New insight into the mechanism of hypervalent iodine oxidation of flavanones

Article abstract of DOI:10.1016/S0040-4020(02)00360-5

Flavanone (1) on oxidation with iodobenzene diacetate (PIDA) in the presence of sulfuric acid in trimethyl orthoformate (TMOF) undergoes a stereospecific ring contraction by an aryl shift to result in trans methyl 2-aryl-2,3-dihydrobenzo[b]furan-3-carboxy

Full text of DOI:10.1016/S0040-4020(02)00360-5

TETRAHEDRON
Pergamon
Tetrahedron 58 ,2002) 4261±4265
New insight into the mechanism of hypervalent iodine oxidation
of ¯avanones
a
a
a,p
b
b
Laszlo Juhasz, Laszlo Szilagyi, Sandor Antus, Julia Visy, Ferenc Zsila and Miklos Simonyi
b
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aDepartment of Organic Chemistry, University of Debrecen, P.O. Box 20, H 4010 Debrecen, Hungary
bInstitute of Chemistry, CRC Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary
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This paper is dedicated with respect and admiration to Professor Andras Messmer on the occasion of his 80th birthday
Received 3 January 2002; revised 4 March 2002; accepted 28 March 2002
AbstractÐFlavanone ,1) on oxidation with iodobenzene diacetate ,PIDA) in the presence of sulfuric acid in trimethyl orthoformate
,TMOF) undergoes a stereospeci®c ring contraction by an aryl shift to result in trans methyl 2-aryl-2,3-dihydrobenzo[b]furan-3-carboxylate
,4a) as a major product. The mechanism of this transformation has been discussed on the basis of NMR, CD and chiral HPLC evidence.
q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
Recently, hypervalent iodine reagents such as iodobenzene
diacetate ,PIDA), iodobenzene bis,tri¯uoroacetate) ,PIFA),
and [hydroxy,tosyloxy)iodo]benzene ,HTIB) are exten-
sively used in organic synthesis.1±5
Among the various transformations, a reaction involving
rearrangement6±10 is of broad interest since similar
oxidative rearrangements with Tl,III) salts have been
reported.11±14 One of the important advantages of these
transformations is the oxidation of ¯avanones ,1) resulting
in ¯avones ,2), iso¯avones ,3), or alkyl 2-aryl-2,3-dihydro-
Scheme 1.
benzo[b]furan-3-carboxylates ,4) depending on the reaction
conditions15±19 ,Scheme 1).
When trimethyl orthoformate ,TMOF) is employed as the
solvent, oxidation of ¯avanones ,1) with PIDA in the
presence of a catalytic amount of sulfuric acid proceeds
with ring contraction by an aryl shift to give 4 ,R00ˆMe)
as the major product.19
A plausible mechanism was proposed by Prakash and
Tanwar,19 ,Scheme 2) which involves ,i) the formation of
a hypervalent iodine intermediate ,7) by the electrophilic
attack of PIDA on the enol ether ,6) generated in situ
from ¯avanone as depicted in Scheme 2, ,ii) aryl migration
to result in 4 ,broken line). Although a similar mechanism
for the transformation of 1 to 4 was postulated by Kapoor
et al.20 using thallium,III)nitrate as the oxidizing agent in
Keywords: 2,3-dihydrobenzo[b]furans; ¯avanones; hypervalent iodine;
stereospeci®c ring contraction.
p
Corresponding author. Tel.: 136-52-512900/2471; fax: 136-52-453-
836; e-mail: antuss@tigris.klte.hu
Scheme 2.
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,02)00360-5

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L. Juhasz et al. / Tetrahedron 58 32002) 4261±4265
4262
Table 1. Chemical shift differences for diastereomers of 4
the presence of perchloric acid in TMOF, they also did not
take sides regarding either the stereochemistry of the aryl
migration or the relative con®guration of the chirality
centres of 4 ,cis or trans).
