Thiazolium-catalyzed intermolecular Stetter reaction of linear and cyclic alkyl α-diketones

Article abstract of DOI:10.1039/c1ob06480k

An efficient method for the N-heterocyclic carbene (NHC)-catalyzed conjugate addition of acetyl anions to various α,β-unsaturated acceptors (Stetter reaction) has been optimized by using 2,3-butandione (biacetyl) as an alternative surrogate of acetaldehyde. The disclosed procedure proved to be compatible with microwave dielectric heating for reaction time reduction and with the use of different linear α-diketones as acyl anion donors (e.g. 3,4-hexanedione for propionyl anion additions). Moreover, the unprecedented umpolung reactivity of cyclic α-diketones in the atom economic nucleophilic acylation of chalcones is herein presented. Mechanistic aspects of the thiazolium-based catalysis involving linear and cyclic α-diketone substrates are also discussed. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06480k

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PAPER
Thiazolium-catalyzed intermolecular Stetter reaction of linear and cyclic
alkyl a-diketones†
Olga Bortolini, Giancarlo Fantin, Marco Fogagnolo, Pier Paolo Giovannini, Alessandro Massi* and
Salvatore Pacifico
Received 29th August 2011, Accepted 14th September 2011
DOI: 10.1039/c1ob06480k
An efficient method for the N-heterocyclic carbene (NHC)-catalyzed conjugate addition of acetyl
anions to various a,b-unsaturated acceptors (Stetter reaction) has been optimized by using
2,3-butandione (biacetyl) as an alternative surrogate of acetaldehyde. The disclosed procedure proved
to be compatible with microwave dielectric heating for reaction time reduction and with the use of
different linear a-diketones as acyl anion donors (e.g. 3,4-hexanedione for propionyl anion additions).
Moreover, the unprecedented umpolung reactivity of cyclic a-diketones in the atom economic
nucleophilic acylation of chalcones is herein presented. Mechanistic aspects of the thiazolium-based
catalysis involving linear and cyclic a-diketone substrates are also discussed.
acceptors and produces valuable 1,4-dicarbonyl compounds.8
Particular attention has been paid in this work to the conjugate
Introduction
addition of the acetyl anion (MeCO-) due to the relevance of
this simple nucleophile in organocatalytic strategies5 and the
continuous need for improving its generation.9 In the case of
the Stetter reaction, existing methods for the non-enzymatic,10
NHC-catalyzed generation of acetyl anions comprise the use of
acetaldehyde,11 sodium pyruvate12 or acetyldimethylphenylsilane13
as its surrogates (Scheme 1).14 Though operative in both racemic
and asymmetric versions, the first method requires the utilization
of a large excess (10 equiv.) of the volatile acetaldehyde. The
second biomimetic strategy is effective under neutral aqueous
conditions and it has been optimized for the particular class
of unsaturated 2-acyl imidazoles as acceptors. The sila-Stetter
reaction by Scheidt and co-workers is, perhaps, the most effective
and versatile method for the conjugate addition of carbonyl
anions, but in the case of the acetyl anion it requires the synthesis
of its precursor acetyldimethylphenylsilane.15 Herein, we present
the commercially available, inexpensive (ca. € 4/1 g) biacetyl 1
The formation of new carbon–carbon bonds by organocatalyzed
reactions of carbonyl compounds is today a cornerstone of modern
catalysis.1 Surprisingly, however, the number of reports dealing
with the use of a-diketones in organocatalytic approaches is
quite scant in the literature,2 despite the great potential of this
class of substrates.3 a-Diketones are, in fact, highly reactive
compounds bearing a double carbonyl functionality, which allows
them to behave either as an electrophile,2a,b a nucleophile,2c or both
an electrophile and a nucleophile in domino reactions.2d–f The
versatility of a-diketones in organocatalytic strategies is further
demonstrated by their ability to undergo polarity reversal, or
umpolung,4 of the carbonyl functionality under N-heterocyclic
carbene (NHC) catalysis,5 and thus act as acyl anion precursors.
This peculiar behavior of a-diketones was observed in the
early fifties by Mizuhara and Handler, who established that the
thiamine-promoted reaction of 2,3-butanedione (biacetyl) 1 and
acetaldehyde involved scission of biacetyl into two moieties to
form acetoin and acetate.6 This finding, however, was almost
ignored for the next six decades. Recently, we took advantage of
Mizuhara and Handler’s observation and reported the enzymatic7a
and thiazolium-catalyzed7b synthesis of a number of chiral and
achiral a-hydroxyketones by benzoin-type reactions of linear
dialkyl a-diketones. In continuation of our ongoing research in this
field, we present herein our results on the use of alkyl a-diketones
as acyl anion equivalents in a mechanistically related nucleophilic
acylation, that is, the Stetter reaction, which employs conjugate
◦
as a bench stable (bp 88 C), alternative acetyl anion equivalent
for intermolecular Stetter reactions. The unprecedented umpolung
reactivity of cyclic alkyl a-diketones in conjugate additions is also
described to further demonstrate the potential of the proposed
diketone-based carboligation methodology.
Results and discussion
The optimization study of the model reaction of biacetyl 1
with trans-chalcone started by applying the conditions previously
disclosed for the benzoin-type reactions of 1.7b Accordingly, a
1 : 2 mixture of 1 and 2a was suspended in the eco-friendly
polyethylene glycol (PEG400) and treated at room temperature with
a stoichiometric thiamine hydrochloride 3–Et3N couple (Table 1,
entry 1). Disappointingly, the target adduct 7a was isolated
Dipartimento di Chimica, Laboratorio di Chimica Organica, Universita` di
Ferrara, Via L. Borsari 46, I-44121, Ferrara, Italy. E-mail: alessandro.
massi@unife.it; Fax: +39 0532 455183; Tel: +39 0532 455183
† Electronic supplementary information (ESI) available: copies of 1H and
13C NMR spectra for new compounds. See DOI: 10.1039/c1ob06480k
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Table 1 Optimization of the Stetter reaction of biacetyl 1 with trans-
chalconea
Cat.
Entry (mol%) Base (mol%) Solv.
