A New and Facile Iodine(III)-Mediated Approach for the Regioselective Alkoxylation of 2,5-Dihydroxyacetophenone

Article abstract of DOI:10.1055/s-2003-42461

Oxidation of 2,5-dihydroxyacetophenone with iodobenzene diacetate (IBD) in different alcohols leads to regioselective alkoxylation, thereby providing a new and convenient route for the synthesis of 6-alkoxy-2,5- dihydroxyacetophenones.

Full text of DOI:10.1055/s-2003-42461

2768
SHORT PAPER
A New and Facile Iodine(III)-Mediated Approach for the Regioselective
Alkoxylation of 2,5-Dihydroxyacetophenone
Regioselective
A
lk
m
oxylation of 2,5-Dihydrox
P
yacetophenon
r
e
akash,* Rashmi Pundeer, Harpreet Kaur
Chemistry Department, Kurukshetra University, Kurukshetra, Haryana 136119, India
Fax +91(1744)238277; E-mail: oprakash50@sify.com
Received 21 July 2003; revised 25 September 2003
deed, gave the corresponding 6-alkoxy derivatives 2a–g
in moderate yields (Scheme 2).
Abstract: Oxidation of 2,5-dihydroxyacetophenone with iodoben-
zene diacetate (IBD) in different alcohols leads to regioselective
alkoxylation, thereby providing a new and convenient route for the
synthesis of 6-alkoxy-2,5-dihydroxyacetophenones.
Key words: hypervalent iodine, regioselective alkoxylation, 2,5-
dihydroxyacetophenone , iodobenzene diacetate , oxidations
In connection with our ongoing studies on the use of orga-
noiodine(III) reagents in organic synthesis,1,2 we have ear-
lier reported that hypervalent iodine oxidation of m-
dihydric phenolic compounds bearing electron-withdraw-
ing ketonic moieties such as COCH2R leads to a novel
route for the synthesis of o-iodo ethers (Scheme 1).3 The
reaction, providing a unique application of organohyper-
valent iodine reagents, occurs via rearrangement of iodo-
nium ylides leaving the enolizable ketone moiety intact.
In continuation of these encouraging studies, we have
now examined the oxidation of 2,5-dihydroxyacetophe-
none (1) with iodobenzene diacetate [IBD or PhI(OAc)2]
in different alcohols.
Scheme 2
It is worthwhile to note that compounds 2a–g accessible
through the present study are useful precursors for the
synthesis of several unusually oxygenated synthetic and
natural flavone derivatives. For example, 2a has recently
been used as a key starting material in the synthesis of 5-
hydroxy-6,2 -dimethoxyflavone (3a) and 5,6,2 -tri-
methoxyflavone (3b), isolated from the farinose leaf exu-
dates of Primula denticulata4 species and Sargentia
greggi,5 respectively (Figure 1). However, apart from the
single report of Wollenweber et al.6 on the Elbs oxidation
of 2-hydroxy-6-methoxyacetophenone leading to the for-
mation of 2a (38% yield), no efforts have been made to
develop general synthetic approach(s) for 2.
I
PhO
OH
X
OH
O
OH
O
R
X
R
Scheme 1
O
The aim was to ascertain the influence of the change of
position of the phenolic hydroxy group1 on the course of
this reaction and hopefully to develop a new and facile ap-
proach for the synthesis of 6-alkoxy-2,5-dihydroxyace-
tophenones 2 which have potential use in synthesis. Thus,
1 was treated with IBD (1.1 equiv) in methanol at room
temperature. The usual work-up, followed by column
chromatographic separation of the crude
OCH3
CH3O
OR
O
3a, R=H
3b, R=CH3
Figure 1 Structures of flavones 3a,b
product afforded 2,5-dihydroxy-6-methoxyacetophenone
(2a) in 48% yield. To test the scope of this method, 1 was
subjected to oxidation with IBD in several alcohols,
namely, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-
methoxyethanol and 2-ethoxyethanol. The reaction, in-
Mechanistically, a plausible pathway for the transforma-
tion 1 2 probably involves the formation of O–I(III) in-
termediate 4 by the ligand exchange between the phenolic
7
hydroxyl group and PhI(OR)2 (generated from IBD-
ROH). The reductive elimination of iodobenzene leads to
5 which on attack by an alcohol gives the corresponding
6-alkoxy-2,5-dihydroxyacetophenones 2 (Scheme 3).
SYNTHESIS 2003, No. 18, pp 2768–2770
x
x.
x
x
.
2
0
0
3
Advanced online publication: 05.11.2003