1H
13C
Dd2H Dd3-H DdOMe DdMe DdC-2 DdC-3 DdOMe DdMe
a vs. e
d vs. f 20.62 20.24
0.19 20.27 0.68
±
±
0.61
20.2 1.0
4.8 4.8
2.1
±
±
1.9
In order to establish these important details of the trans-
formation, we decided to investigate the oxidation of
racemic and laevorotatory ¯avanone [,rac-1, ,2)-2S-1,
RˆR0ˆH)] with PIDA±H2SO4 in TMOF.
tion of their relative stereochemistry, although it is widely
applied in the literature.23±25
2. Result and discussion
From the data given in Table 1 it can be concluded that only
the H-chemical shift differences of substituents at C-3 are
1
Oxidation of racemic ¯avanone ,1, RˆR0ˆH) with PIDA±
H2SO4 in TMOF at room temperature resulted in rac-methyl
2-phenyl-2,3-dihydrobenzo[b]furan-3-carboxylate ,4a) as
the major product as described by Prakash and Tanwar.19
The stereochemistry of 4a was proven to be trans on the
basis of NMR evidence, and by chemical correlation with
the cis-2,3-dihydrobenzo[b]furan derivatives 4e and 4f
synthesized in stereocontrolled reaction ,Scheme 3).
suitable for this purpose. Thus, the values of the correspond-
ing chemical shifts of the cis compounds ,4e, 4f) have been
found to be signi®cantly different ,Dd3Hˆ20.27 and
20.24 ppm; DdOMeˆ0.68 ppm; DdMeˆ0.61 ppm) from
those of the trans ones ,4a, 4d) due to the anisotropic effect
of the phenyl ring at C-2. Our ®ndings are in good
accordance with the observations on chemical shift
differences of methyl groups at C-3 of the isomeric
2-phenyl-3-methyl-2,3-dihydrobenzo[b]furan derivatives
published by Ollis26 and Pappas et al.27 In addition to this
result, NOE experiments also proved the trans ,0.8% effect
between H-2 and H-3 of 4a, 4b and 4d)/cis ,6% effect
between H-2 and H-3 of 4f) relative con®guration of these
compounds.
The stereoselectivity of the addition of the electrophilic
iodine,III) reagent at C-3 of the enol ether 6 followed by
its rearrangement into 4a could be proven by the trans-
formation of ,2)-2S-¯avanone [,2)-2S-1] prepared as
Â
28
described by Bognar et al. Since the enantiomeric excess
of ,2)-2S-1 ,50%) determined by HPLC using Chiralcel OJ
column as stationary phase has been found to be practically
the same with that of ,1)-4b and ,2)-4d prepared from the
ring contraction product ,1)-4a, the base line separation of
which could not be achieved under various conditions.
Therefore both the addition of PIDA to the enol ether
,6!7) and the aryl migration ,7!7a) occurred in a stereo-
selective manner controlled by the con®guration of C-2 to
result in ,1)-2S,3S-4a. This absolute con®guration could
Scheme 3.
The synthesis of rac-cis-methyl 2-phenyl-2,3-dihydro-
benzo[b]furan-3-carboxylate ,4e) was achieved from 4a in
two steps. First, 4a was transformed into 5a using 2,6-
dichloro-3,5-dicianoquinone ,DDQ) as the oxidizing agent
according to the literature,21 whose catalytic hydrogenation
over Pd±C in methanol resulted in racemic cis-4f in low
yield ,12%).
1
also be deduced from the negative Lb-band of ,1)-4b and
,2)-4d.
Since the measured Cotton effects at 280 nm ,Fig. 1)
correspond well to the predicted 1Lb transition of
Racemic cis-2-phenyl-3-methyl-2,3-dihydrobenzo[b]furan
,4f) was also prepared by catalytic hydrogenation from
5a, which was synthesized from 2-benzoyloxyacetophenone
under McMurry conditions.22
Finally, the product of the ring contraction of 1 ,4a) could
be very simply transformed into 4d in three steps
,4a!4b!4c!4d) and the reduction of 4a with LiAlD4
furnishing 4g clearly showed that the relative con®guration
of C-2 and C-3 has not changed in this step.
Comparison of NMR data of 4a and 4d [1H and 13C
chemical shifts and coupling constants ,J2,3)] ,see Section
3) with those of the corresponding cis compounds ,4e, 4f)
clearly indicated that the coupling constant between the
hydrogen at C-2 and C-3 can not be used for the determina-
Figure 1.

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L. Juhasz et al. / Tetrahedron 58 32002) 4261±4265
4263
dihydrobenzo[b]furan chromophore, the hetero-ring of both
compounds should adopt the P-helicity29 according to our
helicity rule.30 Taking into account that the substituents
attached to the hetero-ring at C-2 and C-3 are equatorially
oriented, their absolute con®gurations are therefore 2S,3R
,4b) and 2S,3S ,4d), which is in full agreement with the
2S,3S absolute con®guration of ,1)-4a mentioned above.
This total diastereo- and enantioselectivity is in full
accordance with reaction proceeding via 7a ,dihydro-
benzo[b]furan-type ion, Scheme 2, route A) and casts
doubt on route B.