Temp. (◦C) Time (h) Yield (%)b
1
2
3
4
5
6
7
8
3 (100) Et3N (200) PEG400
3 (100) Et3N (200) EtOH
4 (20) Et3N (100) EtOH
5 (20) Et3N (100) EtOH
25
25
25
25
25
25
25
5
24
24
24
24
24
24
24
24
24
24
2
10
55
58
38
6 (20) DBU (20)
4 (20) Et3N (20)
EtOH
THF
< 5
< 5
< 5
20
< 5
69
5 (20) Cs2CO3 (20) THF
4 (20) Et3N (100) i-PrOH 25
4 (20) Et3N (100) t-BuOH 30
4 (20) Et3N (100) EtOH
4 (20) Et3N (100) EtOH
Scheme 1 Direct methods for acetyl anion generation in Stetter reactions
(addition to trans-chalcone as the benchmark).
9
10c
11c
25
50
91
75
12c,d 4 (20) Et3N (100) EtOH 100
in poor yield (10%), very likely because of the heterogeneous
reaction conditions. Indeed, the application of the above procedure
to a homogeneous ethanolic reaction solution resulted in a
higher yield of 7a (55%, entry 2). Notably, formation of acetyl
acetoin (1 self-condensation product) and compounds arising
from conjugate addition of either the nucleophilic thiazolium
species or EtOH were not observed (GC-MS and 1H NMR
analyses) under these conditions. We next focused on developing
a catalytic procedure; thiazolium 4 and 5, and triazolium 6 pre-
catalysts (20 mol%) were screened in combination with suitable
bases (Et3N, DBU, and Cs2CO3) in alcoholic (EtOH, i-PrOH, and
t-BuOH) and aprotic (THF) solvents (entries 3–9; only diagnostic
experiments are reported).16 A higher product yield (58%) was
achieved with a thiazolium 4–Et3N couple in EtOH (entry 3).
The thiazolium derivative 5 was less effective than 4 (entry 4),
while the triazolium 6 pre-catalyst failed to produce the desired
product 7a (entry 5), thus showing the strict dependence of process
efficiency on the stereoelectronic features of the heteroazolium-
derived carbene.17 With regard to the effect of solvent, the results
shown in Table 1 (entries 6–9) demonstrate that utilization of
an amphiprotic solvent is crucial for a successful procedure, in
full agreement with the proposed reaction mechanism (vide infra).
For further optimization, the 1/2a ratio and temperature were
varied (entries 10–11) and the best yield (91%) was achieved with
an excess of diketone 1 (2 equiv.) at 50 ◦C for 24 h (entry 11).
Aiming at decreasing the reaction time, we finally considered
the use of microwave (MW) dielectric heating18 and found the
optimal compromise between product yield (75%) and selectivity
(formation of side-products was detected at temperatures higher
than 70 ◦C) by irradiating the reaction mixture at 100 ◦C for 2 h
(entry 12).
a Reactions performed with 1.00 mmol of 2a (0.5 M) and 0.50 mmol of 1.
b Isolated yield. c Reactions performed with 0.50 mmol of 2a and 1.00 mmol
of 1 (0.5 M). d Microwave-assisted reaction performed with a single-mode
cavity dedicated reactor (Biotage Initiator).
Table 2 Catalytic Stetter reactions of linear dialkyl a-diketones 1 and 8
with different a,b-unsaturated acceptorsa
Entry
R1
R2
R3
R4
Prod.
Yield (%)b
1
2
3
4
Me
Me
Me
Me
Me
Me
Me
Et
Ph
H
H
H
H
H
EtO2C
H
H
H
Ph
Ph
Ph
Ph
Me
7a
7b
7c
7d
7e
7f
7g
9a
9b
9h
91/75
88/72
71/62
82/65
80/—
68/—
58/42
65/51
62/50
55/47
4-BrPh
4-MePh
Me
H
Me
–(CH2)3–
Ph
4-BrPh
4-ClPh
5c
6c
7d,e
8
OEt
d
Ph
Ph
Ph
9
10
Et
Et
H
a Reactions performed with 1.00 mmol of a-diketone (0.5 M) and 0.50
mmol of 2. b Isolated yields (method A/method B). c Reaction performed
at 25 ◦C. d Structure of 2g:
1.
e Reaction performed with 4 equiv. of
was examined by reacting 1 with various a,b-unsaturated car-
bonyl electrophiles 2. Chalcone derivatives having both electron-
withdrawing and electron-donating substituents on the aro-
matic ring gave the corresponding adducts in comparable yields
Under the optimized thermal and MW conditions (methods
A and B, Table 2), the substrate scope of the proposed system
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(88–71%) to those previously reported (entries 2–3).11–13 Notably,
the unprecedented addition to the less reactive alkyl chalcone 2d
resulted almost equally effective (82%, entry 4). Highly activated
substrates such as methyl vinyl ketone 2e and diethyl ethylidene-
malonate 2f could also be used in this transformation by reducing
the reaction temperature (25 ◦C) to minimize the competitive
EtOH addition (entries 5–6). Cyclohexenone 2g was a competent
coupling partner as well, but a higher excess of biacetyl 1 (4 equiv.)
was required to reach a satisfactory reaction conversion (entry 7).
To further validate the versatility of the proposed methodology,
the bis-homologue of 1, that is 3,4-hexanedione 8, was tested
as a propionyl anion equivalent in the nucleophilic acylation of
chalcones 2a,b and 2h. Gratifyingly, the corresponding addition
products 9a,b and 9h were recovered in similar yields (65–55%)
to those obtained by using propionaldehyde as the acyl anion
source.19a
EtOH to the alkoxide II as shown in the transition state TS.
In support of our hypothesis we found that the utilization of the
bulkier and less acidic t-BuOH solvent in the model 1/2a coupling
resulted in no formation of the expected 7a adduct (Table 1,
entry 9).
From the analysis of the proposed reaction mechanism in-
volving linear a-diketones (Scheme 2), the interest of utilizing
their cyclic counterparts in the Stetter reaction becomes apparent
since both carbonyl functionalities of the a-diketone donor
can be maintained. As depicted in Scheme 3, the nucleophilic
attack of EtOH on thiazolium intermediate V would in fact
result in the formation of the Breslow intermediate VI bear-
ing an ester group ready for subsequent product elaboration.20
Hence, the atom economic nucleophilic acylation of trans-
chalcone with 1,2-cyclohexanedione 10 was next investigated
(Table 3).
