Comparison of convenient alternative synthetic approaches to 4-[(3-tert-butyldimethylsilyloxy)phenyl]-4-methoxyspiro[1,2-dioxetane-3, 2′-adamantane]

Article abstract of DOI:10.1055/s-2006-942357

The preparation of 4-(3-tert-butyldimethylsilyloxyphenyl)-4-methoxyspiro[1, 2-dioxetane-3,2′-adamantane] by two different approaches is described and the results are compared with previously reported data. The precursor olefin, 1-[3-(tert-butyldimethylsilyloxy)phenyl]-1-methoxy-2-spiroadamantylidene is obtained from 3-hydroxybenzaldehyde by both Horner-Wadsworth-Emmons and McMurry coupling reactions in 42% overall yield in both cases. 1,2-Dioxetane preparation by singlet oxygen addition, obtained through calcium peroxide diperoxohydrate thermolysis, is compared with conventional photooxygenation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942357

PAPER
1781
Comparison of Convenient Alternative Synthetic Approaches to 4-[(3-tert-Bu-
tyldimethylsilyloxy)phenyl]-4-methoxyspiro[1,2-dioxetane-3,2¢-adamantane]
A
lternative Syn
r
thetic
A
p
i
proach
c
es toa 1,2-
k
D
ioxetane Leite Bastos,a Luiz Francisco Monteiro Leite Ciscato,a Dieter Weiss,b Rainer Beckert,b Wilhelm Josef Baader*a
a
Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes, 748, Bl 12S, 05508-900 São Paulo, SP, Brazil
Fax +55(11)30912371; E-mail: wjbaader@iq.usp.br
b
Institut für Makromolekulare Chemie und Organische Chemie, Friedrich-Schiller-Universität, Humboldtstraße 10, 07743 Jena, Germany
Received 25 November 2005; revised 17 January 2006
O
O
O
O
Abstract: The preparation of 4-(3-tert-butyldimethylsilyloxyphe-
nyl)-4-methoxyspiro[1,2-dioxetane-3,2¢-adamantane] by two dif-
ferent approaches is described and the results are compared with
previously reported data. The precursor olefin, 1-[3-(tert-butyldi-
methylsilyloxy)phenyl]-1-methoxy-2-spiroadamantylidene is ob-
tained from 3-hydroxybenzaldehyde by both Horner–Wadsworth–
Emmons and McMurry coupling reactions in 42% overall yield in
both cases. 1,2-Dioxetane preparation by singlet oxygen addition,
obtained through calcium peroxide diperoxohydrate thermolysis, is
compared with conventional photooxygenation.
O
O
deprotection
– PG
X
X
X: O, S, C
PG: Protecting Group
PG
O
O
O
+
+ hν
Key words: 1,2-dioxetanes, chemiluminescence, cross-coupling
reactions, singlet oxygen, CIEEL
X
Scheme 1 Chemiluminescence of aromatic spiroadamantyl-substi-
tuted 1,2-dioxetanes
Chemiluminescence is used in clinical research to mea-
sure enzymes expressed by reporter genes, cellular lumi- cleavage
with
concomitant
chemiexcitation
(Scheme 1).2,3,5 Examples of efficient chemiluminescent
substrates are 3-(4-methoxyspiro{1,2-dioxetane-3,2¢-tri-
cyclo[3.3.1.13,7]decan}4-ylphenyl phosphate (AMP-
PD®), CSPD®, and CDP-Star®, which are sensitive to the
presence of 10–21 mol of alkaline phosphatase in solution.1
nescence, blotted proteins (Western blotting), and nucleic
acids (Northern and Southern blotting).1 The most impor-
tant chemiluminescent approach for analytical and bio-
technological purposes is the detection of horseradish
peroxidase (HRP) and alkaline phosphatase labels. Al-
though luminol is the most used chemiluminescent sub-
strate for HRP, 1,2-dioxetanes are widely used for the
detection of alkaline phosphatase in enzyme immuno-
assays.1,2
The tert-butyldimethylsilyl analogue of AMPPD, 4-(3-
tert-butyldimethylsilyloxyphenyl)-4-methoxyspiro[1,2-
