Domino Michael/retro-Michael/Mukaiyama-aldol reactions of 1,3-bis-silyl enol ethers with 3-acyl- and 3-formylbenzopyrylium triflates - Synthesis of functionalised 2,4′-dihydroxybenzophenones

Article abstract of DOI:10.1002/ejoc.200600082

The reaction of 1,3-bis-silyl enol ethers with 3-acyl- and 3-formylbenzopyrylium triflates, which can be generated in situ from 3-acyl- and 3-formylchromones, affords a great variety of functionalised 2,4′-dihydroxybenzophenones and 4-(2-hydroxybenzoyl)sa

Full text of DOI:10.1002/ejoc.200600082

FULL PAPER
DOI: 10.1002/ejoc.200600082
Domino Michael/Retro-Michael/Mukaiyama-Aldol Reactions of 1,3-Bis-Silyl
Enol Ethers with 3-Acyl- and 3-Formylbenzopyrylium Triflates – Synthesis of
Functionalised 2,4Ј-Dihydroxybenzophenones
Bettina Appel,[a] Sven Rotzoll,[b] Remo Kranich,[c] Helmut Reinke,[b] and Peter Langer*[b,d]
Keywords: Benzophenones / Cyclisations / Chromones / Domino reactions / Silyl enol ethers
The reaction of 1,3-bis-silyl enol ethers with 3-acyl- and 3-
formylbenzopyrylium triflates, which can be generated in
situ from 3-acyl- and 3-formylchromones, affords a great
variety of functionalised 2,4Ј-dihydroxybenzophenones and
4-(2-hydroxybenzoyl)salicylates. These products are formed
by a domino Michael/retro-Michael/Mukaiyama-aldol reac-
tion. This methodology is successfully applied to the synthe-
sis of novel UV-A/B and UV-B filters. Three 4-(2-hydroxyben-
zoyl)salicylic acids show a good in vitro activity in a selectin
bioassay.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
widely used as sun-protecting materials.[5] Long exposure to
sunlight may cause photoallergic and cytotoxic reactions
and skin cancer; the latter is induced by photochemical re-
actions of the DNA (e.g. [2+2] cycloadditions of thymin).
The most dangerous irradiation of sunlight lies in the range
320–290 nm, although higher wavelengths also contribute
significantly to the negative effects of sunlight. Optimal
sun-protecting materials should have a broad and strong
absorption of UV-A (400–320 nm) and UV-B irradiation
(320–280 nm). Other important parameters of sun-protect-
ing materials include photostability, thermostability, chemi-
cal stability (particularly against water) and a moderate li-
pophilicity. In fact, a high water-solubility decreases the
protection in water; in contrast, a too high lipophilicity re-
sults in rapid absorption of the material by the skin and
thus reduced protection. Sun-protecting materials often
contain a mixture of UV-A and UV-B filters.[5] Salicylates
(e.g. ethylhexyl salicylate) and dibenzoylmethanes (e.g. 4-
butyl-4Ј-methoxydibenzoylmethane) are widely used UV-B
and UV-A filters, respectively. Alternatively, UV-A/B filters,
which combine a UV-A and UV-B filter in one molecule,
are also frequently employed. Functionalised benzophe-
nones, such as benzophenone-3 (oxybenzone), are widely
used UV-A/B filters.[5] However, due to allergic reactions
brought about by the photosensitizing effects of oxyben-
zone, the development of new UV-A/B filters is of consider-
able interest.
Introduction
Functionalised benzophenones have found various me-
dicinal and technical applications. They occur in a variety
of natural products and represent important core structures
for the development of pharmaceuticals.[1] For example, the
benzophenone phenstatin has been reported to be an anti-
tubulin agent.[2] Microtubules are an important target for
anticancer therapy. Recently, Hsieh and co-workers re-
ported the synthesis of cytotoxic 2-hydroxy- and 2-amino-
benzophenones as potent antitubulin agents.[3a,3b]
Benzophenones are widely used as photosensitizers and
represent one of the most important substance classes in
photochemistry.[4] 2-Hydroxybenzophenones are also
[a] Institut für Biochemie, Universität Greifswald,
Soldmannstr. 16, 17487 Greifswald, Germany
[b] Institut für Chemie, Universität Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax: +49-381-498-6412
E-mail: peter.langer@uni-rostock.de
[c] Revotar Biopharmaceuticals AG
Neuendorfstr. 24a, 16761 Hennigsdorf, Germany
[d] Leibniz-Institut für Katalyse an der Universität Rostock e. V.,
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Classic syntheses of benzophenones mainly rely on reac-
tions of aryllithium or -magnesium reagents with aldehydes
and subsequent oxidation of the alcohol thus formed;[3a]
Friedel–Crafts acylations have also been used.[6] For the
synthesis of functionalised benzophenones (e.g. containing
a hydroxy, halide or ester group), however, these methods
give unsatisfactory results due to competing side-reactions.
3638
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3638–3644

Synthesis of Functionalised 2,4Ј-Dihydroxybenzophenones
FULL PAPER
The development of alternative methods is therefore of con-
siderable interest.[7] Recently, we reported[8] a new approach
to 4-(2-hydroxybenzoyl)salicylates by domino Michael/
retro-Michael/Mukaiyama-aldol reactions of 3-formylchro-
mones[9–11] with 1,3-bis-silyl enol ethers.[12,13] Herein, we re-
port full details of these studies. The preparative scope has
been considerably extended with regard to our preliminary
communication,[8]and the method has been applied to the
synthesis of novel selectin antagonists and UV-A/B filters.