3.1.2. )2S,3S)-3-Carboxymethyl-2-phenyl-2,3-dihydro-
benzo[b]furan [)1)-4a]. Starting from 700 mg
,3.12 mmol) ,2)-2S-1 gave 312 mg ,39%) ,1)-4a as a
colourless oil. [a]Dˆ32.0 ,cˆ0.3, CHCl3). Chiraspher NT
,heptane), 5.8 min.
3.1.3. )2Sp,3Rp)-3-Hydroxymethyl-2-phenyl-2,3-dihydro-
benzo[b]furan )rac-4b). ,A) A solution of 4a ,500 mg,
1.97 mmol) in dry ether ,20 mL) was added dropwise to a
suspension of LiAlH4 ,100 mg) in dry ether ,10 mL) at 08C
and the reaction mixture was stirred for 20 min. Then ethyl
acetate ,2 mL) and water ,10 mL) were added, the organic
layer was separated, washed with water and dried. Evapora-
tion of the solvent gave an oil which was puri®ed by column
chromatography ,toluene±ethyl acetateˆ4:1) to furnish 4b
,390 mg, 87.6%) as a colourless oil.
In conclusion, it is to be noted that the present stereo-
selective oxidative approach followed by reduction of the
ester group to hydroxymethyl allows a simple synthesis
starting from the appropriate optically active ¯avanone
derivatives to yield naturally occurring O-heterocycles
carrying 2-aryl-3-hydroxymethyl moieties.
,B) To a stirred solution of 4a ,87.7 mg, 0.34 mmol) in dry
ether ,10 mL), 1.1 equiv. of DIBAL-H in THF was added at
08C under argon atmosphere and stirring was continued for
50 min. Then the reaction mixture was acidi®ed ,1 mL 10%
HCl), and the organic layer was washed with water and
dried. Evaporation of the solvent gave an oil which was
puri®ed by preparative TLC ,toluene±ethyl acetateˆ4:1)
3. Experimental
3.1. General
1
to obtain 4b ,32 mg, 41%) as a colourless oil. H NMR:
1.89 ,1H, brs, OH), 3.53 ,1H, m, H3), 3.88 ,2H, d,
Jˆ5.48 Hz, CH2), 5.59 ,1H, d, J2,3ˆ6.21 Hz, H2), 6.84±
7.40 ,9H, m, aromatic protons). 13C NMR: 53.5 ,C-3),
64.5 ,CH2), 86.7 ,C-2), 109.6 ,C-7), 120.7 ,C-5), 124.5
,C-4), 125.6 ,C-30, C-50), 126.3 ,C-3a), 127.9 ,C-40),
128.6 ,C-20, C-60), 129.1 ,C-6), 141.7 ,C-10), 160.1
,C-7a). HRMS m/z 226.0999 ,calcd for C15H14O2,
226.0994).
Analytical and preparative TLC were done on plates
Kieselgel 60 F254 ,Fa. Merck). The reagents were
purchased from Sigma-Aldrich. For workup the solutions
1
were dried ,MgSO4) and concentrated in vacuo. H- and
13C NMR spectra were recorded on a Bruker WP-200 spec-
trometer with TMS as internal standard in CDCl3. The
chemical shifts are given in d ,ppm). Optical rotations
were measured on a Perkin±Elmer 341 polarimeter
,lˆ10 cm) at room temperature. CD spectra were recorded
on a Jasco J-715 spectropolarimeter at room temperature
in online mode with LCCD-311 HPLC ¯ow cell unit.
Experimental details of the HPLC analysis are reported
for all compounds in the form: column ,mobile phase),
enantiomeric ratio, retention time ,Rt) in min. HRMS
were recorded in FAB mode ,glycerol) on a VG 70HS
MS spectrometer.
3.1.4. )2S,3R)-3-Hydroxymethyl-2-phenyl-2,3-dihydro-
benzo[b]furan [)1)-4b]. Starting from ,1)-2S,3S-4a
,250 mg) using method B to furnish ,1)-4b ,150 mg,
67%) as a colourless oil. [a]Dˆ15.3 ,cˆ0.24, CHCl3);
enantiomeric excessˆ52%; Chiral AGP; ,0.01 M phosphate
buffer: iPrOHˆ9:1); 6.58 and 9.82 min.
