide

in ethanol. The reaction of cis-2,6-diaryl-4-piperidones 1 and their I-methyl derivatives with selenium dioxide in ethanol at reflux affords a good yie ld of diarylideneacetones 2 (Table I) .

The 'H NMR spectrum of I ,5-diphenylpenta-1 ,4-dien-3-one clearly shows two doublets characteristic of trans-olefinic protons at both ends of the mUltiplet of the phenyl ring, one centering at 6.80 ppm and the other at 7.50 ppm. The latter signal slightly overlaps with the multiplet of the phenyl rings. The yield of I ,5-diphenylpenta-1 ,4-dien-3-one from Ie was computed after isolation and purification while that for the products from other piperidones have been obtained by HPLC analysis of the reaction mixtures (Table I).

1

a:

b: e:

d: e:

f:

g: h:

2

Ar = Cr,H,; R = H

Ar = Cr, H40Me-4; R = H

Ar = Cr, H.jCI-4 ; R = H

Ar = Cr,H4Me-4: R = H

Ar = Cr,H,; R = Me

Ar = Cr,H.jOMe-4; R = Me

Ar = Cr,H.jCl-4; R = Me

Ar = Cr, H4Me-4; R = Me

Table I-Retro-aza Michael ring open ing reaction of 4-piperidones with selenium dioxide in ethanol for 7 hr at retlux

Compd Ar R Dienone Yield" 2 (% )

Ia Cf,H5 H 2a 74

Ib Cf,H4OMe H 2b 70

Ie Cr, H4C1 1-1 2e 69

Id Cf,H4Me H 2d 65

Ie Cf,HS Me 2a 74h

If C(,H4OMe Me 2h 71

Ig Cr,H4C1 Me 2c 71

Ih C6H.jMe Me 2d 68

"Yield by HPLC analysis

~ After isolation and purification

This reaction presumably proceeds V[(l an electrophilic attack of selenium dioxide over the nitrogen atom. The ring cleavage probably proceeds

910 INDIAN 1. CHEM SEC. B, AUGUST 1999

Ar

o

N Ar

I R PH, O=Se \J

\ OH

R= H /C H3

Scheme I

via the reactions depicted in Scheme I involving (i) e lectrophilic attack of selenium dioxide over nitrogen atom, (ii ) cleavage of a carbon-nitrogen bond with concomitant elimination of a proton from one carbon

a - to carbonyl and (iii) another carbon-nitrogen bond cleavage and e limination of hydrogen from the other

a-carbon.

The stability of the product, dienone might provide the impetus for the reaction. Both N-Me and N-H piperidones display almost equal reac tivity in thi s reac tion .

Reac tion of cis-2,6-diaryl-4-piperidones with selenium dioxide in acetic :!cid. The reaction was carried out in acetic ac id to see whether in this solvent the di ketone ;s fonned. However, the reaction

of both the N-Me and N-H piperidones in acetic ac id also afforded diaryl ideneacetone 2 (Table II ). However, the reaction of 1 with se lenium dioxide in acetic acid occurs faster (ca. 3hr) than in e thanol (ca. 7hr) suggestip g the invo lvement of a more active species of selenium reagent in the fonner so lvent.

Reaction of 4-piperidones with acetic acid alone. With a vi ew to investigating whethe r acetic acid alone effects the retro-aza Michae l ring opening, the 4-piperidones were heated in acetic acid in the absence of selenium diox ide at 100°C for longer period (Table III). The data in the Table III show

that the piperidones (la and Ie) which do not have an alkyl group at 3-pos iti on afforded an exce llent yield of the diarylideneacetone in 10 hr. Thi s react ion in acetic' acid could have conce ivabl y occurred via protonation at nitrogen followed by ring c leavage (Scheme II) .

