HYDROXYMETHYLATION OF FLAVONES

ORGANI C PREPARA nONS AND PROCEDURES INT.,23 (6),741.747 ll'&)

HYDROXYMETHYLATION OF FLAVANONES

György Litkei', Tamás Patonay, László Szilágyi and Zoltán Dinya

Department of Organic Chemistry

KossI/r!J Lajos Uni\'ersity, H-40JO Debrecen, HUNGARY

In the contcxt of :1 search for new derivatives in úle 3-substiruled flavanone and flavone

serics, a previolls paper Jescribed Últ synthesis of Mannich compounds derived from fuvanone.1

Some of the C-3 SUbSÜltltcd llav;U1ones possessed rcmarkablc pharmacological activity, which will

be disCllsscd in a fonhcoming papcr,2

It is wdl-known lhal thc aClivc mcthylcnc group of org:lnic carbonyl compollnds rcaets with

formaldehydct,.7 or with parafonnaldchydc: innon-aqucolls nwdium1.·I,x under basic conditions to givc

Ct,a-bis(hydroxymcthyl) dcriv:!Iives as the lmjor prCXlllCl.3-')'l1lLlS, acctophcnonc,J chroJllanonc,~·H 1·

thilXhroll1anone:1 indanonc:1 tctra!onc,J··l,X as wcll as acclone,5 eyclohexanollc,(' cyclopcl1t;ulOnc~ and

the 17-oxostcroids7 c:.ln bc rcadily conve11cd into thc con'csponding a, o.,Ct-bis(hydroxymethyl)

analogues. 111,' Jirect hydroxym<:thylation of flavano!lc has not bcen studicll. Introduction or the

hydroxymcthyl group changes dle hydrophilic character of flavanone, and furthermore, il provides

possibiJjty for the preparalion of novel types of 3-substitutcd f1avanoncs. 'TIlis paper describcs our

work on úle direcl hydroxymeulyl3tion of f1avanoncs.

The rc~cti(J11 of flavanone (1) wÍth formaldchyde in dioxane in the presence of sodilllTI

carbonatc ga ve 3,3-bis(hydroxymeúly\)flavimone (2a); il was separated from ú1e by-products by

means of column chromatography. Whcn l,3-dioxanc 3 was boi lcd in ethano! with dilutc

o

~o 1. formalin, Na~CO~~,,~ 2. 2a AcylalionO Ph

o

©l:EoRO OR

O Ph

2a - e

(:) 1991 hy Orga01;" ':rr!.):lr;.linns and Prondllre:-.lnc.

a) R = H h) R = CH3CO e) R = Ph COct) R = p-CH)C6H4SOZ e) R = CH3SOZ

LITKEl, PA TONA Y, SZILAGYl AND VINY A

hydrochloric acid, the 2a was also formed. Compound 2a could also be obtained from 1 uran

treatment with paraformaldchyde in dimeth)'I sulfoxide in the presence of potassium hydroxide.

AcyIation of the sympy crude 2a then gave crystalline acyl derivatives 2b-e.

A recent paper9 has repo!1ed that úle acid-catalyzed hydroxymethylation of aliphatic ketones

gives exc1usively ~-hydroxyketones. However, to OUf surprise, the tr,lDsformation of flavanone with

paraformaldehyde in trifluoroacetic acid afforded the l,3-dioxane 3. This compound W3S 31so

produced from 2a with paraformaldehyde in the presence of p-toIuenesuIfonic acid, or from the

cmde 2a under the conditions of the Ritter reaction performed in absolute ether-acetonitriIe in the

presence of conc. sulfuric acid. This latter reaction aIso indicates that 2a does not give the expected

Ritter product. Lumma and MaID have shown the formation of similar 1,3-<lioxanes upon treatmen!

of unsymmetrieal aliphatic ketones with formaIdehyde in trifluoroaeetie acid.

The reaetion of 2,3-rralls-3-hydroxyflavanone 4 with formaldehyde in rnethanoI in the

presence of sodium hydrogen carbonate led to dehydrogenation into 3-hydroxyDavolle 5.

o

©(x0HO Ph

4

fOnllaIin•..