dioxetane-3,2'-adamantane] (1), is the most often used
model compound for investigating the mechanism for
chemical generation of singlet excited states.6–9 This com-
pound is obtained by [2+2] cycloaddition of singlet
1,2-Dioxetanes containing simple alkyl or aryl substitu-
ents are normally quite unstable compounds and decom-
pose thermally into two carbonyl fragments, one of which oxygen to 1-[3-(tert-butyldimethylsilyloxy)phenyl]-1-meth-
is the electronically excited triplet state.3 As an alternative oxy-2-spiroadamantylidene (2a), performed in most cases
to thermal decomposition, the generation of singlet excit- by photooxidation. This approach can be used either as a
ed states can be achieved by a chemically initiated elec- method to prepare 1 or as a singlet oxygen probe. As this
tron exchange luminescence (CIEEL) mechanism. The reaction is sensitive to 1O2 at a concentration of 10–12 M,
CIEEL approach was originally proposed by Schuster4 for this oxidant is trapped in the form of the stable dioxetane
diphenoyl peroxide and is well documented, in its in-
tramolecular variation, for aryl 1,2-dioxetanes containing
electron rich substituents.5
1 and quantified by the chemiluminescence signal, trig-
gered by the addition of TBAF.10,11
In this paper, olefin 2a is obtained by both Horner–Wads-
There are some structural similarities between designed worth–Emmons and McMurry coupling reactions, both
1,2-dioxetanes and bioluminescent substrates, such as
firefly luciferin, including an energy source, a fluoro-
phore, and a trigger group.2 A specific chemical agent or
enzyme can trigger the formation of a negatively charged
aryl intermediate capable of transferring one electron to
the peroxidic bond, which results in 1,2-dioxetane ring
starting from 3-hydroxybenzaldehyde. Next, the prepara-
tion of the 1,2-dioxetane 1 is performed with singlet oxy-
gen generated by calcium peroxide diperoxohydrate
thermolysis and by conventional photooxygenation.6,12–15
The results obtained are analyzed and compared with lit-
erature data. This comparison appears to be valuable since
1 is an important model compound in studies related to
chemiexcitation and due to the recent use of spiroadaman-
tyl-substituted olefins as selective traps for singlet oxy-
gen.
SYNTHESIS 2006, No. 11, pp 1781–1786
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Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-942357; Art ID: M07905SS
© Georg Thieme Verlag Stuttgart · New York

1782
E. L. Bastos et al.
PAPER
Although most 1,2-dioxetanes are thermally labile com- vanadium(V) oxide and hydrogen peroxide with metha-
pounds, a high degree of stabilization can be obtained by nol–water as solvent and hydrogen perchlorate as cata-
the introduction of large substituents, e.g. spiroadamantyl lyst.24,25 The proposed mechanism for this transformation
and isopropyl groups, onto the peroxidic ring.16–18 Steri- postulates the formation of a complex between vanadi-
cally hindered and spiro-substituted olefins can be pre- um(V) oxide and hydrogen peroxide that reacts with the
pared by several methods; including dehydration, hemiacetal formed from the aromatic aldehyde 5 and
McMurry, and Horner–Wadsworth–Emmons couplings methanol in acidic conditions.26 This method provides a
(Scheme 2).6,15,19–21
high-yielding, one-step alternative to the conventional
transformation.
