Application of the intramolecular isomerisation - Aldolisation from allylic alcohols and allylic silyl ethers to the synthesis of indanones and indenones

Article abstract of DOI:10.1002/chem.200700613

A new access to indanones was discovered through a one-step nickel or iron-mediated transposition of 2-hydroxyisobenzofurans. Starting from the corresponding silylenol ethers, a new one-pot tandem isomerisation-Mukaiyama aldol process was also developed. These versatile strategies will be useful for the preparation of various types of indanones and indenones.

Full text of DOI:10.1002/chem.200700613

DOI: 10.1002/chem.200700613
Application of the Intramolecular Isomerisation–Aldolisation from Allylic
Alcohols and Allylic Silyl Ethers to the Synthesis of Indanones and Indenones
Julien Petrignet,[a] Thierry Roisnel,[b] and RenØ GrØe*[a]
Abstract: A new access to indanones was discovered through a one-step nickel or
iron-mediated transposition of 2-hydroxyisobenzofurans. Starting from the corre-
sponding silylenol ethers, a new one-pot tandem isomerisation–Mukaiyama aldol
process was also developed. These versatile strategies will be useful for the prepa-
ration of various types of indanones and indenones.
Keywords: aldol reactions · allylic
alcohols · indanones · indenones ·
iron · nickel
Introduction
Indanones and indenones are important classes of com-
pounds in organic chemistry as these structural motifs are
found in various types of natural compounds. Representa-
tive examples include the indenone 1, isolated from the
fruits of Verola sebifera,[1] indanones 2a and 2b which
belong to the family of pterosins, known for their cytotoxic
and antibacterial activities,[2] and compound 3 isolated from
the cyanobacterium Lyngbya majuscula.[3] In addition, these
structures can play an important role in medicinal chemistry.
Various drugs or pharmaceutical candidates contain these
indanone or indenone skeletons, such as donepezil hydro-
chloride (Aricept) 4 used for the treatment of Alzheimerꢀs
disease,[4] (+)-indacrinone 5 (with antihypertensive activi-
ty),[5] or indenone 6, a structural analogue of the selective
COX-2inhibitor nimesulid.
Because of the importance of such structures, various
methods for their preparation have been reported in the lit-
erature recently. These methods include the synthesis of
substituted indanones by intramolecular Friedel–Crafts reac-
tions,[7] by using rhodium,[8] and also by photochemical[9] and
[6]
microwave-assisted Nazarov cyclizations.[10] On the other
hand, preparation of indenones have been achieved by clas-
sical Friedel–Crafts reactions,[11] by reaction of diaryl propy-
nones in superacidic media,[12] or by using various metal-
mediated reactions,[13] as well as palladium-based catalysts.[14]
In particular, the Heck–Larock annulation, starting from o-
halobenzaldehydes and alkynes afforded various substituted
indenones in good yields.[14b–e] More recently, ring-closing
metathesis (RCM) was also successfully employed in order
to prepare various indenols, indenones and indanones.[15]
Our group has developed a tandem isomerisation–aldoli-
sation reaction, in which an allylic alcohol 7 was isomerised
by a transition-metal catalyst (Fe, Ru, Rh, Ni) to an enol in-
termediate which was trapped in situ by aldehydes to give
aldol products 8 (Scheme 1).[16] Thereby, we now extend this
approach to an intramolecular process in order to prepare
type B indanones, starting from isobenzofuran precursors A.
These aldol products, with the appropriate R2 substituents,
[a] J. Petrignet, Dr. R. GrØe
Synth›se et Electrosynth›se Organiques CNRS UMR 6510
UniversitØ de Rennes 1, Avenue du GØnØral Leclerc
35042Rennes Cedex (France)
Fax : (+33)223-236-978
E-mail: rene.gree@univ-rennes1.fr
[b] Dr. T. Roisnel
Centre de DiffractomØtrie X, Sciences Chimiques de Rennes
CNRS UMR 6226 UniversitØ de Rennes 1
Avenue du GØnØral Leclerc
35053 Rennes Cedex (France)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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Table 1. Direct isomerisation–aldolisation of the 12–12’ mixture.[a]
should be easily transformed into type C indenones by cro-
tonisation reactions (Scheme 2).
Entry
Catalyst (%)[a]
t [h]
Yield [%][b]
Ratio[c]
1
[Fe(CO)5] (10), hn
5] (20), hn
0
22
232
20
65:35
60:40
2[Fe(CO)
3
4
A
N
5
70
80:20
80:20
A
N
20
[a] Reaction conditions: 12 (0.62mmol) in THF (1 mL) was irradiated in
the presence of [Fe(CO)5] or was added to a solution of [NiCl2(dppe)],
ACHTREUNG
LiBHEt3 and MgBr2 in THF (1 mL). [b] Isolated yield. [c] trans/cis ratio.
Scheme 1. A tandem isomerisation–aldolisation reaction.
As summarised in Table 1, the mixture of 12 and 12’ was
reacted with iron and nickel catalysts to afford the expected
indanones in variable yields. Indeed with iron catalysts, 13
was obtained only in low yields (entries 1 and 2), although
all the starting material was consumed after 2h of irradia-
tion. In the case of the nickel catalyst, yields increased sig-
nificantly by using 20 mol% of catalyst (entry 4) instead of
5 mol% (entry 3), whilst 20 h were required to complete the
reaction. Moreover, the nature of catalyst did not change
significantly the trans/cis diastereoisomeric ratio for inda-
1
none 13. This ratio was established by H NMR spectrosco-
py based upon the 3J coupling constants between CHOH
and CHCH3 which were 3.8 Hz for 13 trans, in agreement
with literature,[18] and 6.7 Hz for 13 cis. Moreover, conforma-
tion that the reaction is under kinetic control can be found
by the fact that each aldol is stable under the reaction condi-
tions.
Scheme 2. Strategy for indanone synthesis through the intramolecular iso-
merisation–aldolisation.
Results and Discussion
From early studies it has been demonstrated that the iron-
mediated isomerisation of allylic alcohols involved p-allyl
complexes as key intermediates[19] and this was confirmed
recently by spectroscopical evidence[20] and by high-level
computational studies.[21] In the case of nickel hydride medi-
ated reactions, experimental and computational studies were
strongly in favour of a deprotonation–b-elimination–1,4-ad-
dition mechanism.[16e] For this intramolecular reaction, the
starting material existed as a mixture of the closed form 12
and the open form 12’. Based on previous mechanistic data,
the nickel hydride catalyst should be active essentially on
the minor open form 12’. This could explain the longer reac-
tion time, due to a slow interconversion between 12 and 12’.
On the other hand, the iron catalyst could react on both
forms affording the two possible intermediates 12a and 12’a.
This reaction became faster but afforded lower yields in 13.
A possible explanation could be that the closed form of the
enol 12a would be unstable under the reaction conditions
(light and heating) used for the iron carbonyl-mediated re-
action and afforded mainly degradation products
(Scheme 4).
The isobenzofuran 12 was selected as the first model in the
study of the feasibility of this intramolecular tandem isomer-
isation–aldolisation reaction and we chose the most appro-
priate catalysts. The derivative 12 was prepared in three
steps by starting with o-phthalaldehyde 9, which was mo-
noprotected with propan-1,3-diol in presence of PTSA to
afford acetal 10 in 74% yield.[17] Addition of vinylmagnesi-
um bromide to the remaining aldehyde gave allylic alcohol
11 in 66% yield and the acid hydrolysis of the acetal func-
tion afforded the expected compound in a 54% yield.
1H NMR spectroscopy in CDCl3 demonstrated that the iso-
benzofuran 12 was a 60:40 mixture of diastereoisomers, in
equilibrium with the open form, aldehyde 12’ (ꢀ10%,
Scheme 3).
These preliminary results were encouraging, but an alter-
native strategy was considered for the preparation of these
indanones. Taking into account the tentative mechanism in-
dicated in Scheme 4, it appeared attractive to stabilise the
intermediate 12a. Therefore, the hydroxyl group of 12 was
protected with a tert-butyldimethylsiloxy ether (TBS). Start-
ing from the mixture of 12 and 12’ in presence of TBSCl,
the isobenzofuran 14 was obtained exclusively in a closed
form and in 83% yield. This intermediate was reacted with
Scheme 3. a) Propan-1,3-diol (1 equiv), PTSA, toluene, reflux 6 h, 74%;
b) vinylmagnesium bromide (1.2equiv), THF, 0 8C, 2h, 66%; c) PTSA,
THF/H2O, 80 8C, 16 h, 54%; d) see Table 1. PTSA=p-Toluenesulfonic
acid.
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R. GrØe et al.
catalyst. No purification of intermediate 15 was necessary
and aldol 13 was efficiently obtained from 14 in an 88%
yield.
With this optimised catalytic process in hand, it appeared
of interest to extend this method to the preparation of more
substituted indanones. In a first step, type 17 isobenzofurans
in which the R1 group is different from hydrogen were se-
lected. For that purpose, the cross-metathesis reaction (CM)
starting from 12 and 14, with different alkenes and by using
Grubbs second-generation catalyst,[23] appeared the reaction
of choice for the introduction of various R1 substituents
(Scheme 6).
Scheme 4. Influence of equilibrium on the direct isomerisation–aldolisa-
tion reaction.
each of the catalysts used in Table 1. In both cases, the iso-
merised compound 15 (characterized by NMR spectroscopy)
was obtained in excellent yield (83 and 88%). However, the
(E/Z) diastereoisomeric ratio and reaction time changed ac-
cording to the catalyst: 20 h were necessary to have a com-
plete conversion to 15 with nickel hydride, whereas the reac-
tion was achieved in only 1 h by using [Fe(CO)5]
(Scheme 5).
Scheme 6. Chain extension by using
a cross-metathesis reaction and
access to substituted indanones 18 (R1: see Tables 3 and 4).