Mechanistically we propose that the nucleophilic acylation of
a,b-unsaturated acceptors 2 proceeds through the formation of
the intermediate II resulting from the addition of the thiazolin-
2-ylidene I to the a-diketone 1, and its evolution to the Breslow
intermediate III by attack of EtOH to the carbonyl of II with
elimination of ethyl acetate (Scheme 2). Subsequent addition
of the Breslow intermediate to the b-position of the conjugate
acceptor 2 leads to the formation of product 7 and regeneration
of the catalyst I. For the key step of the catalytic cycle (C–C
bond breaking) we postulate an alkoxide-assisted nucleophilic
attack of the amphiprotic solvent involving a proton transfer from
Scheme 3 Proposed reaction pathway for the thiazolium-catalyzed Stetter
reaction of cyclic a-diketones and side tandem Michael–aldol reaction
affording bicycle 12 by-product.
An initial experiment was performed with a 1 : 2 mixture of
10 and 2a in EtOH at room temperature using the optimal
catalytic 4–Et3N couple (entry 1). Under these conditions, the
expected adduct 11a was isolated in poor yield (10%) along with
a major product (38%), which was identified as the diastere-
omeric bicyclo[3.2.1]octan-8-one derivative 12 (d.r. > 19 : 1).21
We supposed that this compound was formed under the basic
reaction conditions through a tandem sequence involving the
initial Michael addition of 10 to chalcone 2a followed by an
intramolecular aldol reaction (Scheme 3).22 Indeed, the above
nucleophilic acylation conducted in the absence of pre-catalyst
4 afforded the bicycle 12 (88%) as the sole reaction product (entry
2).21 After some experimentation (entries 3–6), we could almost
suppress this side-reaction and obtain the target adduct 11a in
Scheme 2 Proposed reaction pathway for the thiazolium-catalyzed Stetter
reaction of linear a-diketones 1 and 8 (substrate 1 as representative
example).
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Table 3 Optimization of the Stetter reaction of 1,2-cyclohexanedione 10
with trans-chalconea
Table 4 Intermolecular Stetter reactions of cyclic a-diketones 10 and 13
with chalconesa
Entry 10/2a 4 (mol%) Base (mol%) Temp. (◦C) 11a + 12 (%)b
1
2
3
4
5
6
7c
1 : 2
1 : 2
1 : 2
1 : 2
1 : 2
2 : 1
1 : 2
20
0
30
20
20
20
100
Et3N (100)
Et3N (100)
DBU (30)
Et3N (50)
Et3N (50)
Et3N (50)
Et3N (50)
25
25
25
25
50
50
100
10/38
—/88
12/39
10/32
67/5
20/32
51/5
Entry
1
Diketone
Chalcone
Product (%)b
10
2a
a Reactions performed with 1.00 mmol of 2a (0.5 M). b Isolated yield.
c Microwave-assisted reaction performed with Biotage Initiator (reaction
time: 2 h).
2
10
10
13
2b
2h
2a
satisfactory 67% yield by warming (50 ◦C) for 24 h a 1 : 2 mixture of
10 and 2a in the presence of catalytic 4 (20 mol%) and a diminished
amount (50 mol%) of Et3N (entry 5). As previously observed,
the use of MW irradiation in the 10/2a coupling shortened the
reaction time (2 h) but slightly lowered the product yield (51%,
entry 7).
Next, the scope and limitations of the Stetter reaction with cyclic
alkyl a-diketones was briefly investigated (Table 4). Satisfactory
yields were obtained under the optimized conditions for the
reaction of 1,2-cyclohexanedione 10 with chalcones 2b and 2h
(entries 2–3). 3-Methylcycopentane-1,2-dione 13 was also tested
as acyl donor in the addition to chalcone 2a (entry 4). Diketone 13
appeared to be less reactive than 10 as a satisfactory yield (48%)
of the diastereomeric adduct 14a (d.r. 1 : 1) could only be achieved
by means of MW irradiation (100 ◦C, 2 h). It is worth noting,
however, that the 13/2a coupling proceeded regioselectively by
a putative preferential attack of thiazolium 4-derived carbene
to the less hindered carbonyl of unsymmetrical diketone 13
(Scheme 3).
3
4c
a Reactions performed with 1.00 mmol of 2 (0.5 M) and 0.50 mmol of
diketone. b Isolated yield. c Microwave-assisted reaction performed with
Biotage Initiator (100 ◦C, 2 h).
Experimental
Reactions were monitored by TLC on silica gel 60 F254 with
detection by charring with phosphomolybdic acid. Flash column
chromatography was performed on silica gel 60 (230–400 mesh).
Bulb-to-bulb distillation was performed with a Bu¨chi Glass
Conclusions
1
In summary, we have demonstrated that biacetyl 1 may be
employed as an effective, bench-stable, inexpensive acetyl anion
equivalent in thiazolium 4-catalyzed Stetter reactions with dif-
ferent a,b-unsaturated acceptors. Detected yields of the corre-
sponding adducts were comparable to those obtained for the same
transformations by known NHC-based methods. In some cases,
the application to our procedure of microwave dielectric heating
significantly increased the chemical efficiency of the addition
process in virtue of a substantial reduction of reaction time.
The method optimized for biacetyl 1 proved to be successful
for 3,4-hexanedione 8 as well, thus offering a novel strategy for
propionyl anion conjugate additions. The unprecedented atom
economic nucleophilic acylation of chalcones with cyclic a-
diketones was finally optimized to furnish 1,4-diketone deriva-
tives displaying a suitably spaced ester functionality in their
structure. Investigations to disclose an asymmetric variant of the
described carboligation reaction are currently underway in our
laboratories.
Oven B-580 apparatus. H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded in CDCl3 solutions at room temperature.
Peaks assignments were aided by 1H-1H COSY and gradient-
HMQC experiments. GC-MS spectra were recorded using a
Varian 4000 GC-MS/MS system equipped with a fused capillary
column Megadex 5 (25 m ¥ 0.25 mm) containing dimethyl-n-
pentyl-b-cyclodextrin on OV 1701. Analyses were carried out
with a gradient of 1.5 C min-1 (from 80 ◦C up to 200 ◦C).