5

2,3-rr(Jns-3-0romoflavanone did not react with fannaIdehydc, and the start ing material was

recovered. However, under similar conditions 2,3-ris-3-brornoflavanone 6 gave two products which

were scparated by lllC~UlSof column chromatography. The major product was ShOWll to be 2.3-eis-3­

bromo-3-hydroxymethylflavanonc 7 whcreas the structure of the minor product was idclltified as 3­

hydroxymethyIflavone 8. The structure of 7 was also supported by thc fact that upon trcatment

o o o

roB' oc:( ©ccfomlalinO ""''-OH NaOCH;lMcOH •. O I OH..o ph

Na2CO)o'" ph o ph

6

7 8

with sodium methoxide, flavone 8 was formed via rralls-elimination of hydrogen bromide.

Presumably the by-product flavone 8 was prodllCed from Úle flavanone 7 during the reaction by Úle

action of sodium hydrogen carbonate.

Recently Giles er al. II reported Úle preparation of 3-chloromelliyI chromone 10 by means of

treatment of chroman-4-one 9 willi phosphorus oxychIoride in N,N-dimeÚlylformamide. In contrast,

we found that upon heating of flavanone 1 in N,N-dimethylformamide with 5 equivaIents of

phosphorus oxychloride for 8 hrs, only (3-formyl-4-chloro)flav-3-ene lIa was produced.

742

o

ro9

IIa) R ::: CI b) R ::: OH

POClyfDMF

HYDROXYMETHYLA TION OF FLA VONES

10

O

CI

12

Under analogous condiÜons after 80 IHS. the reaction mixture did not contam tJ1Cfbv-3-ene

lIa but two new products wcre obscrvcd by TLC. Separation of this mixrurc by me;U1S of column

chromatography thcn resulted in the isoliHion of (3-formyl-4-hydroxy)flav-3-ene llb and 3­

chloromclhylcncflavanone 12 in pure form. FUrlher tral1sfonnaÜons of 2a-c arc in progress.

EXI'ERIMENTAL SECTION

Mell ing poil115 wen: dClcnnincd on a Kollcr hot-stagc apparatlls and arc tlncorrccted. 1 H NMR

spectra were obtained with a Ilmkcr WI' 200 SY spectromctcr at 200 Mllz.. by using TMS as the

internal standard (o::: O.CX) ppm). IR slJCClra werc recorded with a I'erkin-Elmcr 283 instl1lment.

Mass spectra were oblained with a VG-7035 (VG Analytical. Manchester) mass spcctro!11eter,

elcctron irnpact at 70 eV. Kicsclgel 40 or 60 (Merck, 0.063-0.2 111m) was used for column

chromatography. TLC was perfonned on Kieselgel 60 F25-l (DC-Alurolle, Merck).

3,3-b;s(lIydroxymcthyl)nuvunone la.- a) A mixture of flavanone 1 (23.5 mrnol), 37% aqueous

formaldehyde (50 mL) and sodium carbonate (5 g) in dioxane (200 mL) was stirreu at room

temperaiure for 24 hrs. The reaclion was monitored by thin layer c11fOmatography (4:1 roluene-etJlyl

acetate). Af1er removal ofule solid materials by filtration, tlle mixture was poured mto dilllte aqlleous

hydrochloric acid (250 mL) and extracted WitJl dichlorometllane. TIle dried (MgSO~) organic phase

was concentrated and the colorless syrupy residue (yield 90%) was purified by column

chromatography (10: 1 benzene-methanol) to afford pure 2a, mp. 127-129° (MeOH). IR (KBr): (br)

3360 (OH), 1665 (CO) cm-I• IH NMR (CDCI3): CS 7.0-8.0 (m, 9H. ArH), 5.60 (s, IH, C-2-H), 4.10

(d, IH, J = la Hz), 3.95 (d, IH, J = la Hz, C~), 3.60 (m, 2H, CH), 2.80 (IH. OH, exchanges witll

DP), 2.40 (IH, OH, exchanges with DP).