O O
O
O
H
O
H
i
90%
[Lit.38 99%]
OTBDMS
OH
OPiv
1
5
6
97%
75–89% (3)
O
P
vii
ii
[Lit.24 96%]
[Lit.12 99%]
EtO
OEt
Horner–Wadsworth–
Emmons
O
O
O
+
O
O
O
O
2a R = TBDMS
b R = Piv
OPiv
OR
3
OH
OPiv
7
8
McMurry
83%
91%
[Lit.22 94%]
viii
iii
[Lit.12 90%]
O
O
O
+
OEt
O
O
O
P
OEt
OTBDMS
O
4
OTBDMS
Scheme 2 Retrosynthetic pathways for the preparation of 1
OPiv
4
3
The Horner–Wadsworth–Emmons approach requires the
phosphonate 3, which can be obtained in three steps start-
ing from 5 (Scheme 3).14 The phenolic aldehyde 5 is first
converted into the corresponding pivaloyl (Piv) ester by
base-catalyzed esterification of pivaloyl chloride. Next,
under acid conditions, 3-formylphenyl pivalate (6) reacts
with trimethylorthoformate to give the corresponding ac-
etal 8, which, in the presence of triethyl phosphite and bo-
ron triflouride etherate as a Lewis acid catalyst, gives 3-
[(diethoxyphosphoryl)(methoxy)methyl]phenyl pivalate
(3). Olefin 2b is obtained by the reaction between the
phosphate-stabilized carbanion, derived from the reaction
of 3 with butyl lithium, and 2-adamantanone in 53–65%
yield after purification. The pivaloyl spiroadamantyl ole-
fin 2b is converted into the tert-butyldimethylsilyl ana-
logue 2a by reaction with sodium ethoxide, followed by
microwave-assisted protection as the TBDMS ether in the
absence of solvent.22 It is important to note that in addition
to the stability of the pivaloyl protecting group in acidic
media, it can be converted effortlessly into several other
protecting groups, including the phosphate present in
AMPPD.13,15,23
39–48% (6)
53–65% (3)
[Lit.12 67%]
ix
iv
[Lit.19 41–59%]
O
O
v
95%
OPiv
2b
TBDMSO
2a
10 21%]
I: 50–76% (3) [Lit.
II: 52–58% (3)
vi
O O
O
TBDMSO
1
Scheme 3 Synthesis of 1 by McMurry (left) and Horner–Wads-
worth–Emmons (right) routes. Reagents and conditions: (i) PivCl,
Et3N, CH2Cl2, r.t.; (ii) p-TsOH, HC(OEt)3, MeOH; (iii) P(OEt)3,
BF3·OEt2, CH2Cl2, –55 °C; (iv) n-BuLi, 2-adamantanone, THF, –78
°C; (v) a) NaOEt, EtOH; (b) TBDMSCl, microwave 90/180 W, 2 min;
(vi) I) O2, PPh3, hn, 3 h, CH2Cl2; II) CaO2·2H2O2, THF, r.t., 5 h; (vii)
V2O5, H2O2, MeOH–H2O (9:1), 2 h; (viii) TBDMSCl, microwave 90/
180 W, 2 min; (ix) TiCl3, Et3N, LiAlH4, 2-adamantanone, THF, 5 h.
Numbers in parenthesis indicate the number of repetitions. Yields of
a representative literature reference are given.
The alternative route to 2a is based on the McMurry keto
ester cross-coupling reaction (Scheme 3).13,19 Ester prepa-
ration is based on the conversion of 5 into 3-hydroxyben-
zoic acid methyl ester (7) using a combination of
Synthesis 2006, No. 11, 1781–1786 © Thieme Stuttgart · New York

PAPER
Alternative Synthetic Approaches to a 1,2-Dioxetane
1783
The reaction of 7 with tert-butyldimethylsilyl chloride TBAF solution, which results in a characteristic blue
(TBDMSCl), in the presence of imidazole under micro- chemiluminescence emission due to induced dioxetane
wave irradiation, results in the formation of 3-(tert-bu- decomposition.
tyldimethylsilyloxy)benzoic acid methyl ester (4) in high
Large amounts of calcium peroxide diperoxohydrate (4–
13 equiv) are required to generate sufficient amounts of
yields.22 The conversion of 4 into the hindered olefin 2a is
performed by a McMurry low-valent titanium keto ester
singlet oxygen to provide complete conversion of the ole-
cross-coupling reaction.21,27–29 Ti(0) is obtained by reduc-
fin to 1.35 The amount of calcium peroxide diperoxohy-
drate necessary for complete conversion depends on the
tion of Ti(III) chloride by lithium aluminum hydride in the
presence of triethylamine. Despite the fact that low-valent
solvent used and requires the physical quenching con-
titanium can also be obtained by reduction of titanium(IV)
stants of singlet oxygen by the specific organic substrate
chloride with zinc, the coupling yields obtained with the
to be known.35 As such data are not available for several
latter method in our laboratory are significantly lower
compounds, including compound 2a, a large excess of
calcium peroxide diperoxohydrate was used (55 equiv).