◦
ESI-MS analyses were performed in positive ion mode with
samples dissolved in 10 mM solution of ammonium formate
in 1 : 1 MeCN/H2O. Elemental analyses were performed with
FLASH 2000 Series CHNS/O analyzer (ThermoFisher Scien-
tific). Microwave-assisted reactions were carried out using a single-
mode cavity dedicated reactor (Biotage InitiatorTM). Reactions
were performed with temperature-controlled programs in glass
vials (0.5–2 mL or 2–5 mL depending on the scale) sealed with a
Teflon septum. Temperatures were measured externally by an IR
sensor. The reaction time was counted when the reaction mixture
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reached the stated temperature. Pressure was measured by a non-
invasive sensor integrated into the cavity lid. a-Diketones 1, 8, 10,
and 13, heteroazolium salts 3–6, and unsaturated acceptors 2a and
2d–g are commercially available (Sigma-Aldrich). trans-Chalcones
2b–c and 2h were prepared according to a known procedure.23
Spectroscopic data of compounds 7a,11–13 7b,11 7c,11 7e,11,24 7f,25
7g,26 and 9a19 were identical to those reported in the literature.
132.6, 130.3, 128.9, 128.4, 122.0, 53.5, 42.5, 29.6. ESI MS (330.0):
353.9 (M + Na+). Found: C, 61.78; H, 4.44. C17H15BrO2 requires
C, 61.65; H, 4.56%.
1-Phenyl-3-p-tolylpentane-1,4-dione (7c)
Column chromatography with 12 : 1 cyclohexane–AcOEt afforded
1
7c11 (189 mg, 71%; method A) as a white amorphous solid. H
NMR: d = 8.00–7.90 (m, 2 H, Ar), 7.60–7.50 (m, 1 H, Ar), 7.45–
7.40 (m, 2 H, Ar), 7.18 (s, 4 H, Ar), 4.36 (dd, 1 H, J2b,3 = 4.0 Hz,
J2a,3 = 10.0, Hz, H-3), 3.98 (dd, 1 H, J2a,3 = 10.0 Hz, J2a,2b = 18.0
Hz, H-2a), 3.12 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,2b = 18.0 Hz, H-2b),
2.33 (s, 3 H, CH3), 2.21 (s, 3 H, CH3). 13C NMR: d = 207.8, 198.6,
137.7, 136.8, 135.2, 133.5, 130.1, 128.9, 128.5, 128.4, 53.8, 42.6,
29.5, 21.4. ESI MS (266.1): 305.4 (M + K+). Found: C, 81.29; H,
6.63. C17H18O2 requires C, 81.17; H, 6.81%.
Optimized procedures for the Stetter reaction of linear a-diketones
1 and 8 with conjugate acceptors 2a–h
Method A. To a vigorously stirred mixture of a-diketone 1
or 8 (1.00 mmol), a,b-unsaturated acceptor 2 (0.50 mmol), 3-
benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride 4 (54 mg,
0.20 mmol), in absolute EtOH (2 mL), was added Et3N (139 mL,
1.00 mmol) in one portion. The mixture was warmed at 50 ◦C,
stirred at that temperature for 24 h, and then cooled to room
temperature and concentrated. The residue containing the target
adduct 7 or 9 was purified by either flash chromatography or
bulb-to-bulb distillation. When chalcones 2b and 2h were used as
acceptors, the addition to the reaction mixture of a few drops of
THF was required to obtain a fully homogeneous solution.
3-Methyl-1-phenylpentane-1,4-dione (7d)
Column chromatography with 12 : 1 cyclohexane–AcOEt afforded
7d (156 mg, 82%; method A) as a white foam. IR (film) nmax: 2969,
1712, 1680, 1449, 1355, 1209, 1003, 689 cm-1; 1H NMR: d = 8.00–
7.95 (m, 2 H, Ar), 7.60–7.52 (m,1 H, Ar), 7.50–7.40 (m, 2 H, Ar),
3.54 (dd, 1 H, J2a,3 = 8.0 Hz, J2a,2b = 18.0 Hz, H-2a), 3.32–3.18 (m,
1 H, H-3), 2.94 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,2b = 18.0 Hz, H-2b), 2.24
(s, 3 H, CH3), 1.20 (d, 3 H, J3,Me = 5.5 Hz, CH3). 13C NMR: d =
211.4, 198.5, 136.7, 133.1, 128.5, 128.0, 41.7, 41.6, 28.6, 16.7. ESI
MS (190.0): 213.5 (M + Na+). Found: C, 75.98; H, 6.43. C12H14O2
requires C, 75.76; H, 7.42%.
Method B. A 2.0–5.0 mL process vial was filled with a-
diketone 1 or 8 (1.00 mmol), a,b-unsaturated acceptor 2 (0.50
mmol), 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride
4 (54 mg, 0.20 mmol), and absolute EtOH (2 mL). Then, Et3N
(139 mL, 1.00 mmol) was added in one portion. The vial was
sealed with the Teflon septum and aluminium crimp by using an
appropriate crimping tool. The vial was then placed in its correct
position in the Biotage Initiator cavity where irradiation for 2
h at 100 ◦C was performed. After the full irradiation sequence
was completed, the vial was cooled to room temperature and
then opened. The mixture was concentrated and the residue
containing the target adduct 7 or 9 was purified by either flash
chromatography or bulb-to-bulb distillation. Product yields for
Method B are reported in Table 2.
Hexane-2,5-dione (7e)
◦
The crude reaction mixture was bulb-to-bulb distilled (90 C, 25
mmHg) to give 7e11,24 (91 mg, 80%) as a colorless liquid. Lit:23 bp
88–89 ◦C (25 mmHg). IR (film) nmax: 2915, 1715, 768 cm-1; H
1
NMR: d = 2.68 (s, 4 H, 2 H-2,2 H-3), 2.20 (s, 6 H, 2 CH3). 13C
NMR: d = 207.4, 37.0, 30.0.
1,3-Diphenylpentane-1,4-dione (7a)
Diethyl 2-(3-oxobutan-2-yl)malonate (7f)
Column chromatography with 12 : 1 cyclohexane–AcOEt afforded
7a11 (229 mg, 91%; method A) as a pale yellow oil. 1H NMR: d =
7.99–7.92 (m, 2 H, Ar), 7.58–7.50 (m, 1 H, Ar), 7.49–7.45 (m, 2
◦
The crude reaction mixture was bulb-to-bulb distilled (112 C, 5
mmHg) to give 7f25 (156 mg, 68%) as a colorless liquid. Lit:25 bp
110–120 ◦C (3 mmHg). IR (film) nmax: 2930, 1745, 1720 cm-1; 1H
NMR: d = 4.20 (q, 2 H, J = 7.0 Hz, OCH2CH3), 4.15 (q, 2 H, J =
7.0 Hz, OCH2CH3), 3.74 (d, 1 H, J2,2¢ = 10.0 Hz, H-2), 3.28 (dq, 1
H, J1¢2¢ = 7.0 Hz, J2,2¢ = 10.0 Hz, H-2¢), 2.28 (s, 3 H, CH3), 1.28 (t,
3 H, OCH2CH3), 1.25 (t, 3 H, OCH2CH3), 1.14 (d, 1 H, J1¢2¢ = 7.0
Hz, CH3). 13C NMR: d = 209.6, 168.5, 61.2, 54.4, 45.2, 28.4, 14.0,
13.9, 13.8.
