Indian Journal of Chemistry Vol. 38B, November 1999, pp. 1237 - 1241

~,~-Dimethylacrylophenones : BF3.Et20-POCh catalysed acylation of phenols using ~, ~-dimethylacrylic acid

Niveta Jain & H G Krishnamurty* Department of Chemistry, University of Delhi, Delhi 110 007. India

Received 16 December 1998; accepted (revised) 8 February 1999

Boron trifluoride etherate - phosphoryl chloride reagent is a useful reagent for the condensation between phenols and p,p-dimethylacrylic acid. The main products are acrylophenones. But surprisingly hydroquinone gives mono and diac­rylates.

Preparation and evaluation of substituted 2,2-dimethylchromenes is receiving the attention of many chemists and agrochemists as potential compounds showing antijuvenile hormone (AJH) activities in in­sects. As a consequence of this attractive bioactivity, several methods for their ' synthesis have been re­ported. The most straight forward of these procedures is the condensation of phenols with ~,~­dimethylacrylic acid (DMAA) in the presence of acid catalyst (HFI,SbCI/, BF3-C6HsNOl, ZnCh-POCh4, CH,SO,H - P20 5

6, PPA7, AICh-POChs, TFA8

) to af­ford 2,2-dimethylchromanones which by reductioll' and dehydration are readily converted to chromenes. 2-Hydroxy-~,~-dimethylacrylophenones are the in­termediates in this sequence. During the last ten years a number of hydroxy(methoxy) acrylophenones have been identified as natural products co-occurring with chromanones 9.10 . Though the biological role of these acrylophenones is not yet known, their role as plant defence compounds against insects has been indi­cated II. The synthesis of acrylophenones is, therefore, of interest. 2-Hydroxyacrylophenones are not obtain­able during acid-catalysed condensation between di­methylacrylic acid and a phenol, the chief product is 2,2-dimethylchromanone, and also by ring opening of chromanones l 2

. In an effort towards developing a method for the synthesis of phenolic acrylophenones, we investigated a milder Friedel-Crafts catalyst BF,.EtzO in combination with POCh as acylating agent 13. An equimolar quantity of dimethylacrylic acid and the phenol was added to a reagent compris­ing two fold excess of phosphoryl chloride and four fold excess of BF, .Et20 and stirred at room tempera­ture for 6-8 hr. The reaction was worked up in the

usual manner and products were isolated. The con­densation reactions were carried out at 50-60°C where the reaction was too slow at room temperature. Identi­fication of the products was based on comparison with reference samples, literature data, spectra and chemical tests. The results are shown in Table I.

The reagent comprising of BF3.Et20 - POCh is most efficient for the condensation between reactive phenols (eg. resorcinol, phloroglucinol) and DMAA, the chief product being acrylophenone. 2,2-DimethyIchromanones were isolated as minor com­pounds in some cases. Other possible products such as dihydrocoumarin, indanone were not formed. Sur-• prisi'1gly, phenol gave the acrylate ester 9 (10%) as the only product. Orcinol gave the acrylophenone 4 as the only isolable product. Methyl ethers were less reactive as compared to free phenols. Demethylation of 2-methoxy group in 2-methoxyacrylophenone was observed as a side reaction which was often noted in many cases. The reagent system was not applicable to substrates like hydroxyacetophenone, hydroxybenzoic acid and hydroxybenzoates. Saturated acids like phenylacetic acid, 3-methylbutyric acid, 3-phenoxypropionic acid (intramolecular cyclisation) did not react.