The obtained raw conversion yields of 1, before chro-
matographic purification, indicate that one mol of calcium
(15%). After refluxing for five hours in THF the starting
material was completely consumed and an aqueous work-
up led to the formation of 2a as a light-yellow oil in 39–
48% yields after purification.
peroxide diperoxohydrate is able to convert approximate-
The precursors for the coupling reactions are prepared in ly 0.02 mol of olefin 2a into the 1,2-dioxetane under the
yields comparable to those previously reported (Scheme described experimental conditions.
3), with exception of step ii, which was performed three
times with yields varying from 75–89% (Lit. 99%). Olefin
2a was synthesized in an excellent 95% yield from 2b,
whereas the maximum yield from benzoyl 4, after six at-
The yields for the preparation of 1,2-dioxetane 1 obtained
by both oxygenation methods are comparable (Scheme 3)
and in some cases proved to be considerably higher than
those reported in the literature for photooxygenation (9–
tempts was 48%, compared to 59% previously reported
21%).6,27,36
(Scheme 3).11 Interestingly, both approaches result in the
In conclusion, we have shown that hindered olefins,
which can be converted into thermally stable spiroada-
mantyl-1,2-dioxetanes, can be obtained in similar yields
preparation of olefin 2a in 42% overall yield.
1,2-Dioxetane 1 is obtained by traditional photo-
oxidation30,31 using home-made apparatus cooled to –78 °C
(42%) by both McMurry and Horner–Wadsworth–Em-
(a Schlenk flask with a glass tube adapted to the cap to al-
mons coupling reactions. Nevertheless, the McMurry ap-
low O2 bubbling). This apparatus was surrounded by two
proach is two steps shorter and seems to be operationally
500 W halogen lamps and the whole apparatus was pro-
simpler, since the precursor ester can be obtained directly
tected with a polycarbonate shield. Dry oxygen was bub-
from an aromatic aldehyde and protection steps can be
bled through a solution of 2a and tetraphenylporphyrin in
performed using solvent free microwave-assisted synthe-
anhydrous dichloromethane and irradiated for approxi-
sis. We also have shown here that the use of calcium per-
mately three hours. After chromatographic purification, 1
oxide diperoxohydrate as an alternative source of singlet
oxygen is adequate to produce the CIEEL-active dioxet-
was isolated as a pale-yellow oil in 50–76% yield.
Contrarily to unstable 1,2-dioxetanes,32 the purification of ane 1, which was obtained in yields comparable to that ob-
1 can be achieved by low-temperature flash silica gel col- served using photooxygenation in this work, and indeed
umn chromatography.32–34 However, we obtained good are much higher than those previously reported in the lit-
yields even by room-temperature radial chromatography, erature.
due to reduced elution periods. The purity of 1, as deter-
mined by 1H NMR spectroscopy, is greater than 98% in all
cases, with decomposition products being the only detect-
able impurities.
All reactants were purchased at the highest available purity and
were used without purification, unless otherwise stated. Solvents
were purified and dried as described by Armarengo and Perrin.37
Bulb-to-bulb distillations were made using a Kugelrohr apparatus
(Büchi Glass Oven B-580). A Samsung 6730W (900 W) microwave
oven was employed. Radial chromatography was performed with a
Calcium peroxide diperoxohydrate (CaO2·2H2O2) repre-
sents an environmentally friendly, clean solid source of
singlet oxygen.35 This reactant has already been used in
the preparation of bis(adamantylidene)-1,2-dioxetane,
1
Harrison Research Chromatotron apparatus Model 8924. The H
and 13C NMR spectra were obtained in CDCl3 using TMS as inter-
however, its application to the synthesis of 1,2-dioxetanes nal reference on a Bruker AC-200F or a Varian Innova 300 at 25 °C.
Mass spectra were obtained on a CG-MS Hewlett-Packard 5890/
to produce induced chemiluminescence (CIEEL active
5988. FTIR spectra were recorded with a Bruker Vector 22 spectro-
photometer.