3.1.5. )2Sp,3Rp)-2-Phenyl-3-p-tosyloxymethyl-2,3-dihydro-
benzo[b]furan )rac-4c). To a stirred solution of 4b
,300 mg, 1.37 mmol) and p-TsCl ,310 mg, 1.63 mmol) in
dry CH2Cl2 ,20 mL) 20 drops of dry pyridine were added
and stirring was continued for 24 h. Subsequently, the reac-
tion mixture was washed with 10% HCl ,10 mL), water and
dried. Evaporation of the solvent gave an oil which was
puri®ed by column chromatography on silica gel ,hexane±
ethyl acetateˆ3:1) to obtain 4c as a colourless oil ,300 mg,
3.1.1. )2Sp,3Sp)-3-Carboxymethyl-2-phenyl-2,3-dihydro-
benzo[b]furan )rac-4a). To a stirred solution of ¯avanone
,1) ,2.24 g, 10 mmol) in trimethyl orthoformate ,250 mL)
H2SO4 ,0.5 mL) was added a solution of PIDA ,3.5 g,
10.8 mmol) in trimethyl orthoformate ,100 mL) dropwise
at room temperature over 20 min and stirring was continued
for 12 h. Subsequently, the solvent was removed and water
,150 mL) was added to the residue and stirring was con-
tinued for 2 h. Then the mixture was extracted with
dichloromethane ,3£50 mL), washed with an aqueous
solution of NaHCO3 and dried. Evaporation of the solvent
gave an oil ,3.2 g) which was puri®ed by column chromato-
graphy on silica gel ,hexane±ethyl acetateˆ9:1) to furnish
4a ,620 mg, 25%) as a yellowoil. 1H NMR: 3.80 ,s, 3H,
COOMe), 4.27 ,1H, d, J2,3ˆ7.7 Hz, H3), 6.10 ,1H, d,
J2,3ˆ7.7 Hz, H2), 6.85±7.45 ,9H, m, aromatic protons) 13C
NMR: d: 52.6 ,C-3), 55.7 ,OMe), 85.4 ,C-2), 109.8 ,C-7),
120.9 ,C-5), 123.7 ,C-3a), 125.1 ,C-4), 125.6 ,C-40), 128.3
,C-20, C-60), 128.7 ,C-30, C-50), 129.6 ,C-6), 140.6 ,C-10),
159.2 ,C-7a), 171.3 ,CvO); HRMS m/z 254.0947 ,calcd for
C16H14O3, 254.0943).
1
60%). H NMR: 2.48 ,3H, s, CH3), 3.72 ,1H, m, H3), 4.27
,2H, m, CH2), 5.49 ,1H, d, J2,3ˆ5.48 Hz, H2), 6.91 and 7.82
,2H, d, Jˆ7.68 Hz, aromatic protons) 7.05±7.45 ,9H, m,
aromatic protons). HRMS m/z 380.1078 ,calcd for
C22H20O4S, 380.1082).
3.1.6. )2Sp,3Sp)-3-Methyl-2-phenyl-2,3-dihydrobenzo[b]-
furan )rac-4d). A solution of 4c ,300 mg, 0.79 mmol) in
dry THF ,20 mL) was added dropwise to a suspension of
LiAlH4 ,300 mg, 8.1 mmol) in dry THF ,20 mL) and the
reaction mixture was re¯uxed for 40 min. Then ethyl acetate
,2 mL) and water ,10 mL) were added and the organic layer
was separated, washed with water and dried. Evaporation of

Â
L. Juhasz et al. / Tetrahedron 58 32002) 4261±4265
4264
the solvent gave an oil which was puri®ed by column chro-
matography ,hexane±ethyl acetateˆ3:1) to furnish 4d
atmosphere and the stirring was continued for 8 h. Subse-
quently, the mixture was ®ltered and the solvent was
removed upon evaporation. Puri®cation by column chroma-
tography ,hexane) gave 4f as a colourless oil ,195 mg,
1
,116 mg, 70%) as a colourless oil. H NMR: d: 1.38 ,3H,
d, Jˆ6.94 Hz, CH3), 3.38 ,1H, m, H3), 5.11 ,1H, d,
J2,3ˆ8.77 Hz, H2), 6.78±7.45 ,9H, m, aromatic protons).
13C NMR: d: 18.1 ,CH3); 45.6 ,C-3); 92.4 ,C-2); 109.4
,C-7); 120.8 ,C-5); 123.6 ,C-6); 126.0 ,C-20, C-30); 128.2
,C-4); 128.2 ,C-40); 128.6 ,C-30, C-50); 131.8 ,C-4a); 140.9
,C-10). HRMS m/z 210.1051 ,calcd for C15H14O, 210.1045).