The condensation between resorcinol and cinnamic acid was briefly examined and the results are inter­esting. The reaction between resorcinol and unsub­stttuted cinnamic acid gave 2',4'-dihydroxychaIcone 10 (45%) but 4-methoxycinnamic acid gave exclu­sively 7 -hydroxy-4-( 4'-methoxyphenyl)-3,4-dihydro­coumarin 11 (90%)14. In a similar maJVler reaction between ~-methylcinnamic acid gave 2',4'-dihydroxy­p~methyIchaIcone 12 (85%) (Scheme I). Similar re-

1238 INDIAN J CHEM, SEC B, NOVEMBER 1999

Table I-Reaction of phenols with DMAA using BF3.Et20-POCI3

-a0H

R I + ~

3

~1? 20H

R I a and/or 5~

6

o W:, ~

R I 6~ 3

5 o

Phenol/Methyl ether Reactio'n Product (compd No.) Ref. Yield (%)" period (hr)a

Resorcinol 5 1-(2,4-(OHhphenyl)-3-Me-2-butenone-1 1 5 80

Pyrogallol 6 1-(2,3,4-(OHhphenyl)-3-Me-2-butenone-1 2 18 75

Phloroglucinol 5 5,7-(OHh-2,2-(Meh-chromanone 3 18 90

Orcinol 4h 1-(2,4-(OHh-6-(Me)phenyl)-3-Me-2-butenone-1 4 19 10

1,3-(OMeh -benzene 24 1-(2-(OH)-4-(OMe)phenyl)-3-Me-2-butenone-1 Si 20 50 7-(OMe)-2,2-(Meh-chromanone Sii 20 10

1,2:4-(OMeh-benzene 24 1-(2-(OH)-4,5-(OMehphenyl)-3-Me-2-butenone~ 1 6i 10 1-(2,4,5-(OMehphenyl)-3-Me-2-butenone-1 6ii 50

1,2,3,5-(OMe)4-benzene 24 1-(2,3,4,6-(OMe)4phenyl)-3-Me-2-butenone-1 7i 30 5,7,8-(OMeh-2,2-(Meh-chromanone 7ii 15

3,4,5-(OMehphenol 12 1-(2-(OH)-3.4,5-(OMehphenyl)-3-Me-butenone-1 8 45

(a ) Room temperature, 25 "C; (h) 50-60 "C; (e) Yield refers to isolated yield.

(to)

R'=R=H

0

HOVO" ~R "wo (\2) " _ BF3·Et20-POCl3 I P -I + R'=Me ~ (l

~ R=H 0

0

0

R=OCHJ H.

R'=H (11)

Scheme I

suits were recorded earlier during PPA mediated con­densations 15. Thus, the condensation reaction using BF,.Et20-POCI" is applicable to a,~-unsaturated acids.

The reagents BF3.Et20 and POCh individually are ineffective compared to the combined reagent. The mechanism of the reaction catalysed by BF3.Et20-POCl , is not clear. The active acylating species may

-I

W'.

JAIN et at.: /3,/3-DIMETHYLACRYLOPHENONES 1239

be RCO.OPOCh. There is a possibility of Fries mi­gration of a preformed phenolic ester.

Hydroquinone -DMAA condensations The condensation between DMAA and hydroqui­

none is of particular interest and deserves special mention because (i) acrylophenone 13 is a natural product isolated from Nama JohnstonU l6

, (ii) the re­action was little investigated. Fries rearrangement of the bis-dimethylacrylate to the dihydroxyacrylophe­none 13 has been reported unsuccessful 17 (AICh, CS2, M. Subsequently, the acrylophenone was prepared by Friedel-Crafts reaction between hydroquinone di­methylether and acryloylchloride followed by de­methylation. This, perhaps, is the only reported syn­thesis of 2,5-dihydroxy-~,~-dimethylacrylophenonel7.

In the present study, the direct condensation be­tween 1,4-dihydroxybenzene and DMAA was inves­tigated using (i) BF, .Et20- POCh, (ii) TFA and (iii) ZnCh - POCI,. The reagents (i) and (ii) gave a mix­ture of products consisting of the monoester 14 and the diester 15 in 70% and 5% yields respectively. They were separated by column chromatography. The structure of the products were readily established by IR, IH NMR and MS spectra and chemical tests and also by comparison with an authentic sample in the case of the diester 15 (pyridine-~,~-dimethylacryloyl

(9)

chloride). The reaction using ZnCh-POCb gave along with the esters 14 and 15, one more product in 15% yield. Its structure was established as 4,4,9,9-tetramethyl-3, 4, 8, 9-tetrahydro-2H,7H-benzo(1,2-b : 5,4-b']dipyran-2,7-dione 16. Neither the 6-hydroxy-2 ,2-dimethylchromanone nor the acrylophenone was formed (Scheme II).