Ana!. Calcd. forC'7HI60~: C. 71.82; H, 5.67. Found: C, 72.15; H, 5.55

h) To a stirrcd mixture of par3formaldehydc (35 mmol), potassium hydroxide (75 mg), ethanol (0.5

743

LIT KEl, PATONA Y, SZILAGYI AND DINY A

mL) and dimethyl sulfoxide (5 mL) a solution of flavanone 1 (IS mmol) in dimethyl slilfoxide (5

mL) was added dropwise. After stirring for I hr at room temperature the red solution was diluted

with aqueous hydrochloric acid. The precipitate was purified by means of column chromatography as

previou51y (70%), mp. 1270 (MeOH). 'H NMR (CDCI]): 87.0-8.0 (m, 9H, ArH), 5.65 (5. IH, C-2­

H), 4.15 (d, IH, J = 10 Hz), 4.05 (d. IH. J = 10 Hz, C~), 3.70 (d. ]H. J = 2 Hz), 3.55 (d, IH, J = 2

Hz). 2.85 (IH. OH. exchange5 with DP), 2.20 (IH. OH, exchange5 with DP)·MS: 284, 253. 235. 223. 207,159,12] (100%).

3,3-bis(AcetoxymethyI)Oavanone 2b.- A mixture of crude 3,3-bis(hydroxymethyl)flavanone 2a (10

mmol) acetic anhydride (20 mL) and ab5. pyridine (2 mL) was kept on the hot water balh for 2 hrs.

After pouring into water the precipitated amorphou5 product was isolated by filtration and then

purified by column chromatography (15:1 benzene-ethyl acetate) to afford 5 mmo] (50%) of 2b as

homogeneous syrup. IR (nujol): 1710, 1690 (CO) cm·l. IH NMR (CDCIJ): 87.0-8.0 (m, 9H, ArH),

5.70 (s. IH, C-2-H). 4.95 (d. IH, J = 10 Hz), 4.55 (d, IH, J = 10 Hz, CH1). 4.10 (d. IH. J = 10 Hz),

3.80 (d, IH, J = 10 !-Iz. C~), 2.10 (s, 3H, CHJ), 1.90 (s, 3H, CHJ). MS: 368.

3,3-bis(Benzoyloxymethyl)navanone 2e.- To an ice-cold solution of cmde 3,3-bis(hydroxy­

methyl)flavanone la (10 mmo]) in abs. pyridine (20 mL) benzoy] chIaricIe (25 mmol) was addccl

dropwise. After standing for ovemight the reaction mixture was poured onta iee, the solid material

was filterecl off ,mL! erystallized from methanol to give 7.5 mlllol (70%) of 2e, Inp. 65-670. IR (KOr):

1725. I óS5 (CO) cm .1. 'll NMR (CDeII): 87.05-8.0 (m, 191I. Arll). 5.90 (s. III, C-2-1I). 5.25 (el,

1H, J :::10 Hz). 4.75 (d. IlU = 10 Hz, CIJ1).4. 40 (d, lll,] ::: 10 lIz). 4.20 (el. II I.J = 10 lll.. CJIz)'

Anal. Cakd. for CJI !-~Pú:C, 75.59; 11,4.91. found: C, 75.Cl2; ll. 5.10

3,3-bis(Tosyloxymcthyl)f1avllnonc 2d.- A mixturc of cmdc 3.3-bis(hydroxymcthyl)f]avanonc 2a

(10 mmol), chlorofoml (20 mL), pyridinc (3.7 mL) and tosyl chloridc (25 mmol) was stirrccl at room

tempcrature for 24 hrs. Af tcr addition of a furthcr amou nt of tosyl chioricIc (5 mmol), Ú1Creaction

mixture \Vas stirred for one day and then pourcd into water ancl extractecl WiÚl chlorofonn. The

8rganic laycr was washcd -,vith aqucous sodium hydrogen carbonate and wakr. After drying and

evaporation thc residue was crystallized from ethanol to yield 8.3 mmoI (83%) of 2d, mp. 154-1560.