Table H-Retro-aza-Michael rin g ope ning rcac ti()n of 4-piperidones with SeOl/ AcOH for 3hr at I (J(JDe

Compd. Ar R Yi eld of 2 (% )

1a C6H\ H XS :L

Ib C6H~OMe-4 H 7<yi'

Ie C6H~C I-4 H 75 10

Id C"H~Me-4 H 7110

Ie C"H5 Me g<)"

If C(,H.pMe-4 Me xi' 1" b C(,H~C1-4 Me xi' 1h C6H~Me-4 Me XX h

"Arter purific ation by chromatogra ph y "Yickl by HPLC analys is

Ta hle III- Retro-aza-Michael ring open ing reaction or 4-piperidones 1 in acetic ac id ;lIld tandem reacti() n of 3 with seleni um diox ide in acetic ac id at 100DC

C mpd Ar R R' Reagent/Sol vent

la C6H, H ArOH

Ie C(,H, Me AcOH

3a C,H, H Me AcOl1

3h Cr,l-l , H i-Pr AcOl1

3e C(,f-I, Me Me AcOl1

3d C(,I I, Ivlr; i ·f'r AcOl l

3a C"H, I; i\.ic ScO),\JHI

3b Cc,!-l , If I-Pr ScC/,\cOH

"Yield by IIPLC anal ys is hArter puri fication by chromatography 'These products Ilia tandem a-hydroxylation-retro-aza-Michael ring opening

Reaction period (hr)

10

10

10

10

10

!O .\

J

Pr()duct

2:1

2h

61>

Yi eld (I;' )

7510

No rC;lcti()n

No re;lctioil

No rC;1Ct ion

Nu n.\ lcti () 11

VIJA Y ABASKAR e/ af.: REACTION OF PIPERIDONES WITH SELENIUM DIOXIDE 911

Scheme II

However, surprisingly in the case of piperidones carrying alkyl substituents such as methyl or isopropyl at 3-position (3, Table III) no reaction occurred in the absence of selenium dioxide and the starting materials remained unaffected.

Probably, the steric interaction between the 3-methyl and the 2-phenyl groups in the transition state 4 might render the cleavage of the N-C2 bond and the subsequent elimination of the proton difficult. The cleavage of the N-C6 bond and the elimination of proton from C-5 of the protonated piperidone could occur readily in the case of piperidones lacking 3-substituents. However, the intermediate 5 that might be formed in this reaction can revert back to the piperidone itself if the elimination of methyl amine is rendered difficult by the steric interaction between the methyl and aryl group as referred to in 4 earlie r.

As the ring opening of 3-substituted piperidones failed to occur in acetic acid alone, it was thought that the reaction of these compounds with selenium dioxide in acetic acid might succeed in e ffecting the

a-functionalisation . Thi s reaction with selenium dioxide in acetic acid medium at retlux afforded a good yield of a single product in about 3 hr. whose analytical and spectral data (vide illfra) reveal the product to be 4-alkyl-I ,5-diphenyl-2-hydroxy-penta­I ,4-dien-3-ones 6 (Table III) .

The IR spectra of 6a and 6b support the ir structure . The [R spectrum of 6a showed a broad band at 3225 cm- I attributed to hydrogen bonded hydroxyl group.

The characteristic bands at 1568 and 1467 cm- I

observed are abnormally at low frequencies for a carbonyl group conjugated with double bonds. The carbonyl stretching frequenc ies observed for thi s compound are si gnificantly lower than that (1645 and 1605 cm- I) reported by Ramalingam et al .8 for 2-methyldibenzylideneacetone. It has been observed that conjugated carbonyl in vo lved in hydrogen bonding absorbs around thi s region9 further supporting the structures.

Jr.' Ph N Ph

I R

H 5

6

3 4 R=H or Me; RI=Me or i- PI'

R=H or Me; R I=Me or i-Pr 5 6a :R1=M c: 6h :R1=i-Pr

The IH NMR spectra for 6a and 6b ha ve a multiplet in the aromatic region viz. 7.00-7.70 ppm for 6a and 7.30-7.60 ppm for 6b accounting for the aryl alld olefinic hydrogens. The methyl si gnal of 6a appears at 2 .20 ppm while the isopropyl hydrogens in 6b show a doublet at 1.40 ppm and a septe t at 3.00 ppm. The I3C NMR spectra of these compounds also support the structure, the signal around 158 ppm could be ascribed to the o le fini c carbon attached to hydroxyl group.