H, Ar), 7.42–7.23 (m, 5 H, Ar), 4.42 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,3
=
10.0, Hz, H-3), 4.00 (dd, 1 H, J2a,3 = 10.0 Hz, J2a,2b = 18.0 Hz,
H-2a), 3.16 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,2b = 18.0 Hz, H-2b), 2.22 (s,
3 H, CH3). 13C NMR: d = 207.6, 198.5, 138.3, 136.8, 133.6, 129.5,
128.9, 128.7, 128.4, 128.0, 54.2, 42.6, 29.5. ESI MS (252.1): 275.5
(M + Na+). Found: C, 80.75; H, 6.22. C17H16O2 requires C, 80.93;
H, 6.39%.
3-(4-Bromophenyl)-1-phenylpentane-1,4-dione (7b)
3-Acetylcyclohexanone (7g)
Column chromatography with 12 : 1 cyclohexane–AcOEt afforded
The crude reaction mixture was bulb-to-bulb distilled (118 ◦C, 0.1
1
7b11 (291 mg, 88%; method A) as a yellow amorphous solid. H
mmHg) to give 7g26 (81 mg, 58%) as a colorless liquid. Lit:26 bp
130 ◦C (0.2 mmHg). IR (film) nmax: 2850, 1710 cm-1; H NMR:
1
NMR: d = 7.95–7.90 (m, 2 H, Ar), 7.60–7.51 (m, 1 H, Ar), 7.50–
7.40 (m, 4 H, Ar), 7.20–7.15 (m, 2 H, Ar), 4.38 (dd, 1 H, J2b,3 = 4.0
Hz, J2a,3 = 10.0, Hz, H-3), 3.95 (dd, 1 H, J2a,3 = 10.0 Hz, J2a,2b = 18.0
Hz, H-2a), 3.12 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,2b = 18.0 Hz, H-2b),
2.20 (s, 3 H, CH3). 13C NMR: d = 207.1, 198.1, 137.2, 136.5, 133.7,
d = 2.94–2.80 (m, 1 H, H-3), 2.54–2.24 (m, 4 H, 2 H-2, 2 H-6),
2.19 (s, 3 H, CH3), 2.14–2.04 and 1.80–1.60 (2 m, 4 H, 2 H-4,
2 H-5). 13C NMR: d = 209.8, 208.1, 50.5, 42.0, 40.5, 28.2, 27.1,
24.5.
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1
1,3-Diphenylhexane-1,4-dione (9a)
661 cm-1; H NMR: d = 7.96–7.90 (m, 2 H, Ar), 7.60–7.50 (m, 1
H, Ar), 7.47–7.40 (m, 2 H, Ar), 7.38–7.20 (m, 5 H, Ar), 4.40 (dd,
1 H, J7,8b = 3.5 Hz, J7,8a = 10.0 Hz, H-7), 4.08 (q, 2 H, J = 7.0 Hz,
OCH2CH3), 4.03 (dd, 1 H, J7,8a = 10.0 Hz, J8a,8b = 18.0 Hz, H-8a),
3.13 (dd, 1 H, J7,8b = 3.5 Hz, J8a,8b = 18.0 Hz, H-8b), 2.70–2.60 and
2.54–2.44 (2 m, 2 H, 2 H-5), 2.25–2.17 (m, 2 H, 2 H-2), 1.65–1.45
Column chromatography with 15 : 1 cyclohexane–AcOEt afforded
1
9a19 (173 mg, 65%; method A) as a colorless oil. H NMR: d =
7.98–7.90 (m, 2 H, Ar), 7.58–7.50 (m, 1 H, Ar), 7.46–7.38 (m, 2
H, Ar), 7.35–7.30 (m, 2 H, Ar), 7.28–7.20 (m, 2 H, Ar), 4.43 (dd,
1 H, J2b,3 = 3.5 Hz, J2a,3 = 10.0 Hz, H-3), 4.05 (dd, 1 H, J2a,3 = 10.0
(m, 4 H, 2 H-3, 2 H-4), 1.22 (t, 3 H, J = 7.0 Hz, OCH2CH3). 13
C
Hz, J2a,2b = 18.0 Hz, H-2a), 3.12 (dd, 1 H, J2b,3 = 3.5 Hz, J2a,2b
=
NMR: d = 208.8, 198.2, 173.4, 138.1, 135.6, 133.2, 129.1, 128.6,
18.0 Hz, H-2b), 2.78–2.60 and 2.58–2.42 (2 m, 2 H, 2 H-5); 1.02 (t,
1 H, J = 7.0 Hz, CH3). 13C NMR: d = 210.2, 198.5, 138.6, 136.9,
133.0, 129.1, 129.0, 128.8, 128.5, 127.1, 53.2, 42.2, 35.0, 7.8. ESI
MS (266.1): 289.4 (M + Na+). Found: C, 81.02; H, 6.01. C18H18O2
requires C, 81.17; H, 6.81%.
128.3, 128.1, 127.6, 60.2, 53.3, 42.4, 41.3, 34.0, 24.3, 23.1, 14.2.
+
ESI MS (366.1): 384.7 (M + NH4 ). Found: C, 75.53; H, 7.39.
C23H26O4 requires C, 75.38; H, 7.15%.