Results and Discussion
Mechanism
The reaction of 3-formylchromone (1a) with 1,3-bis-silyl
enol ether 2a, which is readily available from acetyl-
acetone,[13b] affords 2,4Ј-dihydroxybenzophenone (3a). The
presence of TMSOTf (0.3 equiv.) proved to be an important
parameter during the optimisation of the reaction; the use
of stoichiometric amounts of the Lewis acid, however, did
not result in an increase of the yield. The reaction proved
to be robust against minor changes of the reaction time and
temperature. However, the use of no or other Lewis acids
proved to be unsuccessful (decomposition). The formation
of 3a can be explained by a domino Michael/retro-Michael/
Mukaiyama-aldol reaction (Scheme 1). The reaction of 3-
formylchromone with TMSOTf afforded the benzopyryl-
ium triflate A.[14,15] The reaction of A with the terminal
carbon atom of 2a gives intermediate B, which undergoes a
retro-Michael reaction to give the polyketide C. An intra-
molecular aldol reaction gives intermediate D, which is
transformed into 3a by elimination of siloxane.
Scheme 1. Mechanism of the formation of 3a: i) Me3SiOTf
(0.3 equiv.), 20 °C, 10 min; ii) 1. 2a (1.3 equiv.), CH2Cl2, 0 Ǟ 20 °C,
12 h; 2. HCl (10%).
and benzyloxy functionality proved to be unsuccessful. The
cyclisation of 3-acetylchromone with 1,3-bis-silyl enol
ethers gave the methyl-substituted 4-(2-hydroxybenzoyl)sali-
cylates 3ah–aj. The yields vary in the range 36–82%. The
presence of functional groups located at the chromone moi-
ety and the use of substituted 1,3-bis-silyl enol ethers had
no major influence on the yields of the reactions. In some
reactions, a small amount of starting material could be re-
covered. However, the yields could not be improved by vari-
ation of the stoichiometry of the starting materials. The for-
mation of side-products could not be detected.
Synthesis of 2,4Ј-Dihydroxybenzophenones
The cyclisation of 3-formylchromone (1a) with 1,3-bis-
silyl enol ether 2b, which was prepared from benzoylace-
tone, afforded 2,4Ј-dihydroxybenzophenone 3b (Scheme 2,
Table 1). The 4-(2-hydroxybenzoyl)salicylates 3c,d were pre-
pared by reaction of the β-keto ester derived from 1,3-bis-
silyl enol ethers 2c,d with 1a. The alkyl-substituted 4-(2-
hydroxybenzoyl)salicylates 3e–m were prepared by cycli-
sation of 1a with 1,3-bis-silyl enol ethers containing an alkyl
group located at carbon atom C-4. The cyclisation of 1,3-
bis-silyl enol ethers with functionalised 3-formylchromones
afforded the alkyl-, nitro-, chloro- and bromo-substituted
Scheme 2. Synthesis of 3a–aj: i) Me3SiOTf (0.3 equiv.) 20 °C,
10 min; ii) 1. 2a–p (1.3 equiv.), CH2Cl2, 0 Ǟ 20 °C, 12 h; 2. HCl
(10%).
The structure of the products was established by spectro-
1
4-(2-hydroxybenzoyl)salicylates 3n–ae. The reaction of 1a scopic methods. The H NMR spectra show the presence
with 1,3-bis-silyl enol ethers containing a terminal methoxy of two low-field signals assigned to the intramolecular O–
Eur. J. Org. Chem. 2006, 3638–3644
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3639

B. Appel, S. Rotzoll, R. Kranich, H. Reinke, P. Langer
FULL PAPER
Table 1. Products and yields.
H···O hydrogen bonds. The structure of 2,4Ј-dihydroxy-
benzophenone 3b was independently confirmed by an X-
ray crystal structure analysis (Figure 1).[16] Two hydrogen
bonds are present in the solid state.
Yield
of 3
1
2
3
R1 R2 R3 R4
R5
R6
[%][a]
a
a
a
a
a
a
a
a
a
a
a
a
a
b
c
d
d
d
e
f
a
b
c
d
e
f
g
h
i
j
k
l
m
c
b
c
f
g
f
c
f
f
h
a
c
f
g
h
i
j
f
a
b
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
iPr
Cl
Cl
Cl
NO2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
Me
Et
nPr
Allyl
nBu
nOct
nNon
nDec
Bn
H
H
H
Et
nPr
Et
H
Et
Et
Me
Ph
43
61
51
51
56
53
51
42
62
43
61
58
48
57
58
46
55
46
63
56
51
46
47
52
82
42
52
57
53
56
54
0
c
OEt
OR[b]
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Ph
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OEt
OEt
OEt
Biological Evaluation
d
In addition to filtering UV-A/B irradiation, benzophe-
nones including a salicylic substructure, like 4a–j, are inter-
esting compounds for medical applications against inflam-
matory disorders. They belong to a promising compound
class for modulating the lectin domain of selectins. E-, P-
and L-selectin play an important role in the early stages of
inflammatory processes that occur in chronic asthma,
chronic obstructive pulmonary disease (COPD), psoriasis,
dermatitis, rheumatoid arthritis or Crohn’s disease.[17] The
4-(2-hydroxybenzoyl)salicylic acids 4a–j were prepared by
hydrolysis of the corresponding esters in order to increase
their water solubility (Scheme 3, Table 2). The acids 4b–e
and 4g–j were tested for their activity as selectin antago-
nists. With slight modifications, the ELISA-type assay was
performed according to the method of Weitz-Schmidt.[18]
Sialyl Lewisx and tyrosine sulfate modified polymer instead
of Sialyl Lewisa were used as the synthetic selectin ligand.
In addition to E-selectin, P- and L-selectin have also been
used for binding. The concentration of the substrates in the
bioassays was 100 µ. The 4-(2-hydroxybenzoyl)salicylic ac-
ids 4e, 4i and 4j showed a good in vitro activity in our
selectin bioassay (Table 3). The best activity was observed
for 4j. The non-peptidic and non-glycosidic nature of 4e,i,j
and their low molecular weight represent interesting struc-
tural features that are different from those of most of the
known selectin antagonists.
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
Cl Me
Cl Me
f
u
g
g
h
h
h
h
h
h
h
i
a
a
j
j
j
v
Me
Me
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
w
x
y
Allyl
H
H
z
Et
aa
ab
ac
ad
ae
af
ag
ah
ai
aj
nPr
Allyl
nBu
nOct
Et
OMe
OBn
H
n
o
c
f
H
H
H
H
0
42
48
36
Et
p
Me nHex
[a] Isolated yields. [b] R = (CH2)2OCH3.