The formation of this product c learl y reveals th at this reaction is an example of tande m oxidation-retro­

aza-Michael-ring opening in vo lvin g both a ­hydroxylation and ring opening, the former

presumably preceding the latter. The a-hydroxy lati on can occur via the mechani sm shown in Scheme III .

The retro-aza-Michae l ring opening reac ti on from the a-hydroxypiperidone (Scheme III) can occu r as discussed for the ring opening reac t ion of 3-unsubstituted piperidones. In thi s sys te m, probably, the isomer enol 7 might be formed more than the other isomer 8 since the latter could invo lve considerable steric interaction between the methyl and phen yl groups. Further, 7 may be readil y attacked by the selenium reagent in view of the dim inished steric hindrance.

The lack of ring opening in the 3-alkyl subs tituted piperidones in aceti c ac id a lone and the invol ve ment of tandem sequence in the reac ti on with se leniull1 di ox ide in acetic acid sugges ts that the ac ti ve species of seleni ull1 reagent in acetic ac id is 1l10re powerful

912 INDIAN 1. CHEM SEC. B, AUGUST 1999

~ ~ HO .... Se'~ G/H

0

--l.J.. R g ),I....,.R _ HO,S'XxR Ar ~ Ar -Ar,.l....NJ.....Ar Ar N Ar

Me I ~e Me

OH

sl \ OH

. H°irR 9xR Ar N A~ N Ar

I I Me Me

Scheme III-Mechanism of a-hydroxylation

OH OH

Pbb:b Pbb:b I I

Me Me

7 8

electrophile than acetic acid itself. Further, once the hydroxyl group has been introduced at the a-position to the carbonyl group in the first reaction (Scheme III), the retro-aza-Michael ring opening reaction may be facilitaied by the hydroxyl group as it could stabilise the inicipient double bond. This could also bring down the energy of activation enhancing the reactivity.

Experimental Section All melting points work were measured in open

capillaries and are uncorrected. The IH NMR spectra were recorded either at 90 MHz in a Perkin-Elmer instrument or at 200 MHz in a Varian instrument in CDCI) solvent using tetramethylsilane as internal standard; 13C NMR spectra at 50 MHz on a Varian instrument in CDCh solvent (chemical shifts are expressed in 8, ppm) und IR spectra either in a Perkin-Elmer R-32 grating spectrophotometer or in Jasco Ff-IR-5300 instrument in KBr. Shimadzu SPD-6A HPLC ins:. rumcnt was used for HPLC anal yses employing ODS column.

Reaction of cis-l-methyl-2,6-diphenyl-4-piperidone Ie with selenium dioxide in ethanol. To a solution of cis-I-methyl-2,6-diphenyl-4-piperidone (2.66 g, 10 mmoles) dissolved in ethanol (20 mL) was added powdered selenium dioxide (1.Ig, 10 mmoles) and the reaction mixture refluxed for 7 hr. The solid thus obtained was filtered off, the filtrate concentrated, poured into excess of water (100 mL) and extracted with chloroform. Removal of the solvent, afforded a dark red pasty product which was purified by column chromatography over silica gel using chloroform as eluent. The compound, 1,5-diphenylpenta-I,4-dien-3-one, was crystallised from ethyl alcohol : ethyl acetate (I: I) mixture, yield l.4g (74%), m p 112°C.

The reaction of other 4-piperidones (Ia-d, If) was performed similary and the reaction mixture analysed by HPLC and the yields of the products obtained are given in Table I.