Ethyl 7-(4-bromophenyl)-6,9-dioxo-9-phenylnonanoate (11b)
3-(4-Bromophenyl)-1-phenylhexane-1,4-dione (9b)
Column chromatography with 15 : 1 cyclohexane–AcOEt (con-
taining 5% of dichloromethane) afforded 11b (135 mg, 61%) as
a white foam. IR (film) nmax: 2932, 1729, 1710, 1682, 1486, 1178,
1010, 753, 685 cm-1; 1H NMR: d = 7.96–7.90 (m, 2 H, Ar), 7.60–
Column chromatography with 15 : 1 cyclohexane–AcOEt afforded
9b (213 mg, 62%; method A) as a white foam. IR (film) nmax: 2920,
1708, 1676, 1487, 1200, 1010, 747, 675 cm-1; 1H NMR: d = 7.98–
7.90 (m, 2 H, Ar), 7.60–7.40 (m, 5 H, Ar), 7.20–7.10 (m, 2 H, Ar),
4.40 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,3 = 10.0 Hz, H-3), 4.00 (dd, 1 H,
J2a,3 = 10.0 Hz, J2a,2b = 18.0 Hz, H-2a), 3.13 (dd, 1 H, J2b,3 = 4.0
Hz, J2a,2b = 18.0 Hz, H-2b), 2.73–2.58 and 2.56–2.42 (2 m, 2 H, 2
H-5); 1.02 (t, 1 H, J = 7.0 Hz, CH3). 13C NMR: d = 209.5, 197.9,
137.2, 136.3, 133.3, 132.2, 129.9, 128.5, 128.1, 122.6, 52.3, 42.4,
35.1, 7.8. ESI MS (344.0): 283.9 (M + K+). Found: C, 62.85; H,
5.15. C18H17BrO2 requires C, 62.62; H, 4.96%.
7.40 (m, 5 H, Ar), 7.20–7.10 (m, 2 H, Ar), 4.36 (dd, 1 H, J7,8b
=
3.5 Hz, J7,8a = 10.0 Hz, H-7), 4.10 (q, 2 H, J = 7.0 Hz, OCH2CH3),
4.01 (dd, 1 H, J7,8a = 10.0 Hz, J8a,8b = 18.0 Hz, H-8a), 3.12 (dd, 1
H, J7,8b = 3.5 Hz, J8a,8b = 18.0 Hz, H-8b), 2.70–2.60 and 2.52–2.40
(2 m, 2 H, 2 H-5), 2.34–2.19 (m, 2 H, 2 H-2), 1.70–1.48 (m, 4 H, 2
H-3, 2 H-4), 1.24 (t, 3 H, J = 7.0 Hz, OCH2CH3). 13C NMR: d =
208.4, 197.8, 173.4, 137.0, 136.3, 133.4, 130.0, 19.4, 128.6, 128.4,
128.1, 60.2, 52.6, 42.3, 41.4, 34.0, 24.3, 23.0, 14.2. ESI MS (444.1):
+
462.4 (M + NH4 ). Found: C, 62.29; H, 5.38. C23H25BrO4 requires
C, 62.03; H, 5.66%.
3-(4-Chlorophenyl)-1-phenylhexane-1,4-dione (9h)
Ethyl 7-(4-chlorophenyl)-6,9-dioxo-9-phenylnonanoate (11h)
Column chromatography with 15 : 1 cyclohexane–AcOEt afforded
9c (165 mg, 55%; method A) as a white foam. IR (film) nmax: 2978,
1708, 1676, 1490, 1201, 1015, 748, 661 cm-1; 1H NMR: d = 7.98–
Column chromatography with 15 : 1 cyclohexane–AcOEt (con-
taining 5% of dichloromethane) afforded 11h (138 mg, 69%) as
a white foam. IR (film) nmax: 2939,1729,1716, 1682, 1489, 1179,
1014, 755, 685 cm-1; 1H NMR: d = 7.98–7.90 (m, 2 H, Ar), 7.60–
7.52 (m, 1 H, Ar), 7.50–7.40 (m, 2 H, Ar), 7.35–7.25 (m, 2 H, Ar),
7.22–7.15 (m, 2 H, Ar), 4.38 (dd, 1 H, J7,8b = 3.5 Hz, J7,8a = 10.0
Hz, H-7), 4.10 (q, 2 H, J = 7.0 Hz, OCH2CH3), 3.98 (dd, 1 H,
J7,8a = 10.0 Hz, J8a,8b = 18.0 Hz, H-8a), 3.12 (dd, 1 H, J7,8b = 3.5
Hz, J8a,8b = 18.0 Hz, H-8b), 2.72–2.60 and 2.52–2.40 (2 m, 2 H, 2
H-5), 2.35–2.18 (m, 2 H, 2 H-2), 1.70–1.45 (m, 4 H, 2 H-3, 2 H-4),
1.23 (t, 3 H, J = 7.0 Hz, OCH2CH3). 13C NMR: d = 209.8, 199.1,
174.7, 137.8, 137.6, 134.9, 134.6, 130.9, 130.6, 129.9, 129.3, 61.5,
53.9, 43.6, 42.7, 35.2, 25.5, 24.2, 15.4. ESI MS (401.1): 419.8 (M
7.90 (m, 2 H, Ar), 7.60–7.20 (m, 7 H, Ar), 4.41 (dd, 1 H, J2b,3
4.0 Hz, J2a,3 = 10.0 Hz, H-3), 4.00 (dd, 1 H, J2a,3 = 10.0 Hz, J2a,2b
=
=
18.0 Hz, H-2a), 3.14 (dd, 1 H, J2b,3 = 4.0 Hz, J2a,2b = 18.0 Hz,
H-2b), 2.74–2.58 and 2.57–2.42 (2 m, 2 H, 2 H-5); 1.00 (t, 1 H,
J = 7.0 Hz, CH3). 13C NMR: d = 209.6, 197.9, 136.7, 133.5, 133.3,
132.9, 130.8, 129.6, 129.2, 128.9, 128.6, 128.1, 52.3, 42.4, 35.1,
7.8. ESI MS (300.0): 223.6 (M + Na+). Found: C, 71.59; H, 5.98.
C18H17ClO2 requires C, 71.88; H, 5.70%.
Optimized procedure for the Stetter reaction of cyclic a-diketone
10 with chalcones 2a,b and 2h
+
+ NH4 ). Found: C, 68.77; H, 6.45. C23H25ClO4 requires C, 68.91;
To a vigorously stirred mixture of a-diketone 10 (56 mg, 0.50
mmol), chalcone 2 (1.00 mmol), 3-benzyl-5-(2-hydroxyethyl)-4-
methylthiazolium chloride 4 (27 mg, 0.10 mmol), in absolute EtOH
(2 mL), was added Et3N (35 mL, 0.25 mmol) in one portion. The
mixture was warmed to 50 ◦C, stirred at that temperature for
24h, and then cooled to room temperature and concentrated.