Scheme 3. Synthesis of 4a–j: i) 1. aqueous KOH (10%, 13.0 equiv.),
DMSO, 20 °C, 12 h; 2. aqueous HCl (1 ); ii) 1. aqueous KOH
(2 , 4.0 equiv.), 20 °C, 36 h; 2. aqueous HCl (10%); iii) 1. BBr3
(4.0 equiv.), CH2Cl2, 0 Ǟ 20 °C, 12 h; 2. aqueous HCl (10%).
Table 2. Products and yields.
Meth- Yield of
3
4
R1
R2
R3
R4
R5
od[a]
4 [%][b]
c
a
b
c
d
e
f
H
H
H
H
H
Cl
Cl
Me
Me
Cl
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Me
Allyl
nBu
Bn
H
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
i
ii
ii
ii
ii
iii
ii
ii
ii
ii
88[c]
100
100
100
100
82[c]
100
100
100
100
e
h
i
m
t
u
v
w
ac
g
h
i
Et
Et
Me
Me Allyl
Cl nBu
j
Figure 1. ORTEP plot of 3b.
[a] See legend of Scheme 3. [b] Conversion. [c] Isolated yield.
3640
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3638–3644

Synthesis of Functionalised 2,4Ј-Dihydroxybenzophenones
FULL PAPER
Table 3. In vitro activity in selectin bioassays.
4
E-selectin[a]
P-selectin[a]
L-selectin[a]
e
i
j
10
–
16
77
78
94
48
58
89
[a]% Inhibition.
Synthesis of 2,4Ј-Dihydroxynaphthophenones
The reaction of 2-acetylnaphth-1-ol (5) with diethoxy-
N,N-dimethylmethanamine afforded 6, which was trans-
formed into 3-acetyl-4H-benzo[h]chromen-4-one (7). The
cyclisation of 7 with 1,3-bis-silyl enol ethers afforded the
2,4Ј-dihydroxynaphthophenones 8a–c (Scheme 4, Table 4).
The structure of 8a was independently confirmed by an X-
ray crystal structure analysis (Figure 2).[16] As expected, two
intramolecular hydrogen bonds O–H···O are present.
Scheme 4. Synthesis of 8a–c: i) 5 (1.0 equiv.), diethoxy-N,N-dimeth-
ylmethanamine (1.0 equiv.), 20 °C, 12 h; ii) Ac2O (4 equiv.), pyri-
dine, MeCN, 6 h, reflux, then 12 h, 20 °C; iii) 1. Me3SiOTf
(0.3 equiv.), 0 °C, 10 min, 2c,j,q (1.3 equiv.), CH2Cl2, 20 °C, 12 h;
2) HCl (10%).
UV Absorption
Optimal UV-A/B filters require a broad and strong ab-
sorption in the UV-A and UV-B region. Oxybenzone exhib-
its absorptions at λmax = 325 and 288 nm and is a widely
used UV-A/B filter. However, the UV-B absorption of oxy-
benzone is relatively weak and therefore it has to be used
together with a strong UV-B filter.[5] Allergic reactions of
the skin have been reported for oxybenzone due to its pho-
tosensitizing properties.[19] Therefore, sun-protecting mate-
rials containing oxybenzone must be adequately labelled
within the European Union. To develop a new UV-A/B fil-
Table 4. Products and yields.
2
8
R1
R2
% (8)[a]
q
c
j
a
b
c
H
H
nOct
Me
Et
Et
40
36
33
[a] Isolated yields.
ter, we have studied the UV absorptions of a great variety naphthophenone 8a exhibits strong absorptions at λmax
of 2,4Ј-dihydroxybenzophenones (Table 5). The best results 298 and 287 nm and is thus a promising UV-B filter.
=
were observed for benzophenones 3a, 3g, 3j and 3k, all of
which exhibit strong absorptions in the range of λmax
In conclusion, we have reported the synthesis of a variety
of functionalised 4-(2-hydroxybenzoyl)salicylates by a dom-
=
318–323 and 285–291 nm; 3m and 3n show strong absorp- ino Michael/retro-Michael/Mukaiyama-aldol reaction of
tions at λmax = 348 and 289 nm, respectively. The lipophil- 1,3-bis-silyl enol ethers with 3-acyl- and 3-formylbenzo-
icity of these promising UV-A/B filters varies depending on pyrylium triflates. The methodology has been successfully
the alkyl groups. Tuning of the lipophilicity should be also applied to the synthesis of novel UV absorbers and selectin
possible by varying the ester group. The 2,4Ј-dihydroxy- antagonists.
Figure 2. ORTEP plot of 8a. Selected bond lengths [Å] and angles [°]: C(1)–O(1) 1.3375(16), C(2)–C(11) 1.4668(16), C(11)–O(2)
1.2437(18), C(11)–C(12) 1.4975(18), C(12)–C(17) 1.3990(19), C(14)–C(15) 1.4153(16), C(14)–C(19) 1.4825(15), C(15)–O(3) 1.3518(16),
C(19)–O(4) 1.2279(15), C(19)–O(5) 1.3238(14), C(39)–O(14) 1.2267(16), C(39)–O(15) 1.3179(18), C(40)–O(15) 1.4457(18), O(1)–H(1)
0.8400, O(3)–H(3A) 0.8400, O(11)–H(11) 0.8400, O(13)–H(13) 0.8400; O(1)–C(1)–C(2) 122.57(11), O(1)–C(1)–C(10) 116.56(11), C(2)–
C(1)–C(10) 120.87(12).