DOI: 10.1055/s-2003-42461; Art ID: T07103SS
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Regioselective Alkoxylation of 2,5-Dihydroxyacetophenone
2769
HRMS: m/z calcd for C11H14O4: 210.089209; found: 210.089648.
OH
O
OH
PhI(OAc)2, ROH
PhI(OR)2
Anal. Calcd for C11H14O4: C, 62.85; H, 6.66. Found: C, 63.02; H,
6.73.
-PhI
3 -ROH
CH
CH3
O
I
HO
6-Isopropoxy-2,5-dihydroxyacetophenone (2d)
O
Ph
Yield: 780 mg (37%); mp 90 °C (Lit.10 mp 90–92 °C).
1
4
OR
6-n-Butoxy-2,5-dihydroxyacetophenone (2e)
Yield: 760 mg (34%); mp 61 °C (Lit.10 mp 62.5–63.5 °C).
OH
O
2
CH3
CH3
6-(2-Methoxyethoxy)-2,5-dihydroxyacetophenone (2f)
Yield: 1.01 g (45%); mp 36 °C.
IR (Nujol): 3312 (O–H), 1635 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz): = 2.73 (s, 3 H, COCH3), 3.56 (s, 3
H, OCH2CH2OCH3), 3.73–3.76 (m, 2 H, OCH2CH2OCH3), 4.06–
4.09 (m, 2 H, OCH2CH2OCH3), 6.70 (d, J = 9.0 Hz, 1 H, H-3), 7.13
(d, J = 9.3 Hz, 1 H, H-4), 12.02 (s, 1 H, C2-OH).
O
O
OR
H
O
O
ROH
5
6
Scheme 3
The structure of all new alkoxy derivatives 2c, 2f and 2g
were confirmed by spectral data (IR, H NMR and MS)
and elemental analysis, whereas the products 2a, 2b, 2d
and 2e already known in literature were identified by
comparison of their melting points, IR and 1H NMR spec-
tra.
HRMS: m/z calcd for C11H14O5: 226.084124; found: 226.084011.
1
Anal. Calcd for C11H14O5: C, 58.40; H, 6.19. Found: C, 58.52; H,
6.26.
6-(2-Ethoxyethoxy)-2,5-dihydroxyacetophenone (2g)
Yield: 940 mg (39%); mp 34 °C.
IR (Nujol): 3300 (O–H), 1637 cm–1 (C=O).
In conclusion, the new I(III)-mediated approach not only
reports a first convenient method for the regioselective
alkoxylation of 2,5-dihydroxyacetophenone, but also of-
fers an alternative simple synthesis of natural flavones 3a
and 3b via 2a.
1H NMR (CDCl3, 300 MHz):
= 1.34 (t, J = 7.0 Hz, 3 H,
OCH2CH2OCH2CH3), 2.74 (s, 3 H, COCH3), 3.66–3.80 (m, 4 H,
OCH2CH2OCH2CH3), 4.07–4.10 (m, 2 H, OCH2CH2OCH2CH3),
6.70 (d, J = 8.8 Hz, 1 H, H-3), 7.13 (d, J = 8.9 Hz, 1 H, H-4), 12.03
(s, 1 H, C2-OH).
HRMS: m/z calcd for C12H16O5: 240.099774; found: 240.099643.
Melting points were taken in open capillaries and are not corrected.
1H NMR spectra were recorded on a Bruker 300 MHz instrument
using TMS as an internal standard. IR spectra were recorded on a
Perkin-Elmer 1800 IR spectrophotometer. Mass spectra were re-
corded on a 70 eV mass spectrometer. 2,5-Dihydroxyacetophenone
was prepared according to the literature method starting from hyd-
roquinone.8
Anal. Calcd for C12H16O5: C, 60.00; H, 6.66. Found: C, 59.86; H,
6.79.
Acknowledgment
We are thankful to DRDO (ERIP/ER/0103294/M/01), New Delhi
for financial assistance.
Alkoxylation of 2,5-Dihydroxyacetophenone (1); General Pro-
cedure
To a suspension of 2,5-dihydroxyacetophenone (1; 1.52 g, 10
mmol) in the appropriate alcohol (15 mL) was added IBD (4.31 g,
11 mmol) in portions. The reaction mixture was stirred at r.t. and the
progress of the reaction was monitored by TLC. After stirring for 2
h,9 the solvent was evaporated in vacuo to give a crude product con-
taining a mixture of 6-alkoxy derivative, iodobenzene and the start-
ing material. Pure 6-alkoxy-2,5-dihydroxyacetophenone 2 was
obtained by column chromatographic separation on a column of sil-
ica gel using EtOAc–petroleum ether (bp 35–60 °C) as eluent.
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Yield: 870 mg (48%); mp 86–87 °C (Lit.10 mp 90 °C).
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Yield: 900 mg (46%); mp 100 °C (Lit.10 mp 103 °C).
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IR (Nujol): 3300 (O–H), 1633 cm–1 (C=O).
1H NMR (CDCl3, 300 MHz):
= 1.08 (t, J = 7.5 Hz, 3 H,
OCH2CH2CH3), 1.81–1.91 (m, 2 H, OCH2CH2CH3), 2.73 (s, 3 H,
COCH3), 3.84 (t, J = 7.5 Hz, 2 H, OCH2CH2CH3), 5.10 (s, 1 H, C5-
OH), 6.70 (d, J = 9.0 Hz, 1 H, H-3), 7.21 (d, J = 9.0 Hz, 1 H, H-4),
11.82 (s, 1 H, C2-OH).
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O. Prakash et al.
SHORT PAPER
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Synthesis 2003, No. 18, 2768–2770 © Thieme Stuttgart · New York