Reaction of cis-I-methyl-2,6-diphenyl-4-piperidone Ie with selenium dioxide in acetic acid . cis-l-Methyl-2,6-diphenyl-4-piperidone (Ie) (2.66 g, 10 mmoles) was dissolved in glacial acetic acid (15 mL) to which powdered selenium dioxide (1 .1 g, 10 mmoles) was added and the mixture heated at IOODC for 3 hr. Then the deposited solid was filtered off and the filtrate poured into ice-water (100 mL), neutralised with sodium bicarbonate, extracted with chloroform and the product, I ,5-diphenylpenta-I,4-dien-3~one, purified as above, yield 2.0g (89%), m p 112DC.

Reaction of 3a and 3b with selenium dioxide in acetic acid. The above procedure has been adopted for the reaction of 3-alkyl-4-piperidones (3a and 3b) with selenium dioxide in acetic acid and the yields and m ps of the products are given below.

I, 5-Diphenyl-2-hydroxy-4-methylpenta-l, 4-diene-3-one from 3a: Yield 2.1 g (75 %); m p 148°C (Found: C: 81.68, H: 6.01; Calc. C, 81.79; H, 6.10%).

I, 5-Diphenyl-2-hydroxy-4-isopropylpenta- I, 4-diene-3-one from 3b: Yield 2.2 g (74 %), m p 144DC (Found: C, 82.04; H, 6.79; Calc . C, 82. 16; H, 6.89%).

The reaction of Ia-d and If-h with selenium dioxide in glacial acetic acid was performed using the above procedure, the reaction mi xture subjected to HPLC analysis and the yields are Ii :-. (ed in Table II .

Reaction of cis-l-methyl-2,6-diphcnyl-4-pipc­ridone Ie with acetic add a lone. cis- I -MethyI -7.,6-diphenyI-4-piperidone Ie (2.66 g, 10 mmales) was dissolved in glacial acetic acid (15 mL) and heated at

.J.

..

YIJA YABASKAR el al.: REACT[ON OF PIPERIDONES W[TH SELEN[UM D[OXIDE 9 13

IOODe for IO hr. After filtering off the deposited solid, the filtrate poured into ice-water ( 100 mL) , neutrali sed with sodium bicarbonate and extracted with chloroform and the product purified by column chromatography, yie ld 1.70 g (75 %), m p 112De .

The other piperidones (la, 3a-d) have been subjected to reaction under the conditions employed for Ie. All the piperidones having 3-alkyl groups viz. 3a-d fail ed to react. In the case of la the yie ld of the product was obtained by the HPLe analys is of the product.

Acknowledgements Authors (SP and VV) thank the eSIR, New Delhi ,

fo r allocating the Major Research Project and fo r awarding research fe llowship, respecti ve ly.

References I Yijayabaskar Y, Perumal S & Devanathan Y C, IlI iIiall .I

Chelll, 34B, 1995,645. 2 Yijayabaskar Y, Studies 0 11 the SYll thesis 1Ij" Hete/"Ocrclic

Compoullds, Ph.D. Thesis, Madllrai Kalllaraj Un i ve r~ it y.

Madurai, 1997. 3 Trachtenberg E N, in: Oxidatioll, edited hy R L Augustinc

(Dekler) Chapter 3, 1969, p- I. 4 Rabjohn N, Orgal1ic Reactiolls, vu1.24, edi ted hy W G

Dallben (Wiley, London) 1978, p-261. 5 Campos 0 & Cook J M, Tetrahedroll Lett. [979, 1025. 6 Campos 0, Di pierro M, Cain M, Man tei R, Gawish A & Cook

J M, Helerocycles, 14, 1980,975. 7 Chaballd B & Sharpless K 8 , .I Org Chelll , 44. [979,4202. 8 Ramal ingam K, Berlin K D, Loghry R A. He lm D &

Satyamll rthy N, .1 Org Chem. 44. 1979.477. 9 Sil verstei n R M. Bassler G C & Morrill T C, Spectrollletric

Idelilijicalioll of Organic COIIII)O/ /I /{is. Fift h edition. (John Wiley. Toronto), 1963, p- 115.