Eur. J. Org. Chem. 2006, 3638–3644
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3641

B. Appel, S. Rotzoll, R. Kranich, H. Reinke, P. Langer
FULL PAPER
8.7 Hz, 1 H, Ar), 7.10 (dd, J = 8.4, J = 0.8 Hz, 1 H, Ar), 7.53 (m,
1 H, Ar), 7.58 (dd, J = 8.0, J = 1.5 Hz, 1 H, Ar), 7.86 (dd, J = 8.7,
J = 2.2 Hz, 1 H, Ar), 8.20 (d, J = 2.1 Hz, 1 H, Ar), 11.78 (s, 1 H,
OH), 12.68 (s, 1 H, OH) ppm. 13C NMR (DEPT, 75.5 MHz,
CDCl3): δ = 26.8 (CH3), 118.5, 118.7, 118.8 (CH), 119.0, 119.3,
128.8 (C), 132.7, 133.2, 136.3, 137.4 (CH), 163.0, 165.5 (C–OH),
Table 5. UV absorptions.
Compd. λmax (lgε) [nm] in CH3CN
3a
3b
3d
3e
323 (3.93), 285 (4.02), 250 (4.30)
336 (3.95), 261 (4.35)
283 (4.02), 263 (3.98), 235 (4.23), 214 (4.43)
317 (3.92), 287 (3.99), 238 (4.31), 220 (4.33)
316 (3.90), 290 (3.95), 243 (4.21)
198.9, 204.5 (C=O) ppm. IR (KBr): ν = 3081 (m), 2973 (m), 2925
˜
3f
(m), 1644 (s), 1626 (s), 1588 (s), 1482 (m), 1440 (m), 1423 (m), 1363
(s), 1295 (s), 1241 (s), 1221 (s), 1161 (m), 975 (m), 914 (w), 864 (w),
834 (s), 761 (s), 633 cm–1 (m). UV/Vis (CH3CN): λmax (lgε) = 425
(3.16), 403 (3.17), 323 (3.93), 285 (4.02), 250 nm (4.30). MS (EI,
70 eV): m/z (%) 256 (70) [M+], 241 (14), 213 (9), 163 (17), 136 (6),
121 (100), 92 (14), 66 (22). C15H12O4 (256.26): calcd. C 70.33, H
4.72; found C 70.04, H 4.89.
3g
3h
3i
319 (3.91), 291 (3.95), 240 (4.24), 214 (4.46)
317 (3.88), 288 (3.94), 243 (4.20)
320 (3.89), 291 (3.91), 240 (4.24), 215 (4.44)
318 (3.89), 292 (3.92), 244 (4.20)
3j
3k
3l
320 (3.94), 291 (3.97), 241 (4.28), 215 (4.50)
322 (3.85), 292 (3.87), 242 (4.20), 215 (4.41)
348 (4.28), 283 (4.04), 266 (4.07), 236 (3.73)
348 (4.28), 283 (4.04), 266 (4.07), 236 (3.73)
338 (3.53), 263 (3.95), 226 (4.11)
344 (3.73), 286 (3.97), 238 (4.20)
343 (3.77), 297 (3.84), 219 (4.45)
345 (3.78), 297 (3.86), 239 (4.25), 219 (4.48)
344 (3.76), 285 (4.04), 269 (4.02), 223 (4.39), 207 (4.43)
284 (3.40), 247 (4.22)
3m
3n
3o
3p
3q
3r
3t
3u
3v
General Procedure 2 (Synthesis of Benzophenones 3ah–aj): Me3-
SiOTf (0.3 equiv.) was added to 3-acetyl-4H-chromen-4-one 1j
(1.0 equiv.) at 20 °C. After stirring for 10 min, CH2Cl2 (15 mL) was
added, the solution cooled down to 0 °C and the 1,3-bis-silyl enol
ether 2c, 2f or 2p (1.3 equiv.) was added. The mixture was stirred
for 12 h at 20 °C and was subsequently poured into an aqueous
solution of hydrochloric acid (10%). The organic layer was sepa-
rated and the aqueous layer was extracted with CH2Cl2
(4×60 mL). The combined organic layers were washed with water,
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (silica gel, n-
hexane/EtOAc, 20:1 Ǟ 1:1) to give the methyl-substituted benzo-
phenones 3ah–aj.
304 (3.70), 250 (4.09)
3w
3x
3y
3z
3aa
3ab
3ac
3ad
3ae
3ah
3ai
3aj
4a
4f
355 (3.70), 290 (3.98), 271 (3.98), 242 (4.19), 216 (4.38)
289 (3.90), 248 (4.27), 230 (4.16)
347 (3.69), 291 (4.01), 232 (4.27)
307 (3.90), 245 (4.24)
346 (3.78), 307 (3.96), 219 (4.51)
348 (3.75), 304 (3.85), 219 (4.46)
346 (3.76), 308 (3.86), 220 (4.44)
306 (3.87), 243 (4.22)
307 (3.89), 245 (4.26)
325 (3.80), 254 (4.10), 213 (4.50)
324 (3.85), 255 (4.21), 215 (4.48)
324 (3.90), 255 (4.20), 213 (4.50)
283 (3.99), 263 (3.98), 233 (4.19), 212 (4.44)
286 (4.02), 269 (4.01), 222 (4.39), 207 (4.44)
298 (4.19), 287 (4.13), 259 (4.66), 217 (4.67)
298 (4.03), 287 (3.96), 259 (4.42), 215 (4.49)
298 (3.79), 287 (3.69), 259 (4.28), 219 (4.31)
Ethyl 5-(2-Hydroxybenzoyl)-6-methylsalicylate (3ah): Starting with
3-acetyl-4H-chromen-4-one 1j (178 mg, 0.95 mmol), Me3SiOTf
(63 mg, 0.29 mmol) and 1,3-bis-silyl enol ether 2c (365 mg,
1.33 mmol), 3ah was isolated as a colourless solid (120 mg, 42%),
m.p. 109 °C. 1H NMR (300 MHz, CDCl3): δ = 1.44 (t, J = 7.1 Hz,
3 H, OCH2CH3), 2.47 (s, 3 H, CH3), 4.47 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 6.8 (m, 1 H, Ar), 6.94 (d, J = 8.6 Hz, 1 H, Ar), 7.05
(dd, J = 8.4, J = 1.0 Hz, 1 H, Ar), 7.26 (m, 2 H, Ar), 7.50 (m, 1
H, Ar), 11.44 (s, 1 H, OH), 12.20 (s, 1 H, OH) ppm. 13C NMR
(DEPT, 75.5 MHz, CDCl3): δ = 14.1 (CH3), 20.6 (OCH2CH3), 62.2
(OCH2CH3), 113.5 (C), 115.5, 118.3, 118.9 (CH), 120.9 (C), 131.4,
133.1, 133.5, 136.9 (CH), 139.1 (C), 163.2, 163.6 (C–OH), 171.3,
8a
8b
8c
Experimental Section
General Comments: All solvents were dried by standard methods
and all reactions were carried out under an inert atmosphere. For
1H and 13C NMR spectra the deuterated solvents indicated were
used. Mass spectrometric data were obtained by electron ionisation
(EI = 70 eV), chemical ionisation (CI, H2O) or electrospray ioni-
sation (ESI). Silica gel (60–200 mesh) was used for preparative scale
chromatography. The melting points are corrected.