1,2-dioxetanes) is new. The peroxide is added to the olefin
in anhydrous THF at room temperature; after stirring for
approximately five hours, 1 was isolated in 58% yield af-
ter chromatographic purification. THF is the solvent of
choice as it results in higher conversion/yields, compared
to other organic solvents.35 The reaction is followed by
TLC until the reagent was completely consumed. Visual-
ization of 1 is achieved easily by addition of a dilute
3-Formylphenyl Pivalate (6)38
To a stirred solution of 3-hydroxybenzaldehyde (2.0 g, 16 mmol)
cooled to 0 °C, Et3N (19 mmol) in CH2Cl2 (2.7 mL) and pivaloyl
chloride (2.1 mL, 17 mmol) were added dropwise under an argon at-
mosphere. After 15 min, the solution was allowed to warm to ambi-
ent temperature and stirred at this temperature for 2 h. The solution
was acidified and then extracted with CH2Cl2 (3 × 50 mL). The or-
Synthesis 2006, No. 11, 1781–1786 © Thieme Stuttgart · New York

1784
E. L. Bastos et al.
PAPER
ganic layer was dried over anhyd MgSO4, and the resulting brown
oil was filtered through a short column of silica (10 cm, CH2Cl2).
The filtrate was concentrated to give 2.97 g (14.4 mmol, 90%) of 6
as a light-yellow oil.
phy (silica; hexanes–EtOAc, 5:1) to give 187 mg (0.53 mmol, 53%)
of 2b as a light-yellow viscous oil.
IR (neat): 2900, 2838, 2658, 2640, 2624, 1748, 1655, 1600, 1575,
1475, 1270, 1110 cm–1.
IR (neat): 2964, 1745 (C=O, ester), 1690 (HC=O), 1598, 1582,
1475, 1234, 1132, 1105 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.36 [s, 9 H, (CH3)3], 7.24–8.01
(m, 4 H, ArH), 10.01 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 27.4, 38.4, 121.4, 126.7, 127.4,
129.7, 137.9, 151.9, 174.3, 191.0.
1H NMR (200 MHz, CDCl3): d = 1.21 [s, 9 H, (CH3)3], 1.72–2.01
(m, 12 H, adamantane), 2.44 (br s, 1 H, adamantane), 2.65 (br s, 1
H, adamantane), 3.34 (s, 3 H, OCH3), 6.91–7.34 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 28.4, 31.6, 32.8, 37.5, 38.4, 39.2,
57.3, 110.5, 117.8, 120.8, 123.2, 129.1, 130.9, 143.7, 151.3, 174.3.
3-Hydroxybenzoic Acid Methyl Ester (7)24
3-(Dimethoxymethyl)phenyl Pivalate (8)12
H2O2 (60%, 40 mL) and V2O5 (235 mg, 3.2 mmol) were cooled to
0 °C. The mixture was stirred for ca. 20 min until V2O5 had com-
pletely dissolved to give a reddish-brown solution. In another flask,
HClO4 (70%; 4 mL, 49.6 mmol) was added to a solution of 3-hy-
droxybenzaldehyde (15.3 g, 125 mmol) in MeOH–H2O (9:1, 400
mL). After 10 min, the solution containing the aldehyde was poured
into the V2O5/H2O2 solution, and the resulting reaction mixture was
stirred until all the benzaldehyde had been consumed (TLC, ca. 3 h).
The solution was concentrated under vacuum to ca. 10 mL and
EtOAc (300 mL) was added. The organic layer was washed with a
cold sat. solution of NaHCO3 (2 × 50 mL) and water (2 × 50 mL),
until all the peroxide was extracted. The organic layer was dried
over MgSO4, the solvent was evaporated under vacuum, and the res-
idue was purified by column chromatography (silica; hexanes–
EtOAc, 16:1) to give 18.5 g (121.2 mmol, 97%) of 7 as a light-
brown solid.
To a stirred solution of p-TsOH (800 mg, 3.1 mmol) and 3-
formylphenyl pivalate (1.85 g, 8.97 mmol) in anhyd MeOH (25
mL), HC(OEt)3 (1.0 mL, 9.15 mmol) was added dropwise and the
resulting solution was stirred for ca. 14 h. Thereafter, NaHCO3 (500
mg) was added under stirring and the resulting mixture was filtered.
The filtrate was concentrated under vacuum (water bath tempera-
ture 40 °C) to give a slightly yellow oil, which was filtered through
a short column of silica under N2 (4 cm, CH2Cl2). The filtrate was
concentrated under vacuum to give 2.02 g (7.98 mmol, 89%) of 8 as
a light-yellow oil.