In these reactions, yields of 17 varied mainly according to
the alkene partner: by using styrene 16a, methyl acrylate
16b, or 1-octene 16c, alkenes 17a’–17c were obtained in
yields between 43 and 70% (Table 3, entries 1–4), whereas
Scheme 5. a) TBSCl (2equiv), imidazole (2.1 equiv), CH 2Cl2, RT, 16 h,
83%; b) 10% [Fe(CO)5], hn, THF, 1 h, 90% (ratio 55:45), c) 10%
[NiHCl(dppe)]/MgBr2, THF, 20 h, 88% (ratio 80:20), d) see Table 2.
A
TBS=tert-Butyldimethylsilylchloride.
Table 3. Cross-metathesis reaction of 12 or 14 with various alkenes.[a]
Entry
R
R1
Product 17
Yield [%][b]
At this stage it was expected, by analogy with the Mu-
kaiyama reaction,[22] that deprotection of the TBS motif
could afford directly aldol 13. This was performed by using
tetrabutylammonium fluoride (TBAF) in THF and by lower-
ing the temperature; this afforded a significant improvement
in yield: reaction at À788C afforded indanone 13 in an ex-
cellent yield (88%, Table 2, entry 3). Furthermore, it is
1
H
Ph (16a)
17a’
17a
17b
17c
17d
17e
61
44
43
70
22
27
2TBS
Ph (
TBS
TBS
TBS
TBS
16a)
3
4
5
6
CO2Me (16b)
C6H13 (16c)
AHCTREUNG
AHCTREUNG
[a] Reaction conditions: isobenzofuran 12 or 14 (1 equiv), alkene 16 (2–
10 equiv) and Grubbs catalyst (5%) were heated at 408C in CH2Cl2 over-
night. [b] Isolated yield.
Table 2. Tandem deprotection–aldolisation of 15.[a]
Entry
T [8C]
t [h]
Yield [%][b]
Ratio[c]
82:18
5-hexenylacetate 16d and 16e[24] afforded the corresponding
isobenzofurans 17d–e in lower yields (entries 5 and 6).
1
20
3
20
1
À78
1
60
1
55
84:16
88
77:23
The direct isomerisation–aldolisation, starting from com-
pound 17a’ in presence of iron pentacarbonyl, was not only
slow (4 h were necessary to consume all the starting materi-
al) but afforded aldol 18a in only a 17% yield as a 70:30
mixture of diastereoisomers (Table 4, entry 1). This was in
agreement with the results obtained previously with com-
pounds 12–12’ (Table 1, entries 1 and 2). Therefore, the one-
pot isomerisation/Mukaiyama procedure was employed with
the other substituted isobenzofurans. Under these reaction
conditions, starting from 17a, the same indanone 18a was
obtained in a good yield (77%, entry 2). Acceptable yields
[a] Reaction conditions: TBAF (0.42mmol) and 15 (0.38 mmol) were
stirred in THF (1 mL). [b] Isolated yield. [c] trans/cis ratio. TBAF=tetra-
butylammonium fluoride.
worth noting that the diastereoisomeric ratio of vinyl ether
15 had no influence on the selectivity of this Mukaiyama-
type reaction. The same trans/cis ratio for indanone 13 was
obtained by starting either from the 55:45 or from the 80:20
mixture of enol ethers 15. Finally, this reaction has been per-
formed in a one-pot process with iron pentacarbonyl as the
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Intramolecular Isomerisation–Aldolisation
FULL PAPER
Table 4. Isomerisation–aldolisation with substituted isobenzofurans 17.[a]
In a next step, it also appeared of interest to prepare inda-
nones 27 with a quaternary centre at the 2-position and
therefore to extend this reaction to type 26 isobenzofurans
(Scheme 9). Such derivatives can be prepared in one step by
Entry R1
t [h][c] Product 18 Yield [%][d] Ratio[e]
1[b]
2Ph (
3
4
5
6
Ph (17a’)
4
3
1
1
4
3
18a
18a
18b
18c :38
–
17
77
59
4262
0
70:30
72:28
77:23
17a)
CO2Me (17b)
C6H13 (17c)
T
–
H
18e
40
82:18
[a] Reaction conditions: 17 (1 equiv) in THF was irradiated in the pres-
ence of [Fe(CO)5] (10%) until disappearance of the starting material was
observed. After cooling to À788C and addition of TBAF (1.1 equiv), the
solution was stirred 1 h. [b] Direct aldolisation. [c] Time necessary for
conversion of 17 into isomerised compound. [d] Isolated yield. [e] trans/
cis ratio.
Scheme 9. Formation of indanones 27 with a quaternary centre at the 2-
position (Z and R2: see Table 5).
were also obtained with the methyl ester (entry 3) or the ali-
phatic chain (entry 4). The presence of an acetate group in
the chain completely inhibited the reaction and only the
starting material was recovered after 4 h of irradiation (17d,
entry 5). Nevertheless, changing this protecting group by a
p-methoxybenzyl substituent allowed us to obtain the corre-
sponding indanone in a 40% yield (entry 6). Whatever the
nature of the R1 substituent, these indanones were obtained
as a 3:1 to 4:1 mixture of trans/cis isomers.
The stereochemistry of these compounds has been estab-
lished by using NMR spectroscopy, by analogy with the data
of indanone 13. Moreover, a lactonisation reaction was per-
formed by starting from the mixture of diastereoisomeric in-
danones 18b. The cis isomer was transformed quantitatively
into the lactone 19, which was separated from the remaining
trans-aldol 18b (Scheme 7).
a Morita–Baylis–Hillman reaction between o-phthalalde-
hyde 9 and an activated alkene.[25] By using this methodolo-
gy, isobenzofurans 26a–c (Z=H, R2 =COMe, CO2Me, CN)
were easily synthesised.
In addition, the isobenzofuran 26d, with two methoxy
groups on the aromatic ring, was prepared in five steps from
6-bromoveratraldehyde 22. After acetalisation to 23 in 85%
yield, the remaining bromide underwent a halogen–metal
exchange reaction with n-butyllithum and the intermediate
was condensed with dimethylformamide to afford aldehyde
24 in an 80% yield. The dialdehyde 25, obtained after hy-
drolysis of the acetal function (93% yield), was converted
into isobenzofuran 26d in an excellent yield by using the
Morita–Baylis–Hillman conditions (Scheme 10). NMR spec-
Scheme 7. Lactonisation of cis indanone 18b. Conditions: PTSA, CH2Cl2,
reflux, 1 h, quantitative.
Scheme 10. a) Methyl orthoformate (1.1 equiv), PTSA, MeOH, reflux,
2 4 h, 85%; b)nBuLi (1.5 equiv), À788C, then DMF (2equiv), À788C to
08C, 1 h, 80%; c) PTSA, THF/H2O, 80 8C, 4 h, 93%; d) methyl acrylate
(3 equiv), DABCO (1 equiv), dioxane/H2O, RT, 16 h, 95%. DABCO=
These aldols were excellent intermediates for the synthe-
sis of the corresponding indenones. By starting from the dia-
stereoisomeric mixtures of 13 or 18a, activation of the hy-
droxyl function by a mesyl group and b-elimination with
DBU afforded in a one-pot process the indenones 20 and 21
in excellent yields (86 and 97%, respectively, Scheme 8).
1,4-Diazabicyclo[2.2.2]octane.
A
troscopic data indicated that these intermediates 26 were
mostly in the cyclised form with only a small amount (2–
10%) of the open form.
Subsequently, we investigated the direct isomerisation–al-
dolisation of these compounds with iron pentacarbonyl cata-
lyst.[26] Although no reaction was observed when R2 was a
methyl ketone[27] (Table 5, entry 1), a quantitative yield of
indanone 27b was obtained when R2 was a methyl ester
(entry 2). A good yield was also obtained when the elec-
tron-withdrawing group was a nitrile (entry 3). In addition,
the presence of methoxy groups on the aromatic ring did
Scheme 8. Conditions: MsCl (1.5 equiv), triethylamine (1.5 equiv),
CH2Cl2, 08C, 1 h then DBU (1.1 equiv), RT, 1 h, overall yield 86–97%.
DBU=1,8-Diazabicyclo[5.4.0]undec-7-ene, MsCl=mesyl chloride.
A
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R. GrØe et al.
Table 5. Direct isomerisation–aldolisation of Morita–Baylis–Hillman ad-
Taking in account the structure of biologically active inda-
nones, it also appeared of interest to undertake the substitu-
tion of the hydroxyl group of aldols 27 by an aromatic
group by means of Friedel–Crafts reactions. Different sol-
vents and Lewis acid were employed and the best results
were obtained by using the system developed by the group
of Kotsuki: substitution of the corresponding mesylate by an
aromatic donor system in the presence of trifluoromethane-
sulfonic acid (TfOH, Scheme 12).[29] Under these conditions,
ducts 26.[a]
Entry
Z
R2
Indanone 27
Yield [%][b]
Ratio[c]
1[d]
2
3
H
H
H
OMe
COMe (26a)
CO 2Me (26b)
CN (26c)
–
0
98
65
90
–
27b
27c
27d
80:20
50:50
85:15
4
CO2Me (26d)
[a] Reaction conditions: isobenzofuran 26 (1 equiv) was irradiated in the
presence of [Fe(CO)5] (5%) for 1 h in THF. [b] Isolated yield. [c] cis/
trans ratio. [d] Only starting material was recovered.
not affect the reaction as product 27d was also obtained in a
very good yield (entry 4).
Except in the case of nitrile, diastereoisomeric ratios in in-
danones were comparable to those obtained with previous
models. The major diastereoisomer of compound 27d gave
single crystals suitable for X-ray analysis,[28] allowing us to
establish unambiguously a cis relationship between the ester
and the OH (Figure 1). Therefore, the stereochemistry of in-
Scheme 12. Functionalisation of 27 by Friedel–Crafts reactions. Condi-
tions: a) MsCl (1.5 equiv), Et3N (1.5 equiv), CH2Cl2, 08C to RT, 16 h;
b) TfOH (0.1 equiv), benzene, 808C, 16 h or trimethoxybenzene
(1.5 equiv), TfOH (0.1 equiv), dichloroethane, 808C, 16 h.
aldol 27b reacted with benzene and trimethoxybenzene to
afford the corresponding arylindanones 28a and 28b in
moderate yields (Table 6, entries 1 and 2). By starting from
Table 6. Friedel–Crafts reactions starting from aldols 27.