203.9 (C=O) ppm. IR (KBr): ν = 3073 (m), 3028 (m), 2987 (m),
˜
2944 (m), 2913 (m), 1664 (s), 1628 (s), 1590 (s), 1476 (s), 1450 (m),
1399 (m), 1376 (s), 1335 (s), 1310 (s), 1289 (m), 1248 (s), 1205 (s),
1145 (m), 1114 (w), 1029 (w), 1000 (w), 936 (w), 842 (w), 807 (m),
765 (s), 645 cm–1 (w). UV/Vis (CH3CN): λmax (lgε) = 325 nm (3.8),
254 (4.1), 213 (4.5). MS (EI, 70 eV): m/z (%) = 300 (100) [M+], 285
(38), 253 (81), 237 (36), 161 (26), 134 (52), 121 (73), 93 (20), 66
(24), 43 (16). C17H16O5 (300.32): calcd. C 67.99 H 5.37; found C
67.85, H 5.35.
General Procedure 1 (Synthesis of Benzophenones): Me3SiOTf
(0.3 equiv.) was added to the 3-formylchromone 1 (1.0 equiv.) at
20 °C. After stirring for 10 min, CH2Cl2 (8 mL) was added, the
solution was cooled to 0 °C and the 1,3-bis-silyl enol ether
(1.3 equiv.) was added. The mixture was stirred for 12 h at 20 °C
and was subsequently poured into an aqueous solution of hydro-
chloric acid (10%). The organic and aqueous layers were separated
and the latter was extracted with Et2O (3×80 mL). The combined
organic layers were washed with water, dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. The residue was purified by
column chromatography (silica gel, n-hexane/EtOAc, 10:1 Ǟ 3:1).
5-(2-Hydroxybenzoyl)salicylic Acid (4a): Salicylic acid (3c;
1.17 mmol, 336 mg) was added to an aqueous solution of KOH
(381 mg in 190 mL of water). After stirring for 4 h at 80 °C the
solution was poured into an aqueous solution of hydrochloric acid
(1 ). The organic layer was separated and the aqueous layer was
extracted with Et2O (4×10 mL). The combined organic layers were
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography (silica gel, n-
hexane/EtOAc, 3:1 Ǟ 1:5) to give 4a as a colourless solid (266 mg,
1
1-[(2-Hydroxybenzoyl)-2-hydroxyphenyl]ethan-1-one (3a): Starting
with 1a (200 mg 1.15 mmol), Me3SiOTf (77 mg, 0.34 mmol) and
1,3-bis-silyl enol ether 2a (365 mg, 1.49 mmol), 3a was isolated as
a colourless solid (127 mg, 43%), m.p. 129 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.69 (s, 3 H, CH3), 6.91 (m, 1 H, Ar), 7.08 (d, J =
88%), m.p. 171 °C. H NMR (300 MHz, CDCl3): δ = 4.12 (br. s, 1
H, COOH), 6.94 (m, 2 H, Ar), 7.06 (d, J = 8.7 Hz, 1 H, Ar), 7.31
(dd, J = 7.6, J = 1.7 Hz, 1 H, Ar), 7.41 (m, 1 H, Ar), 7.89 (dd, J
= 8.7, J = 2.3 Hz, 1 H, Ar), 8.15 (d, J = 2.3 Hz, 1 H, Ar), 10.18
(s, 1 H, Ar–OH), 12.60 (br. s, 1 H, Ar–OH) ppm. 13C NMR
3642
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3638–3644

Synthesis of Functionalised 2,4Ј-Dihydroxybenzophenones
(DEPT, [D6]DMSO, 75.5 MHz): δ = 113.2 (C), 116.5, 117.5, 119.1 3.19 (s, 3 H, NCH3), 5.83 [d, J = 12.2 Hz, 1 H, C(O)CH=C], 7.20
FULL PAPER
(CH), 125.3, 128.6 (C), 129.8, 132.6, 133.0, 136.1 (CH), 156.0,
164.8 (C–OH), 171.2, 194.7 (C=O) ppm. IR (KBr): ν = 3410 (m),
(d, J = 8.8 Hz, 1 H, Ar), 7.26–7.58 (br. m, 2 H, Ar), 7.66 (d, J =
8.9 Hz, 1 H, Ar), 7.72 (d, J = 7.6 Hz, 1 H, Ar), 7.93 [d, J = 12.2 Hz,
˜
3113 (m), 3081 (m), 2930 (m), 2665 (m), 2605 (m), 1685 (s), 1628 1 H, C=CHN(CH3)2], 8.44 (dd, J = 8.2, J = 0.6 Hz, 1 H, Ar), 15.85
(s), 1591 (s), 1487 (s), 1447 (s), 1341(s), 1305 (s), 1249 (s), 1231 (s), (s, 1 H, OH) ppm. 13C NMR (DEPT, 75.5 MHz, CDCl3): δ = 41.2
1205 (s), 1161 (m), 1083(m), 979 (w), 847 (m), 796 (m), 758 (s), 695
[N(CH3)2], 90.3 (CH), 113.2 (C), 117.1, 123.9, 124.1, 125.2 (CH),
125.9 (C), 127.2, 128.7 (CH), 136.5 (C), 154.5 [CH(N)], 162.6 (C–
(m), 667 (m), 631 cm–1 (m). UV/Vis (CH3CN): λmax (lgε) = 283
(3.99), 263 (3.98), 233 (4.19), 212 nm (4.44). MS (EI, 70 eV): OH), 191.4 (C=O) ppm. IR (KBr): ν = 3064 (w), 2926 (w), 2880
˜
m/z (%) 258 (3) [M+], 213 (2), 165 (2), 149 (2), 121 (6), 108 (17),
(w), 2808 (w), 1914 (w), 1626 (s), 1555 (s), 1500 (s), 1465 (s), 1416
91 (4), 58 (4). HRMS (FT-ICR) calcd. for C14H11O5 ([M + 1]+): (s), 1388 (m), 1365 (s), 1333 (m), 1278 (s), 1245 (s), 1116 (m), 1199
259.06010; found 259.06005.