Ester formation seems to be the preferred reaction in the case of hydroquinone and also with other hy­droquinones (unpublished work).

Experimental Section General. Melting points were taken in open capil­

laries in a sulphuric acid bath. IR spectra were re­corded in KBr on a Shimadzu IR-435 spectropho­tometer. IH NMR on a Hitachi R-699 Ff NMR (60 MHz), I3C NMR spectra on a Varian XL-300 (75 MHz) spectrophotometer in CDCh using TMS as in­ternal standard. Mass spectra were recorded on a leol lMX-DX 300 (70 eV) spectrometer. Column chro­matography was carried out over silica gel (60-120 mesh). BF3.EhO was distilled over CaH2. POCh was used as supplied (E. Merck). Anhydrous zinc chloride was fused before use.

General procedure. POCh (0.1 mole) and BF3.Et20 (0.2 mole) were mixed at O°c. DMAA (0.05 mole) was then added to it and the mixture stirred for

~IOH

HO ~

o

(13)

+

BFJ.Et20 -POCIJ OR

r"y0R HO~

r"y0R RO~

(15)

OOH

I +

HO ~ HoJ.

o

TFA (14)

R=COCH=CMe2

/WI 0 0

(14)+(15) +

o 0 ~

(16)

Scheme II

1240 INDIAN I CHEM, SEC B, NOVEMBER 1999

15 min. Phenol (0.05 mole) was added to the above mixture in small protions and the reaction mixture stirred at room temperature. A bright yellow solid usually separated out (6-8 hrs). The reaction mixture was then poured into ice-water with stirring. Excess of sodium acetate was added and the solution warmed on water-bath and left for sometime to break the boron complex. The product was isolated by ex­traction with a suitable solvent and washed with satu­rated NaHC03 solution. The product was chromato­graphed or crystallized. Characterization data for new products only are included.

1-(2-Hydroxy-4, 5-Dimethoxyphenyl)-3-methyl-2-butenone-l, 6i: m.p. 85°C (hexane). IR : 3400, 2900,1640,1620 em-I. IH NMR : 0 2.0 (s, 3H, CH3),

2.2 (s, 3H, CH3), 3.87 (s, 3H, OCH3) , 3.91 (s, 3H, OCH3), 6.46 (s, IH, H-3), 6.62 (m , IH, Ha ), 7.12 (s, IH, H-6), 13.26 (s, IH, 2-0H) ppm.

This butenone is a natural product isolated from Nama hispidum A16.

1-(2, 4, 5-Trimethoxyphenyl)-3-methyl-2-bute­none-l,6ii : Oil; IR (film) : 3000, 2880, 1650, 1620, 1600,1510 em-I; IH NMR : 02.15 (s, 3H, CH3), 2.38 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.94 and 3.99 (s each, 6H, 2 x OCH3), 6.45 (s, IH, H-3), 6.6-6.85 (m, IH, Ha), 7.22 (s, IH, H-6). Anal. Calcd for CI4HIS04 : C 67.2; H 7.2. Found: C 66.8; H 7.7%.

1-(2, 4, 5, 6-Tetramethoxyphenyl)-3-methyl-2-butenone-l, 7i: Gum; IR (film) : 3000, 2950, 2800, 1645 em-I; IH NMR : 0 1.95 (s, 3H, CH3), 2.1 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 3.9 (s, 6H, 2 x OCH3), 4.0 (s, 3H, OCH3), 6.5 (m, IH, Ha), 6.9 (s, IH, Ar-H) ppm.

2,2-Dimethyl-5,7,8-trimethoxychromanone, 7ii : mp 105°C (ethanol); IR : 3000, 2850, 1670, 1610 em-I; IH NMR : 0 1.45 (s, 6H, 2 x CH3), 2.8 (s, 2H, CH2), 3.86 (s, 3H, OCH3), 3.98 (s, 6H, 2 x OCH3), 6.2 (s, IH, Ar-H). Anal. Calcd forCl4Hl sOs : C, 63.15; H, 6_76. Found: C, 63.50; H, 6.36%.