IR (neat): 2980, 2824, 1748 (C=O), 1606, 1588, 1478, 1235, 1145,
1110, 1055 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.34 [s, 9 H, (CH3)3], 3.31 (s, 6 H,
OCH3), 5.48 [s, 1 H, CH(OCH3)2], 6.98–7.36 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 27.4, 38.4, 53.1, 112.2, 118.8,
120.7, 124.3, 129.1, 137.7, 151.3, 174.3.
IR (CHCl3): 3302, 2952, 1717, 1598, 1455, 1296, 892, 829 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.93 (s, 3 H, OCH3), 5.81 (br s, 1
H, OH), 7.04–7.52 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 50.1, 117.3, 120.2, 122.1, 130.1,
133.5, 162.1, 168.0.
3-[(Diethoxyphosphoryl)(methoxy)methyl]phenyl Pivalate (3)12
To a solution of 3-(dimethoxymethyl)phenyl pivalate (1.23 g, 4.87
mmol) in anhyd CH2Cl2 (50 mL) was added P(OEt)3 (809 mg, 4.87
mmol). The mixture was stirred at 25 °C under an argon atmosphere
for ca. 5 h. Then the mixture was cooled to –55 °C and freshly dis-
tilled BF3·OEt2 (1.8 mL, 5.0 mmol) was added dropwise over 30
min, stirring was continued. After 2 h, all the starting material was
consumed (TLC), and the reaction mixture was allowed to warm to
5 °C. After stirring for an additional 5 h, the reaction mixture was
poured into distilled H2O (100 mL), and extracted with Et2O (3 × 50
mL). The organic layer was dried over MgSO4 and the solvent was
evaporated under reduced pressure; the residue was purified by col-
umn chromatography (silica; hexanes–EtOAc, 3:1) to give 1.45 g
(4.04 mmol, 83%) of 3 as a light-yellow oil.
3-(tert-Butyldimethylsilyloxy)benzoic Acid Methyl Ester (4)22
A round bottom flask, containing 7 (7.5 g, 49.3 mmol), TBDMSCl
(10 g, 65 mmol), and imidazole (10.0 g, 147 mmol) was placed in a
beaker surrounded by vermiculite. The reaction mixture was heated
by microwave irradiation for 2 min at 90 W. Once the heating cycle
was complete, two phases formed inside the flask. After a cooling
period (1 min), the reaction mixture was heated again at 180 W until
the phenol was completely consumed (TLC). The product was pu-
rified by bulb-to-bulb distillation under reduced pressure, without
an intermediate extraction step, resulting in 11.9 g (44.8 mmol,
91%) of 4 as a light-yellow oil; bp 125–128 °C (2 mmHg); Rf = 0.88
(silica; hexanes–EtOAc, 5:2).
IR (neat): 2974, 1745, 1603, 1584, 1475, 1272, 1253 (P=O), 1135,
1110, 1050, 1020, 960 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.14–1.30 (m, 6 H, CH2CH3), 1.33
[s, 9 H, (CH3)3], 3.36 (s, 3 H, OCH3), 3.98–4.16 (m, 4 H, CH2CH3),
4.52 [d, J = 15.8 Hz, 1 H, CHOMe), 7.02–7.31 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 14.8, 27.4, 38.4, 58.1, 62.6, 76.1,
118.8, 120.7, 124.3, 129.1, 132.7, 151.3, 174.3.
1H NMR (200 MHz, CDCl3): d = 0.19 [s, 6 H, Si(CH3)2], 0.97 [s, 9
H, C(CH3)3], 3.89 (s, 3 H, OCH3), 6.99–7.64 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = –4.4, 18.3, 25.8, 51.9, 120.1,
122.2, 122.8, 129.1, 131.3, 155.6, 168.2.
MS: m/z calcd for C14H22O3Si (M+): 266.1338; found: 266.1397.
Anal. Calcd for C14H22O3Si: C, 63.12; H, 8.32. Found: C, 63.21; H,
8.40.