(m), 1151 (m), 1110 (s), 1073 (m), 1020 (w), 981 (w), 939 (m), 863
(w), 794 (m), 772 (s), 603 cm–1 (w). UV/Vis (CH3CN): λmax (lgε) =
385 (4.46), 373 (4.47), 350 (4.35), 276 (4.11), 266 (4.11), 241 (4.28),
218 nm (4.40). MS (EI, 70 eV): m/z (%) 241 (44) [M+], 223 (2), 197
(19), 170 (5), 141 (3), 127 (3), 114 (22), 72 (100), 56 (21), 42 (18).
C15H15NO2: calcd. C 74.66 H 6.26, N 5.80; found C 74.72, H 5.73,
N 5.77.
General Procedure 3 (Synthesis of Salicylic Acids 4b–e/g–j): The
salicylic ester (45 µmol) was dissolved in DMSO (0.5 mL) and an
aqueous solution of KOH (585 µmol, 0.3 mL) was added at 20 °C.
After stirring for 12 h an aqueous solution of hydrochloric acid
(1 , 600 µL) was added. The solvent was removed in vacuo to
afford a solid. The solid was suspended in a small amount of water
(twice) using an ultrasound bath to wash out KCl. The suspension
was centrifuged and the aqueous layer was decanted and the re-
maining crude samples dried in a Speedvac apparatus to obtain the
salicylic acid as a white solid with complete conversion. No further
purification was necessary.
3-Acetyl-4H-benzo[h]chromen-4-one (7): Pyridine (50 mL) and ace-
tic anhydride (4.08 g, 40 mmol) were added to an acetonitrile solu-
tion (300 mL) of 6 (2.41 g, 10 mmol) at 20 °C. After stirring for 6 h
under reflux, followed by stirring for 12 h at 20 °C, most of the
solvent (250 mL) was removed in vacuo and an aqueous solution
of hydrochloric acid (10%) was added. After adding CH2Cl2
(40 mL) the layers were separated and the aqueous solution was
extracted with CH2Cl2 (8×30 mL). The combined organic layers
were dried (Na2SO4), filtered, the filtrate was concentrated in vacuo
and the residue was purified by column chromatography (silica gel,
n-hexane/EtOAc, 5:1) to give 4H-benzo[h]chromen-4-one as a
colourless solid (431 mg, 22%) and 3-acetyl-4H-benzo[h]chromen-
4-one (7) as a yellow solid (1.13 g, 48%), m.p. 175 °C.
5-(2-Hydroxybenzoyl)-3-methylsalicylic Acid (4b): Starting with 3e,
4b was isolated as a colourless solid. 1H NMR (400 MHz, [D6]-
DMSO): δ = 2.20 (s, 3 H, CH3), 3.89 (br. s, 1 H, COOH), 6.92 (t,
J = 7.6 Hz, 1 H, Ar), 6.98 (d, J = 8.0 Hz, 1 H, Ar), 7.29 (dd, J =
7.6, J = 1.5 Hz, 1 H, Ar), 7.39 (td, J = 8.0, J = 1.5 Hz, 1 H, Ar),
7.81 (br. s, 1 H, Ar), 7.99 (br. s, 1 H, Ar), 10.21 (br. s, 1 H, OH),
12.27 (br. s, 1 H, OH) ppm. MS (ESI, negative mode): m/z 271.2
[M – H].
1
7: H NMR (300 MHz, CDCl3): δ = 2.80 (s, 3 H, CH3), 7.68–7.78
5-(5-Chloro-2-hydroxy-4-methylbenzoyl)salicylic Acid (4f): BBr3
(1.20 mmol, 301 mg, 0.11 mL) was added to a CH2Cl2 solution
(5 mL) of 3t (0.26 mmol, 86 mg) at 0 °C. The mixture was stirred
for 12 h at 20 °C and was subsequently poured into an aqueous
solution of hydrochloric acid (10%). The organic layer was sepa-
rated and the aqueous layer was extracted with Et2O (4×10 mL).
The combined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was purified by col-
umn chromatography (silica gel, n-hexane/EtOAc, 3:1 Ǟ 1:5) to
(m, 2 H, Ar), 7.84 (d, J = 8.7 Hz, 1 H, Ar), 7.96 (m, 1 H, Ar), 8.21
(d, J = 8.8 Hz, 1 H, Ar), 8.49 (m, 1 H, Ar), 8.76 (s, 1 H, CH) ppm.