IR (KBr): 1692 (CO) cml. IH NMR (CDCI): 8 6.80-7.70 (m, l7H, ArH), 5.70 (s, IH, C-2-H), 4.60

(ci, IH, J = 9 !-Iz), 4.30 (d, IH, J = 9 !-Iz, C~), 3.80 (d, IH, J = 9 Hz), 3.70 (d, IH, J = 9 Hz, CHz)·

Ana!. Calcd. for CJI ~P8SZ: C, 62.83; H, 4.76; S, 10.81. Found: C, 63.05; H, 4.59; S, 10.44

3,3-bis(Mesyloxymethyl)navanone 2e.- By applying the previous proceclure but lIsing methane­

sulfonyl chloride, úle reaction mixture was kept at 00 for 2 hrs and then aIlowed to stay at room

temperature for 5 hrs. After working up as describccl above for ld the residue was crystaIlizecl from a

mixture of ethyl acetate and hexane to afford 7.5 mmoI (75%) of 2e, mp. 97-1000. IR (KEr): 1690

744

HYDROXYMETHYLA TION OF FLA VONES

(CO) em -1. IH NMR (COCI): 87.0-8.0 (m, 9H, ArH), 5.70 (s, IH, C-2-H), 4.95 (d, IH, J = 10 Hz),

4.65 (d, IH, J = 10 Hz, C~), 4.20 (d, IH, J = 10 Hz), 3.95 (d, IH, J = 10 Hz, C~), 3.15 (s, 3H,

CH3), 2.80 (s, 3H, C~).

Ana!. Calcd. for CI9~008S2: C, 51.80; H, 4.57; S, 14.55. Found: C, 52.05; H, 4.65; S, 14.35

Spiro[Oavanone-3,5'-(1',3'·dioxacyclohcxane)] 3.- a) To a stirred solution of erude 3,3­

bis(hydroxymethyl)f1avanone 2a (15 mmol) in abs. et11er (75 mL) and aeetonitrile (5 mL) a solution

of eone. sulfurie acid (5 ml) in abs. ether (25 mL) was added dropwise with iee-cooling. Stirring

was eontinued at room temperatllre for 24 hrs, and after pouring the reaetion mixture onto iee, it was

extraeted with diehloromethane, the organie phase was washed with water and aqueolls sodillm

hyclrogen earbonate and dried. Following evaporation, t11eresidlle was pllrified by means of eolumn

ehromatography (10: 1 benzene-methanol) to yield 6 rnmol (40%) of 3, mp. 134-136° (MeOH).

b) A mixtllre of tlavanone 1 (10 mmol). paraformaldchyde (30 mmol) in tritllloroaectie acid (2.5

mL) was reaered on tlle water bath for 24 hrs. TI1C reaetion mixrllre was then poured imo an aqllcolls

soclillm hydrogen carbonatc sollIlion :U1dcxtraeted with diehloromcthanc. After washing and c1rying.

thc solvcnt was cvaporated ancllhe rcsidue was pllrificcl by means of colullln chromatography to give

5 mmol (50%) of 3, mp. 134-136° (MeOl!).

e) Crudc 3,3-bis(hydroxymctl1yl)f1avanonc 2a (5 mlllol) was trcatcd wilh parafonnaldchydc (5.5

llllllOl) in bcm:ene (50 mL) in the prescnce of IHolllcncslIlfonic acid (1 g) in arcaction vcsscl

cquippcd with a Dcan-Sral'k apparalus at J 10° for 3 hrs. After washing wirh water. aqllcolls sodilll11

hydrogcn carbonate and drying. the organic solvent was distilled off and the resiclllc was crystallized

from merhanol to yield 3.75 mmol (75%) of 3, mp. 134-136°. IR (KBr): 1675 (CO) cm .1. IH NMR

(COCI3): 86.95-7.85 (111.9H. ArB), 6.12 (s, IB, C-2-H). 5.10 (d. IH, J = 5.0 Hz). 4.70 (d. ll-L J = 5.0

Hz), O-C~-O), 4.30 (d, 2H, J = 10 Hz, C~). 3.80 (d. 2H. J = 10 Hz, C~). MS: 296. 265. 250, 235.

223,207,159,121 (100%).