Entry
Z
X
Indanone 28
Yield [%][a]
Ratio[b]
1
H (27b)
27b)
OMe (27d)
H
OMe
OMe
28a
28b
28c
40
50
68
63:37
68:32
70:30
2 H (
3
[a] Isolated yield. [b] trans/cis ratio.
Figure 1. ORTEP representation of major indanone 27d (C14H16O6,
H2O).
aldol 27d, the reaction with trimethoxybenzene afforded ar-
ylindanone 28c in a better yield (entry 3).
The trans/cis diastereoisomeric ratio of arylindanones 28
was around 3:1 in every case. This stereochemistry was es-
tablished by H NMR spectroscopy, based on the known up-
danones 27b was determined by analogy of their NMR
spectroscopic data with those of 27d.
1
Itꢀs worthy noting that the hydrolysis of aldol 27b, under
acidic conditions, afforded directly indenone 20 by a one-
pot reaction (Scheme 11). This could be a useful alternative
field displacement of the methyl ester signals by an aromatic
group in a cis position to the ester (3.12ppm for 28a cis
compared to 3.78 ppm in the case of 28a trans).[30]
Conclusion
We have extended the tandem isomerisation–aldolisation re-
action of allylic alcohols to intramolecular systems and it is
noteworthy that this process occurred just as well when the
starting molecules were found essentially in the closed lactol
form. Furthermore, we have demonstrated that it was possi-
ble to develop the analogous tandem isomerisation–Mu-
kaiyama aldol reaction by starting from allylic silyl ethers.
These two processes have introduced a new and versatile
synthesis for various types of indanones and indenones,
Scheme 11. Hydrolysis of aldol 27b. Conditions: H+/H2O, DMSO, 1508C,
7 h, 70%.
for the synthesis of indenones as 20 was obtained, by this
route, in only three steps and with a 63% overall yield from
phthalaldehyde 9.
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Intramolecular Isomerisation–Aldolisation
FULL PAPER
with 10% of aldehyde as determined by 1H NMR spectroscopy). M.p.
50–528C; 1H NMR (500 MHz, CDCl3): d=3.80 (d, J=7.8 Hz, 1H; OH),
3.90 (d, J=7.2Hz, 1H; O H), 5.25 (dd, J=16.0, 10.1 Hz, 2H; CH=CH2),
5.46 (d, J=6.5 Hz, 1H; CHCH=CH2), 5.46 (dd, J=16.0, 7.0 Hz, 2H;
CH=CH2), 5.77 (d, J=7.5 Hz, 1H; CHCH=CH2), 5.84 (ddd, J=10.0, 7.5,
7.0 Hz, 1H; CHCH=CH2), 6.00 (ddd, J=10.0, 7.5, 6.5 Hz, 1H; CHCH=
CH2), 6.47 (d, J=8.0 Hz, 1H; CHOH), 6.56 (d, J=7.3 Hz, 1H; CHOH),
7.17–7.20 (m, 2H; Har), 7.36–7.45 (m, 6H; Har), 10.1 ppm (s, 1H, CHO);
13C NMR (75 MHz, CDCl3): d=84.1 (CHCH=CH2), 84.5 (CHCH=CH2),
100.9 (CHOH), 101.1 (CHOH), 116.6 (CHCH=CH2), 117.4 (CHCH=
CH2), 121.8, 121.9, 123.0, 123.1, 128.3, 129.5 (CHar), 137.1 (CHCH=CH2),
138.7 (CHCH=CH2), 138.8, 138.9, 141.2, 141.3 ppm (Car); HRMS (EI,
70 eV): m/z: calcd for C10H10O2: 162.0681 [M]+; found: 162.0685
(2ppm); elemental analysis calcd (%) for C 10H10O2: C 74.06, H 6.21;
found: C 74.20, H 6.26.
useful intermediates in the preparation of bioactive natural
products and their structural analogues. This new transposi-
tion from sugar-type molecules into carbocycles is under
active study in our group.
Experimental Section
General methods: All reactions were carried out under an argon atmos-
phere. TLC spots were examined under UV light and revealed by sulphu-
ric acid–anisaldehyde or phosphomolybdic acid. Chemicals were from
commercial suppliers and were used without further purification. Silica
gel (60 AC.C 40–63 mm by SDS) was used for column chromatography.
Dichloromethane, benzene, and toluene were distilled from calcium hy-
dride, THF was distilled from sodium/benzophenone and methanol was
distilled over magnesium. The NMR spectroscopic data were obtained at
2,3-Dihydro-3-hydroxy-2-methylinden-1-one (13):
A solution of com-
pound 14 (105 mg, 0.380 mmol) and [Fe(CO)5] (3 mL, 0.019 mmol) in
THF (2mL) was irradiated with a Philip HPK 125 W for 1 h. After cool-
ing the solution to À788C, tetrabutylammonium fluoride (420 mL,
0.418 mmol, 1m solution in THF) was added dropwise and then the tem-
perature was allowed to rise to 08C over 1 h. The reaction mixture was
hydrolised with water (5 mL) and extracted with Et2O (3”10 mL). The
combined organic phases were washed with brine (10 mL), dried over
MgSO4, filtered and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel by using pentane/
EtOAc 60:40 as the eluent to afford an inseparable mixture of diastereo-
isomeric indanones 13 as a colourless oil (trans/cis 77:23 as determined
1
300 or 500 MHz for H NMR and 75 MHz for 13C NMR. Chemical shifts
are given in parts per million (d) relative to the solvent residual peak. El-
emental analyses and mass spectral analyses were performed at the
Centre RØgional de Mesures Physiques de l’Ouest (CRMPO), Rennes.
CAUTION: all reactions involving [Fe(CO)5] have to be carried out
under a well-ventilated hood. These iron carbonyl-mediated reactions
have been performed by using the usual pyrex glassware equipment.
General experimental procedures:
2-(1,3-Dioxan-2-yl)benzaldehyde (10): A solution of o-phthalaladehyde 9
(16.7 g, 125 mmol), propan-1,3-diol (9.0 mL, 125 mmol) and p-toluenesul-
fonic acid (235 mg, 1.25 mmol) in toluene (150 mL) was heated under
reflux with Dean–Stark apparatus for 6 h. After this time, the reaction
mixture was quenched with a saturated solution of sodium carbonate
(10 mL) and water (90 mL), decanted and the aqueous layer was extract-
ed with ether (3”50 mL). The combined organic phases were washed
with brine (50 mL), dried over MgSO4 and concentrated. Distillation
under reduced pressure afforded the aldehyde 10 as a pale-yellow liquid
(b.p.[15] =180–1818C, 18.2g, 74%). The spectral data were in agreement
with the literature.[17]
1
1
by H NMR spectroscopy, 54 mg, 88%). H NMR (300 MHz, CDCl3): d=
1.28 (d, J=7.6 Hz, 3H; CH3, cis), 1.40 (d, 3H, J=7.3 Hz; CH3, trans),
2.43 (d, J=7.1 Hz, 1H; OH, cis), 2.52 (dq, J=7.3, 3.8 Hz, 1H; CHCH3,
trans), 2.80 (dq, J=7.6, 6.7 Hz, 1H; CHCH3, cis), 2.98 (d, J=6.6 Hz, 1H;
OH, trans), 4.85 (dd, J=6.6, 3.8 Hz, 1H; CHOH, trans), 5.30 (dd, J=7.1,
6.7 Hz, 1H; CHOH, cis), 7.38–7.44 (m, 2”1H; Har, cis + trans), 7.58–
7.69 ppm (m, 2”3H; Har, cis + trans); 13C NMR (75 MHz, CDCl3): d=
10.2( CH3 cis), 12.9 (CH3, trans), 46.7 (CHCH3, cis), 53.4 (CHCH3, trans),
70.7 (CHOH, cis), 76.5 (CHOH, trans), 123.3, 123.5, 125.3, 126.3, 129.3,
129.6, 135.2, 135.3 (CHar), 135.4 (Car, cis), 135.6 (Car, trans), 153.4 (Car,
trans), 154.1 (Car cis), 204.8 (C=O, trans), 207.1 ppm (C=O, cis); HRMS
(EI, 70 eV): m/z: calcd for C9H7O2: 147.04460 [MÀCH3]+; found:
147.0444 (1 ppm).
1-(2-(1,3-Dioxan-2-yl)phenyl)prop-2-en-1-ol (11): A solution of vinylmag-
nesium bromide (1m, 37.0 mL, 37.0 mmol) in THF was added dropwise
to a solution of aldehyde 10 (6.0 g, 31.2mmol) in THF (40 mL) at 0 8C.