1-(2-Hydroxy-4,5,6-Trimethoxyphenyl)-3-meth­yl-2-butenone-l, 8: Yellow oil; IR (film) : 1635 em-I. iH NMR : 0 1.8 (s, 3H, CH), 1.95 (s, 3H, CH3), 3.95 (s, 3H, OCH,), 4.1 (s, 6H, 2 x OCH) , 6.3-6.5 (m, 2H, Ha and Ar-H), 13.0 (s, IH, OH) ppm; MS : mJz 266 (Mt, 68%), 251 (100),236 (16), 211 (46), 195 (78), 184 (71), 169 (43), 167 (100), 139 (12), 109 (10), 95 (8), 83 (95), 69 (27), 55 (78).

7-Hydroxy -4-( 4' -methoxyphenyl)-3, 4-dihydro­coumarin, 11: mp 178-79°C (ethanol) ; UV A~:~H

(£): 278 (25333); IR : 3400, 1740, 1620, 1610 em-I; iH NMR (MeOH-d6): 0 3.0 (d, 2H, H. and Hb) 3.9 (s, 3H, OCH,), 4.1 (t, unsymm., IH, He), 6.3-6.7(m, 7H, Ar-H) ppm, MS : mJz 270 (M+, 100%), 252 (10) 242 (100), 213 (68), 198 (46), 197 (100), 184 (28), 163 (19), 128 (30), 121 (18), 107 (15), 91 (13), 85 (7), 77 (18),57 (16) .

2',4'-Dihydroxy-~-methylchalcone, 12: Yellow oil; IR (film): 3415, 3110, 3000, 2875, 1631, 1575 em-i. iH NMR : 0 1.95 (s, 3H, CH3), 6.43-6.65 (m, 7H, C-3', C-5' and Ar-H), 6.7 (s, IH, CO-CH=C), 7.7(d, IH, J = 10 Hz C-6'-H), 1O.5(s, IH, 4'-OH), 13.7 (s, I H, 2'-OH) ppm.

Phenyl 1,4-bis-(3-methylbut-2-enoate), 14: mp 113-14°C (ethanol) (Iit17

, mp 115°C). IR : 3000, 1740, 1655, 1518, 1450 cm-' ; 'H NMR : 0 1.85 (s, 6H, 2 x CH,), 2.09 (s, 6H, 2 x CH3), 5.70 (m,2H, 2 x CH = CMe2), 6.9 (s, 4H, Ar-H) ppm; MS : mlz 274 (M+, 13%), 192 (12), 149 (5), 110 (6), III (7), 83 (100), 71 (16), 55 (28).

(4-Hydroxyphenyl)- 3 -methylbut -2- enoate, 15: mp 121-22D C (ethanol); IR : 3400,3100,3000, 1730, 1660, 1525 and 1460 cm-'; 'H NMR : 0 1.98 (s, 3H, CH) , 2.23 (s, 3H, CH), 5.9 (m, IH, CH = CMe2), 6.73 (m, 2H, Ar-H), 6.91 (m, 2H, Ar-H) ppm. MS : mJz 192 (M+, 18%), 159 (10), 135 (13), 110 (24), 91 (17), 83 (loo), 69 (17), 55 (58).

4,4, 9,9-Tetramethyl-3,4,8,9-tetrahydro-2H, 7H­benzo[1,2-b : 5,4-b']dipyrane-2,7-dione, 16: m.p. 240°C. IR : 1780 em-i. 'H NMR : 0 1.4 (s, 12H,4 x CH), 2.6 (s, 4H, 2 x CH2), 7.0 (s, 2H, Ar-H) ppm. '3C NMR : 0 31.5, 37, 46.8,112.5, 130.5, 145, 163.8 (lactone C = 0) ppm. Anal. Calcd for C16H,s04 : C, 70.07; H, 6.56. Found: C, 69.88; H, 6.28%.

Acknowledgement One of the authors (N J) is grateful to CSIR, New

Delhi for the award of Research Associateship (RA).

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