13C NMR (DEPT, 75.5 MHz, CDCl3): δ = 31.6 (CH3), 120.7 (C),
120.8 (CH), 121.9 (C), 122.2 (ArCH), 123.6, 123.9 (C), 126.4,
127.6, 128.2, 129.8 (ArCH), 136.1 (C), 160.5 (CH), 175.2, 196.8
(C=O) ppm. IR (KBr): ν = 3110 (w), 3076 (m), 3012 (w), 2926 (w),
˜
2362 (w), 1689 (s), 1643 (s), 1595 (m), 1552 (s), 1465 (m), 1443 (m),
1394 (s), 1362 (s), 1311 (s), 1264 (m), 1212 (m), 1154 (w), 1101 (s),
1024 (m), 972 (w), 889 (w), 795 (m), 769 (s), 648 cm–1 (m). UV/Vis
(CH3CN): λmax (lgε) = 339 (3.69), 325 (3.69), 301 (3.81), 246 (4.55),
239 (4.52), 222 (4.42), 212 nm (4.38). MS (EI, 70 eV): m/z (%) 238
(95) [M+], 223 (100), 196 (44), 171 (74), 139 (40), 126 (40), 113 (55),
88 (9), 64 (11), 53 (21), 43 (23). C15H10O3: calcd. C 75.62 H 4.23;
found C 75.13, H 4.15.
1
give 4f as a colourless solid (65 mg, 82%), m.p. 210 °C. H NMR
(300 MHz, [D6]DMSO): δ = 2.32 (s, 3 H, CH3), 3.48 (br. s, 2 H,
Ar–OH, COOH), 6.93 (s, 1 H, Ar), 7.05 (d, J = 8.7 Hz, 1 H, Ar),
7.31 (s, 1 H, Ar), 7.88 (dd, J = 8.7, J = 2.3 Hz, 1 H, Ar), 8.13 (d, J
= 2.3 Hz, 1 H, Ar), 10.27 (s, 1 H, Ar–OH) ppm. 13C NMR (DEPT,
75.5 MHz, [D6]DMSO): δ = 19.9 (CH3), 117.6 (CH), 118.9 (C),
118.9 (CH), 123.2, 125.0, 128.3 (C), 129.4, 133.1, 136.1 (CH), 139.9
General Procedure 4 (Synthesis of Naphthophenones 8a–c): Me3-
SiOTf (0.3 equiv.) was added to 3-acetyl-4H-benzo[h]chromen-4-
(C), 154.5, 165.1 (C–OH), 171.1, 192.8 (C=O) ppm. IR (KBr): ν =
˜
3412 (m), 3070 (m), 2988 (m), 2929 (m), 1698 (s), 1931 (s), 1584 one (7; 1.0 equiv.) at 20 °C. Following general procedure 2, the resi-
(s), 1479 (m), 1424 (m), 1354 (s), 1339 (s), 1304 (m), 1258 (s), 1215 due was purified by column chromatography (silica gel, n-hexane/
(s), 1176 (s), 1082 (w), 843 (w), 793 (m), 752 cm–1 (w). UV/Vis EtOAc, 20:1 Ǟ 5:1) to give the methyl-substituted benzophenones
(CH3CN): λmax (lgε) = 343 (3.81), 286 (4.02), 269 (4.01), 222 (4.39), 8a–c.
207 nm (4.44). MS (EI, 70 eV): m/z (%) 306 (15) [M+], 288 (2), 168
Methyl 3-[(1-Hydroxynaphthalen-2-yl)carbonyl]-2-methylsalicylate
(23), 147 (5), 121 (3), 77 (5), 45 (4). HRMS (FT-ICR) calcd. for
(8a): Starting with
7 (238 mg, 1 mmol), Me3SiOTf (67 mg,
C15H12ClO5 [M+1]+: 307.03678; found 307.03726.
1.3 mmol) and 1,3-bis-silyl enol ether 2q (338 mg, 1.3 mmol), naph-
3-Dimethylamino-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one (6): thophenone 8a was obtained as a yellow solid (131 mg, 40%), m.p.
1
Diethoxy-N,N-dimethylmethanamine (5.15 g, 35 mmol) was added
to a THF solution (8 mL) of 1-(1Ј-hydroxynaphthalen-2Ј-yl)etha-
none (5; 6.48 g, 35 mmol) and the mixture was stirred for 12 h at
20 °C to give a precipitate. This precipitate was filtered off and
135 °C. H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3 H, CH3), 3.99
(s, 3 H, OCH3), 6.97 (d, J = 8.8 Hz, 1 H, Ar), 7.15–7.19 (m, 2 H,
Ar), 7.35 (d, J = 8.6 Hz, 1 H, Ar), 7.56 (m, 1 H, Ar), 7.66 (m, 1
H, Ar), 7.74 (dd, J = 8.2, J = 0.7 Hz, 1 H, Ar), 8.52 (d, J = 8.1 Hz,
washed with water to give 3-dimethylamino-1-(1Ј-hydroxynaph- 1 H, Ar), 11.38 (s, 1 H, OH), 14.04 (s, 1 H, OH) ppm. 13C NMR
thalen-2Ј-yl)prop-2-en-1-one (6) as a yellow solid (7.51 g, 89%),
(DEPT, 75.5 MHz, CDCl3): δ = 20.6 (CH3), 52.6 (OCH3), 113.3,
113.8 (C), 115.6, 118.4, 124.5 (CH), 125.2 (C), 126.1, 126.9, 127.5,
m.p. 172 °C. 1H NMR (300 MHz, CDCl3): δ = 2.99 (s, 3 H, NCH3),
Eur. J. Org. Chem. 2006, 3638–3644
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3643

B. Appel, S. Rotzoll, R. Kranich, H. Reinke, P. Langer
FULL PAPER
3-formylchromone with amidines, see: c) W. Löwe, Synthesis
1976, 274 and d) U. Petersen, H. Heitzer, Justus Liebigs Ann.
Chem. 1976, 1663; with enamines: e) D. Heber, Synthesis 1978,
691; with hydrazines: f) F. Eiden, H. Haverland, Arch. Pharm.
(Weinheim Ger.) 1968, 301, 819 and g) C. K. Ghosh, K. K.
Mukhopadhyay, J. Indian Chem. Soc. 1978, 55, 386; with
H2NOH·HCl: h) R. P. Hsung, C. A. Zificsak, L.-L. Wei, L. R.