The reaction mixture was stirred at 08C over 2h and was then quenched
with a saturated solution of NH4Cl (40 mL). The aqueous phase was ex-
tracted with Et2O (3”50 mL). The combined organic phases were
washed with brine (50 mL), dried over magnesium sulfate, filtered and
concentrated in vacuo. The residue was purified by column chromatogra-
phy on silica gel with pentane/Et2O 50:50 as the eluent to afford alcohol
(1,3-Dihydro-1-vinylisobenzofuran-3-yloxy)(tert-butyl)dimethylsilane
(14): A solution of tert-butyldimethylsilyl chloride (1.5 g, 10 mmol) in
CH2Cl2 (5 mL) was added dropwise to a solution of lactol 12 (810 mg,
5 mmol) and imidazole (714 mg, 10.5 mmol) in CH2Cl2 (20 mL) cooled at
08C. The reaction mixture was stirred for 16 h at room temperature and
was then quenched with water (20 mL). After decantation, the aqueous
layer was extracted with dichloromethane (2”20 mL) and the combined
organic phases were dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by column chromatography
on silica gel by using pentane/Et2O 95:5 as the eluent to afford the prod-
uct as a colourless oil (1.14 g, 83%, 55:45 mixture of diastereoisomers as
determined by 1H NMR spectroscopy). 1H NMR (300 MHz, CDCl3): d=
0.17 (s, 3H; SiCH3), 0.20 (s, 3H; SiCH3), 0.24 (s, 3H; SiCH3), 0.26 (s,
3H; SiCH3), 0.96 (s, 9H; tBu), 0.97 (s, 9H; tBu), 5.21 (ddd, J=10.0, 1.2,
1.2Hz, 1H; CH =CH2), 5.30 (dd, J=10.0, 1.2Hz, 1H; CH =CH2), 5.52(m,
3H; CH=CH2 + CHCH=CH2), 5.72–5.75 (m, 1H; CHCH=CH2), 5.80–
6.05 (m, 2H; CH=CH2), 6.51 (s, 1H; CHOSi), 6.59 (d, J=1.8 Hz, 1H;
CHOSi), 7.19–7.21 (m, 2H; Har), 7.34–7.39 ppm (m, 6H; Har); 13C NMR
(75 MHz, CDCl3): d=À4.8, À4.7, À4.1, À4.0 (SiCH3), 18.09, 18.13 (C-
1
11 as a colourless oil (4.5 g, 66%). H NMR (300 MHz, CDCl3): d=1.46–
1.53 (m, 1H; CH2), 2.21–2.37 (m, 1H; CH2), 3.22 (d, J=3.6 Hz, 1H;
OH), 3.98–4.08 (m, 2H; CH2O), 4.27–4.34 (m, 2H; CH2O), 5.33 (ddd, J=
10.7, 1.8, 1.8 Hz, 1H; CH=CH2), 5.52(ddd, J=17.2, 1.8, 1.8 Hz, 1H;
CH=CH2), 5.71–5.75 (m, 1H; CHOH), 5.78 (s, 1H; CHacetal), 6.16 (ddd,
J=17.2, 10.7, 4.3 Hz, 1H; CH=CH2), 7.30–7.40 (m, 2H; Har), 7.45–7.48
(m, 1H; Har), 7.57–7.60 ppm (m, 1H; Har); 13C NMR (75 MHz, CDCl3):
d=25.6 (CH2), 67.5 (2” CH2O), 70.6 (CHOH), 101.3 (CHacetal), 114.6
(CH=CH2), 127.1, 127.9, 128.0, 129.4 (CHar), 135.8, 135.9, 140.7 ppm (Car +
CH=CH2); HRMS (EI, 70 eV): m/z: calcd for C13H14O2 [MÀH2O]+:
202.0994; found: 202.0988 (2 ppm); elemental analysis calcd (%) for
C13H16O3: C 70.89, H 7.32; found: C 70.40, H 7.25.
1,3-Dihydro-3-vinylisobenzofuran-1-ol (12):
A solution of alcohol 11
A
N
(4.5 g, 20.4 mmol) and p-toluenesulfonic acid (40 mg, 0.204 mmol) in a
THF/water mixture (2:1, 45 mL) was heated at 80 8C for 16 h. The reac-
tion mixture was quenched with a saturated solution of NaHCO3 (20 mL)
and then extracted with Et2O (3”30 mL). The combined organic phases
were washed with brine (30 mL), dried over MgSO4, filtered and concen-
trated under reduced pressure. The residue was purified by column chro-
matography on silica gel by using pentane/Et2O 50:50 as the eluent to
afford the lactol 12 as a colourless oil which crystallised slowly in the
fridge (1.78 g, 54%, 50:50 mixture of diastereoisomers in equilibrium
(CHOSi), 116.1, 117.4 (CH=CH2), 121,7, 121.8, 122,5, 122.6, 128.0, 128.8
(CHar), 137.6, 139.1 (CH=CH2), 140.3, 140.6, 141.27. 141.35 ppm (Car);
HRMS (EI, 70 eV): m/z: calcd for C12H15O2Si: 219.0841 [MÀC4H9]+;
found: 219.0849 (3 ppm); elemental analysis calcd (%) for C16H24O2Si: C
69.52, H 8.75; found: C 69.34, H 8.78.
1-Ethylidene-1,3-dihydroisobenzofuran-3-yloxy)(tert-butyl)dimethylsilane
(15) (procedure with nickel hydride): A solution of LiBHEt3 in THF
(1m, 72 mL, 0.072mmol) was added, at room temperature under argon,
Chem. Eur. J. 2007, 13, 7374 – 7384
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7379

R. GrØe et al.
to a solution of [NiCl2
A
CHOSi), 6.62(d, J=1.9 Hz, 1H; CHOSi), 7.00 (dd, J=15.6, 5.9 Hz, 1H;
CH=CHCO2Me), 7.10 (dd, J=15.6, 5.9 Hz, 1H; CH=CHCO2Me), 7.21–
7.25 (m, 2”1H; Har), 7.35–7.40 ppm (m, 2”4H; Har); 13C NMR (75 MHz,
(2mL). This reaction mixture was stirred at room temperature for 5 min
and was then cooled to À508C. A solution of 14 (200 mg, 0.725 mmol) in
THF (0.5 mL) was added, the temperature was raised to room tempera-
ture and the reaction mixture was stirred for a further 20 h. After this
time, it was quenched with water (5 mL) and the aqueous phase was ex-
tracted with Et2O (3”10 mL). The combined organic phases were
washed with brine (5 mL), dried (MgSO4) and concentrated under re-
duced pressure. The residue was purified by filtration on silica gel by
using pentane/Et2O 90:10 as the eluent to afford an inseparable mixture
of diastereoisomers as a colourless oil (80:20 as determined by 1H NMR
spectroscopy, 176 mg, 88%). 1H NMR (300 MHz, C6D6): d=0.00 (s, 2”
3H; SiCH3, major + minor), 0.10 (s, 2”3H; SiCH3, major + minor),
0.87 (s, 2”9H; tBu, major + minor), 1.64 (d, J=7.6 Hz, 3H; CHCH3,
minor), 1.82(d, J=7.0 Hz, 3H; CHCH3, major), 4.83 (q, J=7.0 Hz, 1H;
CHCH3, major), 5.27 (q, J=7.6 Hz, 1H; CHCH3, minor), 6.44 (s, 1H;
CHOSi, minor), 6.50 (s, 1H; CHOSi, major); 7.28–7.44 ppm (m, 2”4H;
Har, major + minor); 13C NMR (75 MHz, C6D6): d=À4.39, À4.28, À3.90,
10.6, 10.9, 18.16, 18.20, 25.94, 25.96, 92.1, 96.0, 100.2, 101.31, 119.4, 122.9,
123.1, 123.2, 129.20, 129.25, 133.9, 134.5, 141.1, 143.1, 153.4, 153.5 ppm.
CDCl3): d=À4.9, À4.7, À4.1, À4.0 (SiCH3), 18.08, 18.12( C
C
AHCTREUNG
(CHOSi), 120.7, 121.4, 121.5, 121.6, 122.8, 128.5, 129.1, 139.6, 140.0, 140.2,
146.3, 147.3 (CHar, Car, CH=CH), 166.6, 166.7 ppm (CO2CH3); HRMS
(EI, 70 eV): m/z: calcd for C18H25O4Si: 333.1522 [MÀH]+; found:
333.1513 (2ppm).
(1,3-Dihydro-1-(oct-1-enyl)isobenzofuran-3-yloxy)(tert-butyl)dimethylsi-
lane (17c): These compounds were obtained by the method used for the
preparation of 17a’ by starting with 14 (311 mg, 1.13 mmol), 1-octene 16c
(1.8 mL, 11.3 mmol), Grubbs catalyst (48 mg, 0.056 mmol) and CH2Cl2
(6 mL). Purification by column chromatography using pentane/Et2O 99:1
as the eluent afforded an inseparable mixture of diastereoisomers 60:40
as determined by 1H NMR spectroscopy as a colourless oil (286 mg,
70%). 1H NMR (300 MHz, C6D6): d=0.32–0.38 (m, 2”3H; SiCH3),
0.93–1.01 (m, 2”3H; CH3), 1.13 (s, 9H; tBu), 1.14 (s, 9H; tBu), 1.25–1.45
(m, 2”8H; CH2), 1.99–2.12 (m, 2”2H; CH=CHCH2), 5.47–5.94 (m, 2”
3H; CH=CH; CHO), 6.65 (s, 1H; CHOSi), 7.79 (d, J=1.8 Hz, 1H;
CHOSi), 7.08–7.40 ppm (m, 2”4H; Har); 13C NMR (75 MHz, C6D6): d=
À4.61, À4.59, À3.8, À3.6, 14.3, 18.30, 18.32, 23.0, 25.9, 26.0, 26.1, 29.11,
2914, 29.3, 31.60, 31.64, 31.98, 32.02, 32.1, 32.3, 32.4, 32.5, 84.5, 85.2,
101.3, 101.4, 122.06, 122.15, 122.8, 122.9, 128.9, 130.3, 132.0, 133.3, 134.5,
1,3-Dihydro-3-styrylisobenzofuran-1-ol (17a’): A solution of 12 (168 mg,
1.04 mmol), styrene 16a (1.1 mL, 10.4 mmol) and second-generation
Grubbs catalyst (26 mg, 0.031 mmol) was heated at 408C in CH2Cl2
(4 mL) over 16 h. The solvent was evaporated and the residue was direct-
ly purified by column chromatography on silica gel with pentane/Et2O
95:5 then 60:40 as the eluent. The compounds 17a’ were obtained as a
brown solid (152mg, 61%, 55:45 mixture of diastereoisomers as deter-
mined by 1H NMR spectroscopy in equilibrium with 10% of aldehyde);
1H NMR (300 MHz, CDCl3): d=3.57–3.79 (m, 2”1H; OH), 5.71 (d, J=
7.8 Hz, 1H; CHO), 5.97 (d, J=8.0 Hz, 1H; CHO), 6.18 (dd, J=15.8 Hz,
8.0 Hz, 1H; CH=CHPh), 6.33 (dd, J=15.8, 7.8 Hz, 1H; CH=CHPh), 6.52
(d, J=7.8 Hz; CHOH), 6.52(d, J=7.8 Hz; CHOH), 6.62(d, J=6.0 Hz;
CHOH), 6.80 (d, J=15.8 Hz, 2”1H; CH=CHPh), 7.22–7.50 (m, 2”9H;
Har), 10.2ppm (s, 1H; C HO); 13C NMR (75 MHz, CDCl3): d=84.0, 84.4,
100.9, 101.2, 122.07, 122.12, 123.07, 123.14, 126.79, 126.84, 128.03, 128.06,
128.2, 128.3, 128.4, 128.6, 129.50, 129.55, 129.8, 132.1, 133.0, 136.2, 139.0,
139.1, 141.48, 141.55 ppm; HRMS (70 eV, EI): m/z: calcd for C16H14O2:
238.0994 [M]+; found: 238.0998 (1 ppm).