The residue containing the target adduct 11 was purified by
flash chromatography. When chalcones 2b and 2h were used as
acceptors, the addition to the reaction mixture of a few drops of
THF was required to obtain a fully homogeneous solution.
H, 6.29%.
7-Benzoyl-1-hydroxy-6-phenylbicyclo[3.2.1]octan-8-one (12)
A mixture of a-diketone 10 (56 mg, 0.50 mmol), chalcone 2a
(208 mg, 1.00 mmol), Et3N (70 mL, 0.50 mmol), and absolute
EtOH (2 mL) was vigorously stirred at room temperature for 24
h and then concentrated. The resulting residue was eluted from
a column of silica gel with 12 : 1 cyclohexane–AcOEt (containing
5% of dichloromethane) to give 12 (141 mg, 88%) as a single
diastereoisomer. IR (film) nmax: 2928, 1749, 1671, 1447, 1227, 1130,
Ethyl 6,9-dioxo-7,9-diphenylnonanoate (11a)
1
747, 682 cm-1; H NMR: d = 8.10–8.00 (m, 2 H, Ar), 7.60–7.50
Column chromatography with 15 : 1 cyclohexane–AcOEt (con-
taining 5% of dichloromethane) afforded 11a (123 mg, 67%) as
a white foam. IR (film) nmax: 2931, 1748, 1672, 1447, 1227, 746,
(m, 1 H, Ar), 7.45–7.38 (m, 2 H, Ar), 7.35–7.15 (m, 5 H, Ar), 4.26
(d, 1 H, J6,7 = 7.0 Hz, H-6), 3.77 (dd, 1 H, J2a,7 = 1.5 Hz, J6,7 = 7.0
Hz, H-7), 3.28 (s, 1 H, OH), 2.80–2.75 (m, 1 H, H-5), 2.45–2.30
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(m, 2 H, H-3a, H-4a), 2.10–1.80 (m, 2 H, H-3b, H-4b), 1.78–1.45
(m, 2 H, 2 H-2). 13C NMR: d = 197.5, 133.5, 129.5, 129.0, 128.6,
128.3, 126.8, 126.7, 81.2, 59.8, 49.8, 40.8, 40.5, 35.9, 17.2. ESI
MS (320.1): 343.8 (M + Na+). Found: C, 78.49; H, 6.01. C21H20O3
requires C, 78.73; H, 6.29%.
Svennebring, P. Nilsson and M. Larhed, J. Org. Chem., 2007, 72, 5851–
5854; (c) S. Wu, A. Fluxe, J. M. Janusz, J. B. Sheffer, G. Browning, B.
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4 D. Seebach, Angew. Chem., Int. Ed. Engl., 1979, 18, 239–258.
5 For recent reviews, see: (a) K. Hirano, I. Piel and F. Glorius, Chem.
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Chem. Res., 2011, DOI: 10.1021/ar2000716; (c) V. Nair, R. S. Menon,
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Catalysis Series No. 6, Royal Society of Chemistry, Cambridge, 2010;
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6 S. Mizuhara and P. Handler, J. Am. Chem. Soc., 1954, 76, 571–573.
7 (a) P. P. Giovannini, P. Pedrini, V. Venturi, G. Fantin and A. Medici,
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DOI: 10.1039/C1OB05928A.
Ethyl 2-methyl-5,8-dioxo-6,8-diphenyloctanoate (14a)
A 2.0–5.0 mL process vial was filled with a-diketone 13 (56 mg,
0.50 mmol), chalcone 2a (208 mg, 1.00 mmol), 3-benzyl-5-(2-
hydroxyethyl)-4-methylthiazolium chloride 4 (27 mg, 0.10 mmol),
and absolute EtOH (2 mL). Then, Et3N (35 mL, 0.25 mmol) was
added in one portion. The vial was sealed with the Teflon septum
and aluminium crimp by using an appropriate crimping tool. The
vial was then placed in its correct position in the Biotage Initiator
◦
cavity where irradiation for 2 h at 100 C was performed. After
the full irradiation sequence was completed, the vial was cooled to
room temperature and then opened. The mixture was concentrated
and the resulting residue was eluted from a column of silica gel with
15 : 1 cyclohexane–AcOEt (containing 5% of dichloromethane) to
give 14a (88 mg, 48%) as a 1 : 1 mixture of diastereoisomers. IR
(film) nmax: 2935, 1747, 1712, 1673, 1447, 1250, 689 cm-1; 1H NMR:
d = 7.98–7.90 (m, 2 H, Ar), 7.60–7.50 (m, 1 H, Ar), 7.48–7.40 (m, 2
H, Ar), 7.38–7.20 (m, 5 H, Ar), 4.40 (dd, 1 H, J6,7b = 3.5 Hz, J6,7a
10.0 Hz, H-6), 4.15–3.95 (m, 3 H, H-7a, OCH2CH3), 3.14 (dd, 0.5
H, J6,7b = 3.5 Hz, J7a,7b = 18.0 Hz, H-7b(1)), 3.13 (dd, 0.5 H, J6,7b
=
=
8 (a) H. Stetter, Angew. Chem., Int. Ed. Engl., 1976, 15, 639–647;
(b) H. Stetter and H. Kuhlmann, Chem. Ber., 1976, 109, 2890–2896;
(c) H. Stetter and H. Kuhlmann, Org. React., 1991, 40, 407–496. For
recent leading references on intermolecular Stetter reactions, see: (d) T.
Jousseaume, N. E. Wurz and F. Glorius, Angew. Chem., Int. Ed., 2011,
50, 1410–1414; (e) D. A. DiRocco and T. Rovis, J. Am. Chem. Soc.,
2011, 133, 10402–10405; (f) J. M. Um, D. A. DiRocco, E. L. Noey, T.
Rovis and K. N. Houk, J. Am. Chem. Soc., 2011, 133, 11249–11254 and
references therein.