1-(3-Phenylpivaloyl)-1-methoxy-2-spiroadamantylidene (2b)12
In a vacuum-flamed round-bottom flask, 3 (359 mg, 1.0 mmol) in
anhyd THF (50 mL) was cooled to –78 °C and n-BuLi (1.6 M, hex-
anes; 625 mL, 1.0 mmol) was added dropwise with stirring. The re-
action mixture was allowed to warm to ambient temperature and
stirring continued for 1 h. The mixture was cooled to 0 °C and a so-
lution of 2-adamantanone (151 mg, 1.0 mmol) in anhyd THF (5 mL)
was added dropwise. The reaction mixture was allowed to warm to
ambient temperature and stirring was continued for 2 h. The reac-
tion mixture was then washed with H2O (2 × 100 mL) and the or-
ganic phase was dried over MgSO4. After evaporation of the
solvent, the residue (280 mg) was purified by column chromatogra-
1-[3-(tert-Butyldimethylsilyloxy)phenyl]-1-methoxy-2-spiro-
adamantylidene (2a)
Method I
To a solution of 2b (187 mg, 0.38 mmol) in anhyd EtOH (25 mL) a
freshly prepared solution of NaOEt (1 M, EtOH; 500 mL) was add-
ed. After stirring at r.t. for 2 h, an aq solution of HCl (0.1 M; 1 mL)
was added and the mixture was extracted with Et2O (2 × 50 mL).
The organic layer was dried over MgSO4, and the solvent was evap-
orated under vacuum to give 128 mg (0.36 mmol) of 1-(3-hydroxy-
phenyl)-1-methoxy-2-spiroadamantylidene as
a white solid.
Synthesis 2006, No. 11, 1781–1786 © Thieme Stuttgart · New York

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Alternative Synthetic Approaches to a 1,2-Dioxetane
1785
TBDMSCl (67.5 mg, 0.45 mmol) and imidazole (50.4 mg, 0.74
mmol) were added to the white solid. The mixture was heated by
microwave irradiation for 2 min at 90 W. Once the heating cycle
was complete, two phases had formed inside the flask. After a cool-
ing period (1 min), the reaction mixture was heated again at 180 W
until the phenol was completely consumed (TLC). The reaction
mixture was cooled to r.t. and extracted with Et2O (3 × 15 mL). The
organic layer was dried over MgSO4 and the solvent was evaporated
under vacuum. The residue was purified by radial chromatography
(silica; heptane–EtOAc, 3:1) to give 192 mg (0.50 mmol, 97%) of
2a as a light-yellow oil.
mantane), 3.01 (s, 1 H, adamantane), 3.21 (s, 3 H, OCH3), 6.85–7.28
(m, 4 H, ArH).
13C NMR (75 MHz, CDCl3): d = –4.4, 18.3, 25.7, 25.9, 26.1, 31.5,
31.6, 31.9, 32.9, 34.7, 36.5, 37.8, 49.9, 95.5, 112.1, 119.5, 121.6,
123.2, 129.3, 136.2, 155.7.
Acknowledgment
Financial support for this work has been provided by Fundação de
Amparo à Pesquisa do Estado de São Paulo (FAPESP; 00/06652-0,
01/07477-0), Coordenação de Aperfeiçoamento de Pessoal de Nível
Superior (CAPES), and Deutscher Akademischer Austauschdienst
(DAAD).
Method II19
A suspension of LiAlH4 (2 M, THF; 50 mL, 100 mmol) was added
to a stirring solution of TiCl3 (29.3 g, 190 mmol) in anhyd THF at
0 °C under an argon atmosphere. The greenish-black mixture was
allowed to warm to r.t. and Et3N (16.8 mL, 120 mmol) was added.
The resulting mixture was refluxed for 30 min and a solution of 4
(5.0 g, 18.8 mmol) and 2-adamantanone (3.38 g, 22.5 mmol) in an-
hyd THF (50 mL) was added dropwise over ca. 25 min. After re-
fluxing for 5 h, the reaction mixture was cooled to r.t., and poured
into H2O (100 mL). H2O (100 mL) and Et2O (100 mL) were added
to the emulsion, the phases were separated, and the aqueous phase
was extracted with EtOAc (3 × 50 mL). The combined organic lay-
ers were dried over MgSO4, the solvent was evaporated under vac-
uum, and the residue was purified by radial chromatography (silica;
heptane–EtOAc, 3:1) to give 4.4 g (9.0 mmol, 48%) of 2a as a light-
yellow oil.
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