141.1, 141.4, 142.6, 142.7 ppm; HRMS (EI, 70 eV): m/z: calcd for
+
À
C18H27O2Si: 303.1780 [M C4H9] ; found: 303.1778 (0 ppm).
6-(3-{[tert-butyl(dimethyl)silyl]oxy}-1,3-dihydro-2-benzofuran-1-yl)hex-5-
A
en-1-yl acetate (17d): These compounds were obtained by the method
used for the preparation of 17a’ by starting with 14 (206 mg,
0.746 mmol), 5-hexenylacetate 16d (920 mL, 3.72mmol), Grubbs catalyst
(24 mg, 0.028 mmol) and CH2Cl2 (5 mL). Purification by column chroma-
tography using pentane/Et2O 95:5 then 90:10 as the eluent afforded an
1
55:45 inseparable mixture of diastereoisomers as determined by H NMR
spectroscopy) as a colourless oil (63 mg, 22%). 1H NMR (300 MHz,
C6D6): d=0.23–0.26 (m, 2”6H; SiCH3), 1.01 (s, 9H; tBu), 1.02(s, 9H;
tBu), 1.11–1.38 (m, 2”4H; CH2), 1.66 (s, 3H; COCH3), 1.68 (s, 3H;
COCH3), 1.79 (dt, J=6.9, 6.9 Hz, 2”2H; CH =CHCH2), 3.90 (m, 2”2H;
CH2OAc), 5.41–5.79 (m, 2”3H; CH=CH; CHO), 6.53 (s, 1H; CHOSi),
6.67 (d, J=1.8 Hz, 1H; CHOSi), 6.99–7.11 (m, 3H; Har), 7.26–7.28 ppm
(m, 1H; Har); 13C NMR (75 MHz, C6D6): d=À6.81, À6.77, À6.0, À5.8,
16.11, 16.14, 18.3, 23.3, 23.9, 26.18, 26.21, 29.6, 29.7, 61.94, 61.97, 82.2,
82.8, 99.3, 119.9. 120.0, 120.6, 120.7, 125.91, 125.94, 126.7, 128.5, 130.3,
130.4, 131.5, 138.9, 139.2, 140.3, 140.4, 167.9 ppm; HRMS (EI, 70 eV):
m/z: calcd for C18H25O4Si: 333.1522 [MÀC4H9]+; found: 333.1513
(2ppm).
(1,3-Dihydro-1-styrylisobenzofuran-3-yloxy)(tert-butyl)dimethylsilane
(17a): These compounds were obtained by the method used for the prep-
aration of 17a’ by starting with 14 (185 mg, 0.670 mmol), styrene 16a
(711 mL, 6.70 mmol) and Grubbs catalyst (28 mg, 0.033 mmol) in CH2Cl2
(5 mL). Purification by column chromatography using pentane/Et2O
99:1) as the eluent afforded an inseparable mixture of diastereoisomers
(56:44 as determined by 1H NMR spectroscopy) as
(103 mg, 44%). 1H NMR (300 MHz, CDCl3): d=0.23 (s, 3H; SiCH3),
0.27 (s, 3H; SiCH3), 0.29 (s, 3H; SiCH3), 0.32(s, 3H; SiC H3), 1.01 (s,
9H; tBu), 1.03 (s, 9H; tBu), 5.71 (d, J=8.0 Hz, 1H; CHO), 5.96 (d, J=
8.0 Hz, 1H; CHO), 6.23 (dd, J=15.7 Hz, 8.0 Hz, 1H; CH=CHPh), 6.37
(dd, J=15.7, 8.0 Hz, 1H; CH=CHPh), 6.58 (s, 1H; CHOSi), 6.68 (s, 1H;
CHOSi), 6.80 (d, J=15.7 Hz, 1H; CH=CHPh), 6.85 (d, J=15.7 Hz, 1H;
CH=CHPh), 7.23–7.48 (m, 2”9H; Har); 13C NMR (75 MHz, CDCl3): d=
À4.7, À4.6, À4.0, À3.8, 18.1, 18.2, 25.87, 25.90, 83.9, 84.6, 101.2, 121.98,
122.03, 122.6, 122.7, 126.76, 128.80, 127.83, 127.97, 128.05, 128.1, 128.6,
128.7, 128.8, 128.9, 130.4, 131.4, 132.8, 136.4, 136.6, 140.4, 140.7, 141.4,
141.6 ppm.
(1-(6-(4-Methoxyphenoxy)hex-1-enyl)-1,3-dihydroisobenzofuran-3-ylox-
y)(tert-butyl)dimethylsilane (17e): These compounds were obtained by
the method used for the preparation of 17a’ by starting with 14 (253 mg,
0.917 mmol), alkene 16e (283 mg, 1.37 mmol), Grubbs catalyst (39 mg,
0.046 mmol) and CH2Cl2 (5 mL). Purification by column chromatography
using pentane/Et2O 95:5 as the eluent afforded an inseparable mixture of
diastereoisomers as a colourless oil (112mg, 27%). Because of its insta-
bility, the purity of product 17e was controlled only by 1H NMR spectros-
copy and was used directly for the next aldol reaction.
2-Benzyl-2,3-dihydro-3-hydroxyinden-1-one (18a): These aldols were ob-
tained by the method used for the preparation of 13, by starting with 17a
(69 mg, 0.196 mmol), [Fe(CO)5] (4 mL, 0.020 mmol), using 3 h of irradia-
tion, a solution of TBAF in THF (1m, 2 16mL, 0.216 mmol) and THF
(2mL). Purification by column chromatography using pentane/Et 2O
40:60 as the eluent afforded a mixture of diastereoisomeric indanones as
a colourless oil (trans/cis 72:28 as determined by 1H NMR spectroscopy,
36 mg, 77%). The two diastereoisomers were separated by column chro-
matography (pentane/Et2O 50:50). 1H NMR (300 MHz, CDCl3): trans
isomer: d=2.07 (brs, 1H; OH), 2.82–2.97 (m, 2H; CHCH2, CH2Ph), 3.46
(dd, J=13.0, 3.7 Hz, 1H; CH2Ph), 5.12(d, J=3.3 Hz, 1H; CHOH), 7.23–
7.35 (m, 5H; Har), 7.46–7.52(m, 1H; H ar), 7.63–7.68 (m, 2H; Har), 7.76–
7.79 ppm (m, 1H; Har); 13C NMR (75 MHz, CDCl3): d=34.4 (CH2Ph),
59.8 (CHCH2), 73.7 (CHOH), 123.3, 125.5, 128.7, 129.0, 129.4, 135.3
Methyl-3-(3-{[tert-butyl(dimethyl)silyl]oxy}-1,3-dihydro-2-benzofuran-1-
A
yl)acrylate (17b): These compounds were obtained by the method used
for the preparation of 17a’ by starting with 14 (290 mg, 1.05 mmol),
methyl acrylate 16b (944 mL, 10.5 mmol), Grubbs catalyst (44 mg,
0.052mmol) and CH 2Cl2 (6 mL). Purification by column chromatography
using pentane/Et2O 95:5 as the eluent afforded an inseparable mixture of
diastereoisomers (57:43 as determined by 1H NMR spectroscopy) as a
colourless oil (151 mg, 43%). 1H NMR (300 MHz, CDCl3): d=0.17 (s,
3H; SiCH3), 0.23 (s, 3H; SiCH3), 0.24 (s, 3H; SiCH3), 0.27 (s, 3H;
SiCH3), 0.96 (s, 9H; tBu), 0.97 (s, 9H; tBu), 3.74 (s, 3H; CO2CH3), 3.76
(s, 3H; CO2CH3), 5.67 (d, J=5.9 Hz, 1H; CHO), 5.92(d, J=5.9 Hz, 1H;
CHO), 6.23 (d, J=15.6 Hz, 2”1H; CH=CHCO2Me), 6.55 (s, 1H;
7380
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 7374 – 7384

Intramolecular Isomerisation–Aldolisation
FULL PAPER
(CHar), 135.6, 139.1, 153.3 (Car), 203.3 (C=O); cis isomer: d=1.79 (d, J=
5.6 Hz, 1H; OH), 2.89 (dd, J=14.0, 11.2Hz, 1H; C H2Ph), 3.01–3.08 (m,
1H; CHCH2), 3.28 (dd, J=14.0, 3.5 Hz, 1H; CH2Ph), 5.27 (dd, J=5.6,
5.6 Hz, 1H; CHOH), 7.12–7.29 (m, 5H; Har), 7.39–7.45 (m, 1H; Har),
7.54–7.59 (m, 2H; Har), 7.70–7.72ppm (m, 1H; H ar). 13C NMR (75 MHz,
CDCl3): d=30.7 (CH2Ph), 54.7 (CHCH2), 70.1 (CHOH), 123.7, 126.4,
128.7, 128.8, 129.8, 135.3 (CHar), 135.8, 140.1, 153.4 (Car), 205.1 ppm (C=
O); HRMS (EI, 70 eV): m/z: calcd for C16H14O2: 238.0994 [M]+; found:
238.0998 (1 ppm).