1
48%). H NMR: d: 0.77 ,3H, d, Jˆ7.31 Hz, CH3), 3.62
,1H, m, H3), 5.73 ,1H, d, J2,3ˆ8.8 Hz, H2), 6.75±7.82
,9H, m, aromatic protons). 13C NMR: d: 16.9 ,CH3); 40.8
,C-3); 87.6 ,C-2);109.4 ,C-7); 120.7 ,C-5); 124.3 ,C-6);
126.3 ,C-20, C-60); 127.6 ,C-4); 128.1 ,C-30, C-50); 129.7
,C-40); 139.0 ,C-4a); 159.1 ,C-10); 165.4 ,C-7a). HRMS m/z
210.1048 ,calcd for C15H14O, 210.1045).
3.1.7. )2S,3S)-3-Methyl-2-phenyl-2,3-dihydrobenzo[b]-
furan [)2)-4d]. Starting from ,1)-2S,3R-4c gave 16 mg
,2)-4d as a colourless oil ,25%). [a]Dˆ24.8 ,cˆ0.3,
CHCl3); enantiomeric excessˆ46%; Whelk01 ,heptane);
9.2 and 11.2 min.
3.1.12. )2Sp,3Rp)-2-Phenyl-3-)trideuterohydroxymethyl)-
2,3-dihydrobenzo[b]furan )rac-4g). To a stirred suspen-
sion of 50 mg LiAlD4 in dry ether ,5 mL), 100 mg of 4a
,0.43 mmol) was added dropwise in dry ether ,5 mL) at 08C
and stirring was continued for 1 h. Subsequently, the reac-
tion mixture was acidi®ed with the mixture of D2SO4 ,10
drops) and D2O ,2 mL) and the organic layer was separated,
washed and dried. Evaporation of the solvent furnished 4g
,89 mg, 94%) as a colourless oil. 1H NMR: d: 3.51 ,2H, d,
J2,3ˆ6.2 Hz, H3); 5.58 ,2H, d, J2,3ˆ6.2 Hz, H2); 6.83±7.42
,9H, m, aromatic protons). HRMS m/z 229.1184 ,calcd for
C15H11D3O2, 229.1182).
3.1.8. 2-Phenyl-3-carboxymethylbenzo[b]furan )5a). To a
stirred solution of 4a ,406 mg, 1.6 mmol) in dry dioxane
,50 mL) 1.5 g of DDQ ,6.6 mmol) was added. The reaction
mixture was re¯uxed for 96 h, then it was ®ltered and
evaporation of the solvent gave an oil which was puri®ed
by column chromatography ,hexane±ethyl acetateˆ9:1) to
1
obtain ,5b) as a yellowoil ,300 mg, 74%). H NMR: d: 3.85
,3H, s, OCH3), 7.10±7.54 ,6H, m, aromatic protons), 7.88±
8.1 ,3H, m, aromatic protons). HRMS m/z 252.0775 ,calcd
for C16H12O3, 252.0786).
Acknowledgements
3.1.9. )2Sp,3Rp)-2-Phenyl-3-carboxymethyl-2,3-dihydro-
benzo[b]furan )rac-4e). 100 mg ,0.39 mmol) of 5a in dry
methanol ,5 mL) was added to a stirred suspension of Pd,C)
,100 mg, 10%) in dry methanol ,10 mL) under a H2
atmosphere and stirring was continued for 24 h. Subse-
quently, the mixture was ®ltered and the solvent was
removed by evaporation. Puri®cation by preparative TLC
,toluene±hexaneˆ4:1) gave 4f as a colourless oil ,12 mg,
11%). 1H NMR: d: 3.12 ,3H, s, OCH3), 4.54 ,1H, d,
J2,3ˆ10 Hz, H3), 5.91 ,1H, d, J2,3ˆ10 Hz, H2), 6.81±7.40
,9H, m, aromatic protons). 13C NMR: d: 51.6 ,C-3), 53.9
,OMe), 85.6 ,C-2), 109.9 ,C-7), 121.2 ,C-5), 124.6 ,C-3a),
125.8 ,C-4), 126.2 ,C-40), 126.2 ,C-20, C-60), 128.1 ,C-30,
C-50), 128.3 ,C-6), 137.0 ,C-10), 160.4 ,C-7a), 170.4
,CvO). HRMS m/z 254.0939 ,calcd for C16H14O3,
254.0943).
The authors thank the National Science Foundation ,OTKA
T-034250 and T-033109) for valuable ®nancial support.
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