Ana!. Calcd. for ClsH1604: C, 72.96; H. 5.44. Found: C, 72.88; H. 5.39

Reaction of 2,3-trans-3-Hydroxyflavanone 4 wi th Fonnaldehyde. IsoJation of 3-Hydroxyflavone

5.- 2.3-tTal/s-3-Hydroxyflavanone13 4 (15 11111101)was reacted wit11 35% aqueous formaldehyde (40

mL) in metl1anol (125 mL) at room temperarure for 24 hrs in t11e presence of sodiul11 hydrogen

earbonate (4 g). The reaetion l11ixture was poured onta iee, the solid material was filrered off and

crystallized from et11~U1olto afford 10 mmol (75%) of 5. mp. 169-171°, lit.'~ mp. 169-170°. The

mixed mp. of t11eprodllct witl1 a sample of lit. 3-hydroxyflavone showed no depression.

Reaction of 2,3-cis-3-Bromoflavanone 6 with FormaJdchyde. Isolation of 2,3-cis-3-Bromo-3­

hydroxymethylnavanone 7.- 2.3-cis-3-BromoflavanoneI2 6 (30 mmol) was reaetcd with 35%

aqueous forrnaldehyde (SO ml) in met]1Jnol (250 ml) at room tCl11\Xrature for 24 hrs in tl1e prcsencc

745

LIT KEI. P.HO:';..\ Y, SZILM;YI A1'\D DINY A

of sodium hydrogen carbonate (8 g). After addition of water, the mixture was extractecl

dichloromethanc and the of<banic layer was clriecl and concentrated. TI1C residuc was 5ubmitted to

column chromatography (4:] toluene-ethyl acetate) to give 2,3-cis-3-bromo-3-hydroxymethyl­

flavanone 7 and 3-hydroxymethylf1avone 8.

Compound 7: yield 52%, mp. 131-133° (hexane), lit.~ mp. 132-134°. IR (KBr): 3420 (OH), 1673

(CO) cm .1, IH NMR (CDCl)): Ö 7.10-8.90 (m, 9H, ArH), 5. 70 (5, 1H, C-2-H), 4.50 (d, HI, CtS), 3.

45 (d, IH, CH2, lAB = 10 Hz). MS: 333 (10%).

An~ll. Calcd. for CI6H13Br03: C, 57.68; H, 3.93; Br, 23.97. Found: C, 57.75; H, 3.84; Br, 24.09

Compound 8: yield 22%, mp. 163-164° (hexane), lit .~ mp. 160-]63°. IR (KBr): 3386 (OH), 1620

(CO) cm .1. IH NMR (CDCI): Ö 7.45-8.30 (m, 9H, ArH), 4.70 (d, 2H, CH), 3.60 (bs, IH, exchange5

with DP).

Ana!. Calcd. for C16H120J: C, 76.17; H, 4.79. Found: C, 76.25; H, 4.82

3-lIydroxymcthylnavonc 8.- A solution of flav<UlOne 7 (1 mmol) in abs. methanol (15 mL) was

trcated with sodillnl mcthoxidc (2 mmoI) at room tcrnpcrarure for 48 hrs. The mixlllre was then

acidificd with dilwc acetic acid, diltlte with waler and cxtracted with dichlorol11cll1ane. After dry ing

thc organic layer W~l~ concenlralcO and the rcsiduc was crystallil.cd frOI11hcxane to yield 0.6 11111101

(60%) of 8, mr. 162-164°. '111e mixed mp. of the prodll<.:t with a sampIc of fJavanone 8, obtained as

d<.:scribéd above, showcd no deprmion. IR (KBr): 3385 (01I), 1620 (CO) CI11·I.