1H NMR (300 MHz, CDCl3): d=1.18–2.00 (m, 2”10H; CH2, cis
+
trans), 2.47–2.53 (m, 1H; CHCH2, trans), 2.63–2.69 (m, 1H; CHCH2, cis),
3.69 (s, 2”3H; OCH3, cis + trans), 3.85 (t, J=6.4 Hz, CHOAr, 2”2H;
cis + trans), 4.99 (d, J=3.5 Hz, 1H; CHOH trans), 5.33 (d, J=6.3 Hz,
1H; CHOH cis), 6.74–6.76 (m, 2”4H; Har cis + trans), 7.38–7.44 (m, 2”
1H; Har, cis
+ trans), 7.59–7.70 ppm (m, 2”3H; Har, cis + trans);
13C NMR (75 MHz, CDCl3): d=24.0, 25.2, 26.1, 26.2, 27.2, 27.7, 28.9,
29.1, 29.3, 30.3, 53.2, 55.7, 58.2, 68.4, 68.6, 70.4, 74.9, 114.6, 115.4, 123.3,
123.5, 125.5, 126.1, 129.4, 129.7, 135.2, 135.3, 135.8, 135.9, 153.2, 153.6,
153.7, 204.5, 206.1 ppm; HRMS (EI, 70 eV): m/z: calcd for C21H24O4:
340.1675 [M]+; found: 340.1672(0 ppm).
Methyl 2-(2,3-dihydro-1-hydroxy-3-oxo-1H-inden-2-yl)acetate (18b):
These aldols were obtained by the method used for the preparation of 13
and by starting with 17b (104 mg, 0.311 mmol), [Fe(CO)5] (4 mL,
0.0311 mmol), a solution of TBAF in THF (1m, 342 mL, 0.342mmol) and
THF (2mL). Purification by column chromatography using pentane/
Et2O 20:80 as the eluent afforded an inseparable mixture of diastereoiso-
2-Methyl-1H-inden-1-one (20): Mesyl chloride (36 mL, 0.463 mmol) was
added dropwise at 08C to a solution of aldol 13 (50 mg, 0.302mmol) and
triethylamine (65 mL, 0.463 mmol) in CH2Cl2 (2mL). The reaction mix-
ture was stirred for 1 h at 08C and then DBU (50 mL, 0.332mmol) was
added and the solution was stirred for 2h at room temperature. After
quenching with water (2mL), the aqueous layer was extracted twice with
dichloromethane (2”5 mL). The combined organic layers were dried
over MgSO4, filtered and the solvents were evaporated under reduced
pressure. The residue was purified by column chromatography on silica
gel with pentane/Et2O 90:10 as the eluent to afford the indenone 20 as a
yellow solid (37 mg, 86%). 1H NMR (300 MHz, CDCl3): d=1.79 (d, J=
1.7 Hz, 3H; CH3), 6.85 (d, J=7.1 Hz, 1H; Har), 7.01–7.06 (m, 2H; CH=
C, Har), 7.17–7.23 (m, 1H; Har), 7.29 ppm (d, J=7.1 Hz, 1H; Har);
13C NMR (75 MHz, CDCl3): d=10.0 (CH3), 121.1 (CHar), 122.6 (CHar),
127.8 (CHar), 130.7, 133.8 (CHar), 136.2(C ar), 143.3 (CHar), 144.9 (Car),
189.7 ppm (C=O); HRMS (EI, 70 eV): m/z: calcd for C10H8O: 144.0575
[M]+; found: 144.0580 (1 ppm).
1
meric indanones 18b (trans/cis 77:23 as determined by H NMR spectros-
copy) as a colourless oil (40 mg, 59%). This mixture was dissolved in dry
dichloromethane (2mL) in presence of a catalytic amount of PTSA and
heated at 408C for 1 h. After quenching with water (2mL) and extraction
with CH2Cl2 (3”5 mL), the combined organic layers were dried over
MgSO4, filtered and concentrated in vacuo. Purification of the residue by
column chromatography (CH2Cl2/MeOH 95:5) afforded first lactone 19
and then trans-aldol 18b.
trans-aldol 18b: 1H NMR (300 MHz, CDCl3): d=2.65 (dd, J=17.9,
10.8 Hz, 1H; CH2CO2Me), 2.90 (ddd, J=17.9, 3.8, 3.4 Hz, 1H; CHCH2),
3.28 (dd, J=17.9, 3.4 Hz, 1H; CH2CO2Me), 3.78 (s, 3H; CO2CH3), 4.03–
4.04 (m, 1H; OH), 5.12–5.16 (m, 1H; CHOH), 7.50 (dd, J=7.1, 7.1 Hz,
1H; Har), 7.70–7.80 ppm (m, 3H; Har); 13C NMR (75 MHz, CDCl3): d=
33.0 (CH2), 52.4, 54.4 (CO2CH3 + CHCH2), 74.7 (CHOH), 123.3, 125.6,
129.2, 135.4 (CHar), 135.5, 153.1 (Car), 174.4 (CO2CH3), 201.7 ppm (C=
O); HRMS (EI, 70 eV): m/z: calcd for C12H12O4: 220.0743 [M]+; found:
220.0736 (3 ppm); elemental analysis calcd (%) for C12H12O4: C 65.45, H
5.49; found: C 65.50, H 5.52.
Lactone 19: 1H NMR (300 MHz, CDCl3): d=2.74 (dd, J=19.0, 4.5 Hz,
1H; CH2CO2), 3.02(dd, J=19.0, 12.4 Hz, 1H; CH2CO2), 3.52(ddd, J=
12.4, 6.8, 4.5 Hz, 1H; CHCH2), 5.94 (d, J=6.8 Hz, 1H; CHO), 7.51–7.60
(m, 1H; Har), 7.69–7.79 ppm (m, 3H; Har); 13C NMR (75 MHz, CDCl3):
d=31.2( CH2), 45.8 (CHCH2), 79.1 (CHO), 124.5, 127.6, 131.2, 136.1
(CHar), 136.2, 149.7 (Car), 174.7 (C=O lactone), 202.4 ppm (C=O);
HRMS (EI, 70 eV): m/z: calcd for C11H8O3: 188.0473 [M]+; found:
188.0469 (2ppm).
2-Benzyl-1H-inden-1-one (21): This indenone was obtained by the
method used for the preparation of 20, by starting with 18a (19 mg,
0.080 mmol), triethylamine (17 mL, 0.120 mmol), mesyl chloride (10 mL,
0.120 mmol), DBU (18 mL, 0.120 mmol) and CH2Cl2 (1 mL). Purification
by column chromatography using pentane/Et2O 90:10 as the eluent af-
forded indenone 21 as a yellow oil (17 mg, 97%). 1H NMR (300 MHz,
CDCl3): d=3.60 (d, J=1.6 Hz, 2H; CH2Ph), 6.92(d, J=7.1 Hz, 1H; Har),
6.97 (brs, 1H; CH=C), 7.15 (dd, J=7.8, 7.8 Hz, 1H; Har), 7.23–7.37 (m,
6H; Har), 7.41 ppm (d, J=7.1 Hz, 1H; Har); 13C NMR (75 MHz, CDCl3):
d=31.2( CH2Ph), 121.5, 122.8, 126.4, 128.1, 128.6, 129.0 (CHar), 133.9,
138.4, 140.1, 143.8, 144.7 (Car, Calkene), 197.9 ppm (C=O); HRMS (EI,
70 eV): m/z: calcd for C16H12O: 220.0888 [M]+; found: 220.0890 (0 ppm).
1-Bromo-4,5-dimethoxy-2-(dimethoxymethyl)benzene (23): A solution of
6-bromoveratraldehyde 22 (2.5 g, 10.2 mmol), methyl orthoformiate
(1.4 mL, 12.2 mmol) and p-toluenesulfonic acid (20 mg, 0.102 mmol) in
dry methanol (15 mL) was refluxed for 24 h. The reaction mixture was
quenched with a saturated solution of NaHCO3 (10 mL), concentrated
and extracted with Et2O (3”30 mL). The combined organic phases were
washed with brine (30 mL), dried over MgSO4, filtered and concentrated
under reduced pressure to afford 24 as a white solid (2.53 g, 85%) which
was used in next step without further purification. Spectral data were in
agreement with the literature.[31]
2-Heptyl-2,3-dihydro-3-hydroxyinden-1-one (18c): These aldols were ob-
tained by the method used for the preparation of 13 by starting with 17c
(135 mg, 0.375 mmol), [Fe(CO)5] (6 mL, 0.0375 mmol),
a solution of
TBAF in THF (1m, 412 mL, 0.412mmol) and THF (2mL). Purification
by column chromatography using pentane/Et2O 40:60 as the eluent af-
forded an inseparable mixture of diastereoisomeric indanones as a col-
ourless oil (trans/cis 62:38 as determined by 1H NMR spectroscopy,
39 mg, 42%). 1H NMR (300 MHz, CDCl3): d=0.80 (t, J=6.7 Hz, CH3,
2”3H; cis + trans), 1.20–1.96 (m, 2”12H; CH2, cis + trans), 2.12 (d,
J=5.5 Hz, 1H; OH; cis), 2.44–2.50 (m, 1H; CHCH2, trans), 2.60–2.67 (m,
2H; CHCH2, OH; cis + trans), 4.98 (m, 1H; CHOH, trans), 5.32(dd,
J=5.5, 5.3 Hz, 1H; CHOH, cis), 7.37–7.43 (m, 2”1H; Har, cis + trans),
7.57–7.67 (m, 2”3H; Har, cis + trans); 13C NMR (75 MHz, CDCl3): d=
14.1 (CH3), 22.6, 25.3, 27.4, 29.09, 29.13, 29.7, 29.8, 31.8, 31.9 (CH2), 53.3,
58.3 (CHCH2), 70.4, 74.9 (CHOH), 123.2, 123.5, 125.5, 126.1, 129.3, 129.6,
135.1, 135.2( CHar), 135.8, 135.9, 153.7, 154.0 (Car), 204.9, 206.5 ppm (C=
O); HRMS (EI, 70 eV): m/z: calcd for C16H22O2: 246.1620 [M]+; found:
246.1614 (2 ppm); elemental analysis calcd (%) for C16H22O2: C 78.01, H
9.00; found: C 77.83, H 9.03.