Zehnder, F. Park, M. Kim, T.-T. T. Tran, J. Org. Chem. 1999,
64, 8736; with o-phenylenediamine: i) C. K. Ghosh, S. Khan,
Synthesis 1980, 701. For conversions into pyrroles and thio-
phenes, see: j) A. O. Fitton, J. R. Frost, H. Suschitzky, P. G.
Hougton, Synthesis 1977, 133; for reactions with ketene ace-
tals: k) T. W. Wallace, I. Wardell, K.-D. Li, P. Leeming, A. D.
Redhouse, S. R. Challand, J. Chem. Soc., Perkin Trans. 1 1995,
2293; with dienes: l) A. Sandulache, A. M. S. Silva, J. A. S. Ca-
valeiro, Tetrahedron 2002, 58, 105.
For reactions of 3-formylchromone with C-nucleophiles, see: a)
C. K. Ghosh, S. Khan, Synthesis 1981, 903; b) G. Hass, J. L.
Stanton, A. von Sprecher, P. Wenk, J. Heterocycl. Chem. 1981,
18, 607; c) J. Prousek, Collect. Czech. Chem. Commun. 1991,
1361; d) C. K. Ghosh, C. Bandyopadhyay, S. Biswas, A. K.
Chakravarty, Indian J. Chem., Sect. B 1990, 29, 814; e) C. Ban-
dyopadhyay, K. R. Sur, R. Patra, J. Chem. Res. Synop. 1998,
12, 802.
For a review of 1,3-bis-silyl enol ethers, see: P. Langer, Synthe-
sis 2002, 441.
a) T.-H. Chan, P. Brownbridge, J. Chem. Soc., Chem. Commun.
1979, 578; b) G. A. Molander, K. O. Cameron, J. Am. Chem.
Soc. 1993, 115, 830.
For the activation of chromones towards conjugate addition by
the formation of silylated benzopyrylium triflates, see: a) Y.-G.
Lee, K. Ishimaru, H. Iwasaki, K. Ohkata, K. Akiba, J. Org.
Chem. 1991, 56, 2058. For thiobenzopyrylium triflates, see: b)
U. Beifuss, M. Tietze, H. Gehm, Synlett 1996, 182.
For reactions of benzopyrylium triflates from our laboratory,
see: a) P. Langer, N. N. R. Saleh, I. Freifeld, Chem. Commun.
2002, 168; b) P. Langer, B. Appel, Tetrahedron Lett. 2003, 44,
5133; c) U. Albrecht, M. Lalk, P. Langer, Bioorg. Med. Chem.
2005, 13, 1531; d) S. Rotzoll, B. Appel, P. Langer, Tetrahedron
Lett. 2005, 46, 4057.
130.6 (CH), 131.7 (C), 133.3 (CH), 137.6, 138.9 (C), 163.6, 163.8
(C–OH), 171.8, 203.5 (C=O) ppm. IR (KBr): ν = 3056 (m), 3046
˜
(m), 2957 (m), 1656 (s), 1628 (s), 1601 (s), 1503 (m), 1459 (s), 1417
(m), 1385 (s), 1335 (s), 1275 (s), 1251 (s), 1209 (s), 1145 (m), 1032
(m), 983 (m), 809 (s), 766 (m), 669 cm–1 (w). UV/Vis (CH3CN):
λmax (lgε) = 378 (3.94), 308 (4.08), 298 (4.19), 287 (4.13), 259 (4.66),
217 nm (4.67). MS (EI, 70 eV): m/z (%) 336 (14) [M+], 289 (7), 247
(2), 231 (1), 189 (2), 170 (100), 134 (11), 113 (17), 77 (54), 51 (2).
C20H16O5: calcd. C 71.42 H 4.79; found C 70.96, H 4.44.
Supporting Information (see also the footnote on the first page of
this article): Experimental procedures and spectroscopic data.
Acknowledgments
[11]
We are grateful to Dr. M. Noltemeier for carrying out a crystal
structure analysis and to Simon Backhaus for experimental contri-
butions. Financial support by the Deutsche Forschungsgemein-
schaft, Revotar Biopharmaceuticals AG, the state of Brandenburg
(Ministry of Economics), the European Union and by the state of
Mecklenburg-Vorpommern (Landesforschungsschwerpunkt “Neue
Wirkstoffe und Screeningverfahren”) is gratefully acknowledged.
The content of this publication is the sole responsibility of the au-
thors.
[12]
[13]
[1] For salicylic esters and salicylic glycosides (e.g. salicortin), see
for example: Römpp Lexikon Naturstoffe (Eds.: W. Steglich, B.
Fugmann, S. Lang-Fugmann), Thieme, Stuttgart: 1997.
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[5] H. Langhals, K. Fuchs, Chem. Unserer Zeit 2004, 38, 98, and
references cited therein.
[6] E. Buchta, H. Egger, Chem. Ber. 1957, 90, 2760.
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J.-M. Fang, J. Org. Chem. 1997, 62, 4643.
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[9] For reviews of 3-formylchromone, see: a) G. P. Ellis, Heterocy-
clic Compounds (Ed.: A. Weisberger), 1977, 35, 921; b) C. K.
Ghosh, C. Ghosh, Indian J. Chem., Sect. B 1997, 36, 968.
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Umetani, Y. Sanno, Tetrahedron 1974, 30, 3553; b) W. D. Jones,
W. L. Albrecht, J. Org. Chem. 1976, 41, 706; for cyclisations of
[14]
[15]
[16] CCDC-286226 (for 3b) and -286227 (for 8a) contain the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[17] a) K. Ley, Trends Mol. Med. 2003, 9, 263; b) M. Sperandio, B.
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A. B. Tuzikov, N. V. Bovin, Anal. Biochem. 1996, 238, 184.
[19] T. Delatour, T. Douke, C. D’Ham, J. Cadet, J. Photochem. Pho-
tobiol., B 1998, 44, 191.
Received: February 1, 2006
Published Online: June 7, 2006
3644
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3638–3644