3.5 Hz, J7a,7b = 18.0 Hz, H-7b(2)), 2.72–2.60 and 2.57–2.44 (2 m,
2 H, 2 H-4), 2.40–2.30 (m, 1 H, H-2), 1.98–1.62 (m, 2 H, 2 H-3),
1.19 (t, 1.5 H, J = 7.0 Hz, OCH2CH3), 1.15 (t, 1.5 H, J = 7.0 Hz,
OCH2CH3), 1.10 (d, 1.5 H, J2,Me = 7.0 Hz, CH3), 1.04 (d, 1.5 H,
J2,Me = 7.0 Hz, CH3). 13C NMR: d = 208.6, 198.1, 176.2, 176.1,
137.9, 136.4, 133.2, 129.1, 128.6, 128.3, 128.1, 127.6, 127.7, 60.2,
60.1, 53.3, 53.2, 42.4, 39.2, 39.1, 38.6, 38.5, 27.9, 17.1, 16.8, 14.2.
9 For a recent study, see: M. Y. Jin, S. M. Kim, H. Han, D. H. Ryu and
J. W. Yang, Org. Lett., 2011, 13, 880–883.
+
ESI MS (366.2): 384.5 (M + NH4 ). Found: C, 75.45; H, 7.01.
C23H26O4 requires C, 75.38; H, 7.15%.
10 For an enzymatic study on the 1,4-addition activity of pyruvate and for
leading references on this topic, see: C. Dresen, M. Richter, M. Pohl, S.
Lu¨deke and M. Mu¨ller, Angew. Chem., Int. Ed., 2010, 49, 6600–6603.
11 S. M. Kim, M. Y. Jin, M. J. Kim, Y. Cui, Y. S. Kim, L. Zhang, C.
E. Song, D. H. Ryu and J. W. Yang, Org. Biomol. Chem., 2011, 9,
2069–2071.
Acknowledgements
We gratefully acknowledge the University of Ferrara (Progetto
FAR 2010) and the Italian Ministry of University and Sci-
entific Research (Progetto FIRB Chem-Profarma-Net Grant
RBPR05NWWC 008) for financial support. Thanks are also
given to Mr. Paolo Formaglio for NMR experiments and to Mrs.
Ercolina Bianchini for elemental analyses.
12 M. C. Myers, A. R. Bharadwaj, B. C. Milgram and K. A. Scheidt, J.
Am. Chem. Soc., 2005, 127, 14675–14680.
13 A. E. Mattson, A. R. Bharadwaj, A. M. Zuhl and K. A. Scheidt, J.
Org. Chem., 2006, 71, 5715–5724.
14 In general, known classes of acyl anion sources are aldehydes, pyru-
vates, acylsilanes, and benzoins themselves. Very recently, the umpolung
reactivity of Michael acceptors has also been reported: (a) A. T. Biju,
M. Padmanaban, N. E. Wurz and F. Glorius, Angew. Chem., Int. Ed.,
2011, 50, 4812–8415; (b) B.-C. Hong, N. S. Dange, C.-S. Hsu, J.-H. Liao
and G.-H. Lee, Org. Lett., 2011, 13, 1338–1341.
Notes and references
15 Acetyldimethylphenylsilane is also commercially available from Olym-
chemical Ltd (Chunquan Rd. Pudong, Shanghai, 201203-People’s
Republic of China).
1 (a) A. Berkessel and H. Gro¨ger, in Asymmetric Organocatalysis: From
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Int. Ed., 2008, 47, 4638–4660; (c) D. Enders and A. A. Narine, J.
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2 For representative examples, see: (a) S. Samanta and C.-G. Zhao,
Tetrahedron Lett., 2006, 47, 3383–3386; (b) V. Nair, S. Vellalath, M.
Poonoth, R. Mohan and E. Suresh, Org. Lett., 2006, 8, 507–509; (c) D.
Ding and C.-G. Zhao, Tetrahedron Lett., 2010, 51, 1322e–1325; (d) M.
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Fro¨hlich, Chem.–Eur. J., 2010, 16, 4173–4176.
16 As previously observed (see ref. 7b), the use of catalytic thiamine–
hydrochloride 3 (20 mol%) resulted in a sluggish nucleophilic addition.
17 The stereoelectronic preference for thiazolium-derived carbenes (in
contrast to triazolium or imidazolium derived carbenes) has been
observed several times when alkyl acyl anion equivalents are used.
For a discussion on this topic, see: (a) C. S. P. McErlean and A. C.
Willis, Synlett, 2009, 233–236 and Ref. 8a,c and 11. The stereoelectronic
differences between thiazolium, triazolium and imidazolium derived
carbenes have recently been reviewed: (b) T. Dro¨ge and F. Glorius,
Angew. Chem., Int. Ed., 2010, 49, 6940–6952.
18 For a previous study on the MW-accelerated addition of aldehydes to
a,b-unsaturated ketones, see: J. S. Yadav, K. Anuradha, B. V. S. Reddy
and B. Eeshwaraiah, Tetrahedron Lett., 2003, 44, 8959–8962.
3 Selected examples for the application of a-diketones in organic
synthesis: (a) S. Liu and C. Wolf, Org. Lett., 2007, 9, 2965–2968; (b) A.
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19 (a) W. S. Weiner, R. M. Slade, Y. I. Klimova, R. J. Walton and
M. B. Anderson, U.S. Pat. Appl. Publ., 20080249158, 2008; (b) D.
W. Custar, H. Le and J. P. Morken, Org. Lett., 2010, 12, 3760–
3763.
20 In a similar vein, the asymmetric intermolecular Stetter reaction of gly-
oxamides with alkylidenemalonates reported by Rovis and co-workers
produces a-ketoamide products, which can be further functionalized
to give useful intermediates. Q. Liu, S. Perreault and T. Rovis, J. Am.
Chem. Soc., 2008, 130, 14066–14067.
our laboratories and they will be the object of a forthcoming
publication.
22 For the asymmetric Lewis base-catalyzed domino Michael/aldol
reaction of 1,2-cyclohexanedione with a,b-unsaturated aldehydes, see
Ref. 2d.
23 W. S. Murphy and S. Wattansin, Synthesis, 1980, 647–650.
24 A. Treibs and K. Hintermeier, Chem. Ber., 1954, 87, 1163–1166.
25 T. Sakai, T. Katayama and A. Takeda, J. Org. Chem., 1981, 46, 2924–
2931.
21 The assignment of the relative stereochemistry of bicyclo 12 and
its enantioselective synthesis are currently under investigation in
26 R. Ballini, M. Petrini, E. Marcantoni and G. Rosini, Synthesis, 1988,
231–233.
8444 | Org. Biomol. Chem., 2011, 9, 8437–8444
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