4,5-Dimethoxy-2-(dimethoxymethyl)benzaldehyde (24): To a solution of
23 (2.3 g, 7.90 mmol) in THF (30 mL) was added dropwise, at À788C, a
1.6m solution of nBuLi (7.6 mL, 11.8 mmol) in THF. The reaction mix-
ture was stirred between À78 and À408C for 1 h and then a solution of
DMF in THF was added dropwise. The temperature was allowed to rise
to 08C over 1 h and then the reaction mixture was hydrolised with water
(5 mL) and extracted with CH2Cl2 (3”30 mL). The combined organic
phases were washed with brine (30 mL), dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel with pentane/EtOAc 50:50 as the
eluent to afford aldehyde 24 as a yellow solid (1.51 g, 80%). Spectral
data were in agreement with literature.[32]
2-(5-(4-Methoxyphenoxy)pentyl)-2,3-dihydro-3-hydroxyinden-1-one
(18e): These aldols were obtained by the method used for the prepara-
tion of 13, by starting with 17e (87 mg, 0.192mmol), [Fe(CO) 5] (5 mL,
0.038 mmol), with 3 h of irradiation then a solution of TBAF in THF
(1m, 2 11mL, 0.216 mmol) and THF (1.5 mL). Purification by column
chromatography using pentane/Et2O 40:60 as the eluent afforded an in-
separable mixture of diastereoisomeric indanones as a colourless solid
(trans/cis 82:18 as determined by 1H NMR spectroscopy, 26 mg, 40%).
4,5-Dimethoxybenzene-1,2-dialdehyde (25):
A solution of acetal 24
(715 mg, 2.98 mmol) and p-toluene sulfonic acid (6 mg, 0.030 mmol) in a
THF/water mixture (10 mL-5 mL) was heated at 808C for 4 h. The reac-
tion mixture was quenched with a saturated solution of NaHCO3 (5 mL)
and extracted with CH2Cl2 (3”20 mL). The combined organic phases
were washed with brine (30 mL), dried over MgSO4, filtered and concen-
Chem. Eur. J. 2007, 13, 7374 – 7384
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7381

R. GrØe et al.
trated under reduced pressure to afford dialdehyde 25 as a white solid
(540 mg, 93%) which was used in next step without further purification.
Spectral data were in agreement with the literature.[33]
(300 MHz, CDCl3): major cis isomer: d=1.54 (s, 3H; CH3), 3.27 (d, J=
10.1 Hz, 1H; OH), 3.64 (s, 3H; CO2CH3), 3.86 (s, 3H; OCH3), 3.94 (s,
3H; OCH3), 4.92(d, J=10.1 Hz, 1H; CHOH), 7.09 (s, 1H; Har), 7.11 (s,
1H; Har); minor trans isomer: d=1.36 (s, 3H; CH3), 2.61 (d, J=7.6 Hz,
1H; OH), 3.65 (s, 3H; CO2CH3), 3.86 (s, 3H; OCH3), 3.94 (s, 3H;
OCH3), 5.49 (d, J=10.1 Hz, 1H; CHOH), 7.09 (s, 1H; Har), 7.11 ppm (s,
1H; Har); 13C NMR (75 MHz, CDCl3): major cis isomer: d=18.4 (CH3),
2-Methyl 2-(1,3-dihydro-1-hydroxyisobenzofuran-3-yl)acrylate (26d):
Methyl acrylate (417 mL, 4.64 mmol) was added in one portion to a solu-
tion of dialdehyde 25 (300 mg, 1.55 mmol) and DABCO (174 mg,
1.55 mmol) in a dioxane/water mixture (1:1, 16 mL) and the reaction mix-
ture was stirred for 16 h at room temperature. After decantation, the
aqueous layer was extracted with Et2O (3”10 mL), the combined organic
layers were washed with brine (20 mL), dried over MgSO4, filtered and
concentrated in vacuo. The residue was purified by a short filtration on
silica gel with EtOAc as the eluent to afford compound 26d as a beige
solid (416 mg, 95%, 76:23 mixture of diastereoisomers as determined by
1H NMR spectroscopy in equilibrium with 10% of aldehyde). 1H NMR
(300 MHz, CDCl3): d=3.65 (s, 3H; CO2CH3), 3.73 (s, 3H; CO2CH3), 3.78
(s, 2”3H; OCH3), 3.82(s, 3H; OC H3), 3.83 (s, 3H; OCH3), 4.42(d, J=
11.1 Hz, 1H; OH), 5.64 (s, 1H), 5.84 (s, 1H), 6.03 (s, 1H), 6.07 (brs, 1H),
6.22 (s, 1H), 6.28–6.31 (m, 2H), 6.49 (brs, 1H), 6.55 (s, 1H), 6.70 (s, 1H),
6.84 (s, 1H), 6.87 (s, 1H), 10.0 ppm (s, 1H; CHO); 13C NMR (75 MHz,
CDCl3): d=51.9, 52.0, 56.02, 56.04, 67.0, 68.3, 81.2, 83.6, 101.7, 102.4,
103.5, 104.5, 105.1, 105.2, 110.6, 113.9, 126.1, 126.6, 129.1, 130.8, 131.4,
131.9, 133.1, 137.6, 139.8. 140.3, 142.0, 148.4, 149.7, 149.8, 150.47, 150.53,
153.7, 166.0, 166.3, 166.8, 190.9 ppm; HRMS (EI, 70 eV): m/z: calcd for
C14H16O6: 280.0947 [M]+; found: 280.0952 (1 ppm).
52.8 (OCH3), 56.2(O CH3), 56.5 (OCH3), 63.1 (C(Me)), 78.3(CHOH),
A
104.2, 106.2 (CHar), 127.8, 148.6, 151.2, 156.5 (Car), 171.0 (CO2CH3), 197.9
(C=O); minor trans isomer: d=15.8 (CH3), 52.7 (OCH3), 56.2(O CH3),
56.4 (OCH3), 61.7 (C(Me)), 74.2( CHOH), 104.3, 106.7 (CHar), 126.8,
148.7, 151.2, 156.4 (Car), 172.3 (CO2CH3), 199.5 ppm (C=O); HRMS (EI):
m/z: 70 eV calcd for C14H16O6: 280.0947 [M]+; found: 280.0952 (1 ppm).
Typical procedure for the generation of the mesylate intermediate: Mesyl
chloride (1.5 equiv) was added dropwise at 08C to a solution of aldol
(1 equiv) and triethylamine (1.5 equiv) in CH2Cl2. The reaction mixture
was stirred for 16 h at room temperature and was then quenched with
water (10 mL). After decantation, the aqueous layer was extracted with
dichloromethane (2”10 mL) and the combined organic phases were
dried over MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel, with pen-
tane/EtOAc 60:40 as the eluent to afford the mesylate intermediate
which was directly used for next step.
Methyl
2,3-dihydro-2-methyl-1-oxo-3-phenyl-1H-indene-2-carboxylate
Methyl 2,3-dihydro-1-hydroxy-2-methyl-3-oxo-1H-indene-2-carboxylate
(28a): The mesylate intermediate was prepared by the previous proce-
dure by starting from 27b (152mg, 0.695 mmol), Et 3N (146 mL,
1.04 mmol), mesyl chloride (80 mL, 1.04 mmol) and CH2Cl2 (3 mL). A so-
lution of this intermediate and trifluoromethanesulfonic acid (6 mL,
0.069 mmol) in benzene (5 mL) was heated at 808C for 16 h. After this
time, the reaction mixture was quenched with water, and after decanta-
tion, the aqueous layer was extracted with Et2O (3”10 mL). The com-
bined organic layers were dried over magnesium sulfate, filtered and con-
centrated under reduced pressure. Purification by column chromatogra-
phy using pentane/EtOAc 80:20 as the eluent afforded an inseparable
mixture of diastereoisomeric indanones 27b as a colourless oil (trans/cis
63:37 as determined by 1H NMR spectroscopy, 79 mg, 40%). 1H NMR
(300 MHz, CDCl3): d=1.01 (s, 3H; CH3 trans), 1.70 (s, 3H; CH3, cis),
3.12(s, 3H; CO 2CH3, cis), 3.78 (s, 3H; CO2CH3, trans), 4.50 (s, 1H;
CHPh, cis), 5.18 (s, 1H; CHPh, trans), 7.09–7.93 ppm (m, 2”9H; Har, cis
+ trans); 13C NMR (75 MHz. CDCl3): d=18.4, 20.7, 51.5, 52.9, 53.9, 57.9,
60.9, 62.9, 124.5. 124.7, 126.9, 127.1, 127.6, 127.7, 128.2, 128.4, 128.5,
129.2, 129.6, 135.1, 135.4, 135.5, 136.4, 138.3, 138.6, 153.9, 154.9, 170.8,
172.7, 203.1, 203.4 ppm; HRMS (EI, 70 eV): m/z calcd for C18H16O3:
280.1099 [M]+; found: 280.1086 (4 ppm).