(3.Fonnyl-4-chloro)f1av-3-cnc lIa.- A mixturt: of flavanonc 1 (20 1Il111ol) and abs. N,N­

dimcthylformamidt: (25 I;2L) was reacted with phosphorous oxychloridc (100 rrtmol) on thc water

bath for 8 hrs. TIle exce55 of the reagent was distilled off on a rotary evaporator, the rcsicluc was

diJuted with water (l00 mL) and the reSlIlting solution was kept on the water bath for 2 hrs. After

cooling the mlxture was extracted with ether and after washing and drying the organic solvent was

removed by evaporation. The residlle was purified by means of column chromatography (4: 1

hexane-ethyl acetate) to give 7.2 mmoI (36%) of Ua, mp. 106-108° (hexane). IR (KBr): 1660 (CHO)

cm -1. IH NMR (CDCI3): Ö 10.3 (s, IH, CHO), 6.85-7.75 (m, 9H, ArH), 6.40 (s, IH, C-2-H). MS:

270,241 (100%),235,205,193.

AnaL Calcd. for C16HIlCl02 : C, 70.99; H, 4.09; CI, 13.09. Found: C, 71.25; H, 4.19; CI, 12.92

(3-Formyl-4-hydroxy)nav-3-ene Ub and 3-Chloromethylenenavanone 12.~ The product of the

above reaction, conducted for 80 hrs was submitted to column chromatography (4: 1 hexane-ethyl

acetate) to afford Ub (30%), mp. 122-123° (ethyI acetate-hexane) and 12 (25%), mp. 132-134°

(hexane).

746

HYDROXYMETJ-lYLA nON OF FLA VONES

Compound Ub: IR (KBr): 3432 (OH), 1638 (CHO) cm". IH NMR (CDC~): 07.20-8.20 (m, lOH,

ArH and CHO), 5.95 (s, IH, C-2-H), 4.0 (bs, IH exchanges with DP). MS: 252 (100%), 234, 205.

Ana!. Cakd. for C16H1P3: C, 76.18, H, 4.79. Found C, 76.28; H, 4.58

Compound 12: IR (KBr): 1650 (CO) cml. 'H NMR (CDC~ ): 07.30-8.25 (m, 91:-!,ArH), 8.10 (s,

IH, CHCI), 6.40 (s, IH, C-2-H). MS: 270, 235 (100%).

Ana!. Calcd. forCI6HIICl02: C, 70.99; H, 4.09, CI; 13.09. Found: C, 70.82; H, 4.11; CI, 12.60

REFERENCES

1. G. Litkei, T. Patonay and J. Kardos, Org. Prep. Proced. Int., 22, 47 (1990).

2. G. Litkei, T. Patonay and M. Rákosi, In press.

3. B. Wesslcn, Acta CI/em. Scand., 21, 713 (1967).

4. H. Hofm:lnn, G. Salbcck and B. Meycr, Chem. Ber., 103,2084 (1970).

5. Y. Shigcm:lsa, II. Saimoto,R. Nakashima, K. Fukllyama, M. Irie, S. Maeda, M. SlIZlIki, K.I Llrada and S. Saito, Chcm. Üprcss 2, 429 (1987); Chcm. Abstr, 108, 112355 (1988).

6. Y. $higemasa, II. Saimoto, R. Nakashima, S. Macda, M. SlIwki, K. J1arada and S. Saito, ihid.,2, 4X3 (1987); Chem. Ahstr .. lOS, \3 1069 (1ns).

7. G. Sc/meiJer, J. Wöltling. L. Jlack1cr, E. Mcsko and G. Dombi, Synthesis, 194 (1985).

8. G. CignareUa, D. Barloeco, G. Rossi and E. Rossi, ibid., 160 (1990).

9. P. Sulmon, N. Dc Kimpe and N. Schamp, Org. Prcp. Proced. Int., 21. 91 (1989).

10. W. C. Lumma and O. H. Ma,J. Org. Chem., 35, 2391 (1970).

11. P. R. Giles and C. M. Marson. Tetrahedron Lctt., 31,5227 (1990).

12. R. Bognár, M. Rákosi and G. Litkei, Acta Chim. Amd. Sci. Hung., 34. 353 (1962).

13. R. Bognár and J. Stefanovski, Tetrahcdron, 18, 143 (1962).

14. S. Kostanecki and W. Szabranski, BeJ:, 37, 2819 (1904).

(Recei"ed August 5,1991; in n!lisedform OcwMr 3,1991)

7-'+7