(27b):
A solution of isobenzofuran 26b (1.04 g, 4.73 mmol) and
[Fe(CO)5] (30 mL, 0.227 mmol) in THF (12 mL) was irradiated with a
Philip HPK 125 W for 1 h. The solvent was evaporated and the residue
was purified by column chromatography by using pentane/EtOAc 50:50
as the eluent affording a mixture of diasteroisomeric aldols 27b as a col-
ourless oil (1.02g, 98%, cis/trans 80:20 as determined by 1H NMR spec-
troscopy). The two diastereoisomers were separated by column chroma-
tography (pentane/EtOAc 70:30). 1H NMR (300 MHz, CDCl3): major cis
isomer: d=1.55 (s, 3H; CH3), 3.30 (d, J=9.9 Hz, 1H; OH), 3.62(s, 3H;
COOCH3), 4.99 (d, J=9.9 Hz, 1H; CHOH), 7.43–7.48 (m, 1H; Har),
7.64–7.74 (m, 3H; Har); minor trans isomer: d=1.36 (s, 3H; CH3), 2.72
(d, J=7.4 Hz, 1H; OH), 3.66 (s, 3H; COOCH3), 5.60 (d, J=9.9 Hz, 1H;
CHOH), 7.42–7.47 (m, 1H; Har), 7.64–7.73 ppm (m, 3H; Har); 13C NMR
(75 MHz, CDCl3): major cis isomer: d=18.3 (CH3), 52.8 (OCH3), 63.2
(C(Me)
153.1 (Car), 170.6 (CO2Me), 199.6 (C=O); minor trans isomer: d=15.6
(CH3), 52.8 (OCH3), 61.9 (C(Me)(CO2Me)), 74.5 (CHOH), 124.3, 126.0,
(CO2Me)), 78.5 (CHOH), 124.3, 126.0, 129.8, 134.9 (CHar), 135.9,
AHCTREUNG
129.8, 133.8 (CHar), 135.9, 153.1 (Car), 172.1 (CO2Me), 200.9 ppm (C=O);
HRMS (EI, 70 eV): m/z: calcd for C12H12O4: 220.07356 [M]+; found:
220.0743 (2 ppm).
Methyl
2,3-dihydro-1-(2,4,6-trimethoxyphenyl)-2-methyl-3-oxo-1H-
2,3-Dihydro-1-hydroxy-2-methyl-3-oxo-1H-indene-2-carbonitrile
(27c):
indene-2-carboxylate (28b): The mesylate intermediate was prepared by
the general procedure by starting from 27b (110 mg, 0.503 mmol), Et3N
(106 mL, 0.754 mmol), mesyl chloride (58 mL, 0.754 mmol) and CH2Cl2
(2mL). A solution of this intermediate trimethoxybenzene (127 mg,
0.754 mmol) and trifluoromethanesulfonic acid (5 mL, 0.050 mmol) in di-
chloroethane (3 mL) was heated at 808C for 16 h. After this time, the re-
action mixture was quenched with water and, after decantation, the aque-
ous layer was extracted with Et2O (3”10 mL). The combined organic
layers were dried over magnesium sulfate, filtered and concentrated
under reduced pressure. Purification by column chromatography using
pentane/EtOAc 80:20 as the eluent afforded a mixture of diastereoiso-
meric indanones 28b as a white solid (68:32as determined by 1H NMR
spectroscopy, 92mg, 50%). The two diastereoisomers were separated by
column chromatography (pentane/EtOAc 80:20). 1H NMR (300 MHz,
CDCl3): major trans isomer: d=1.16 (s, 3H; CH3), 3.22 (s, 3H; OCH3),
3.70 (s, 3H; CO2CH3), 3.82(s, 3H; OC H3), 3.84 (s, 3H; OCH3), 5.35 (s,
These aldols were obtained by the method used for the preparation of
27b, by starting with isobenzofuran 26c (93 mg, 0.495 mmol), [Fe(CO)5]
(14 mL, 0.107 mmol) and THF (2mL). Purification by column chromatog-
raphy using CH2Cl2/MeOH 98:2as the eluent afforded an inseparable
mixture of diasteroisomeric aldols 27c as a light yellow oil (65 mg, 70%,
50:50 as determined by 1H NMR spectroscopy). 1H NMR (300 MHz,
CDCl3): d=1.52(s, 3H; C H3), 1.68 (s, 3H; CH3), 4.05–4.11 (m, 2H;
OH), 5.11 (d, J=6.5 Hz, 1H; CHOH), 5.63 (d, J=5.8 Hz, 1H; CHOH),
7.43–7.83 ppm (m, 8H; Har); 13C NMR (75 MHz, CDCl3): d=18.1 (CH3),
20.8 (CH3), 49.9 (C(Me)(CN)), 53.0 (C(Me)(CN)), 74.0 (CHOH), 76.2
(CHOH), 117.8, 120.3, 124.7, 125.0, 126.3, 126.7, 130.3, 130.7, 131.9,
132.6, 136.8, 137.0 (CHar), 151.1, 151.7 (CN), 196.0, 196.2ppm ( C=O);
HRMS (EI, 70 eV): m/z: calcd for C11H9NO2: 187.0633 [M]+; found:
187.0645 (1 ppm).
Methyl 2,3-dihydro-1-hydroxy-5,6-dimethoxy-2-methyl-3-oxo-1H-indene-
2-carboxylate (27d): These aldols were obtained by the method used for
the preparation of 27b, by starting with 26d (210 mg, 0.745 mmol),
[Fe(CO)5] (5 mL, 0.037 mmol) and THF (4 mL). Purification by column
chromatography using Et2O as the eluent afforded a mixture of diasteroi-
someric aldols 27d as a white solid (164 mg, 78%, cis/trans 85:15 as de-
À
1H; CH Ar), 6.00 (d, J=2.2 Hz, 1H; CHar), 6.21 (d, J=2.2 Hz, 1H;
CHar), 7.23 (d, J=7.6 Hz, 1H; CHar), 7.34 (dd, J=7.6, 7.6 Hz, 1H; CHar),
7.51 (dd, J=7.6, 7.6 Hz, 1H; CHar), 7.80 ppm (d, J=7.6 Hz, 1H; CHar);
minor cis isomer: d=1.65 (s, 3H; CH3), 3.22 (s, 3H; OCH3), 3.30 (s, 3H;
À
CO2CH3), 3.80 (s, 3H; OCH3), 3.91 (s, 3H; OCH3), 5.02(s, 1H; C H Ar),
1
termined by H NMR spectroscopy). The two diastereoisomers were sep-
5.93 (d, J=2.2 Hz, 1H; CHar), 6.20 (d, J=2.2 Hz, 1H; CHar), 7.20 (d, J=
7.6 Hz, 1H; CHar), 7.35 (dd, J=7.6, 7.6 Hz, 1H; CHar), 7.51 (dd, J=7.6,
arated by column chromatography (pentane/EtOAc 30:70). 1H NMR
7382
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 7374 – 7384

Intramolecular Isomerisation–Aldolisation
FULL PAPER
7.6 Hz, 1H; CHar), 7.82ppm (d, J=7.6 Hz, 1H; CHar); 13C NMR
(75 MHz, CDCl3): major trans isomer: d=16.1, 44.4, 52.5, 54.7, 55.3, 56.1,
59.7, 90.7, 91.2, 107.3, 123.8, 125.5, 126.7, 134.3, 134.8, 158.0, 159.6, 160.7,
173.4, 204.3 ppm; minor cis isomer: d=23.3, 47.4, 51.6, 54.8, 55.2, 56.1,
61.2, 90.5, 90.8, 107.8, 123.9, 125.4, 126.8, 134.4, 134.9, 156.1, 159.3, 159.6,
160.6, 171.9, 204.1 ppm; HRMS (EI, 70 eV): m/z: calcd for C21H22O6:
370.1416 [M]+; found: 370.1420 (0 ppm).
[6] C. H. Park, X. Siomboing, S. Yous, B. Gressier, M. Luyckx, P. Cha-
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[10] a) N. J. Lawrence, E. M. S. Armitage, B. Greedy, D. Cook, S. Ducki,
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Methyl 2,3-dihydro-5,6-dimethoxy-1-(2,4,6-trimethoxyphenyl)-2-methyl-3-
oxo-1H-indene-2-carboxylate (28c): These indanones were obtained by
the method used for the preparation of 28b, by starting with 27d
(164 mg, 0.582mmol), Et 3N (122 mL, 0.873 mmol), mesyl chloride (68 mL,
0.873 mmol) and CH2Cl2 (4 mL), followed by trimethoxybenzene
(104 mg, 0.621 mmol) and trifluoromethanesulfonic acid (5 mL,
0.050 mmol) in dichloroethane (3 mL). Purification by column chroma-
tography using pentane/EtOAc 60:40 as the eluent afforded a mixture of
diastereoisomeric indanones as a white solid (70:30 as determined by
1H NMR spectroscopy, 171 mg, 68%). The two diastereoisomers were
separated by column chromatography (pentane/EtOAc 70:30). 1H NMR
(300 MHz, CDCl3): major trans isomer: d=1.09 (s, 3H; CH3), 3.27 (s,
3H; OCH3), 3.80 (s, 6H; CO2CH3, OCH3), 3.83 (s, 3H; OCH3), 3.92(s,
À
3H; OCH3), 5.40 (s, 1H; CH Ar), 6.00 (d, J=2.2 Hz, 1H; CHar), 6.18 (d,
J=2.2 Hz, 1H; CHar), 6.63 (s, 1H; CHar), 7.20 (s, 1H; CHar); minor cis
isomer: d=1.64 (s, 3H; CH3), 3.28 (s, 6H; CO2CH3, OCH3), 3.81 (s, 3H;
OCH3), 3.84 (s, 3H; OCH3), 3.91 (s, 3H; OCH3), 3.95 (s, 3H; OCH3),
À
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4.92(s, 1H; C H Ar), 5.96 (d, J=2.2 Hz, 1H; CHar), 6.19 (d, J=2.2 Hz,
1H; CHar), 6.61 (s, 1H; CHar), 7.25 ppm (s, 1H; CHar).13C NMR
(75 MHz, CDCl3): major trans isomer: d=16.2, 44.2, 52.4, 54.9, 55.3, 56.0,
56.3, 59.9, 90.6, 91.1, 104.3, 106.5, 106.8, 127.1, 149.0, 153.8, 155.5, 159.7,
160.0, 160.7, 173.5, 202.8; minor cis isomer: d=23.2, 47.3, 51.5, 55.0, 55.2,
56.1, 56.3, 61.7, 90.4, 90.8, 104.3, 106.4, 107.4, 127.6, 149.1, 151.9, 155.5,
159.5, 159.8, 160.6, 172.0, 202.9 ppm; HRMS (EI, 70 eV): m/z: calcd for
C23H26O8 [M]+: 430.1628; found: 430.1626 (0 ppm); elemental analysis
calcd (%) for C23H26O8: C 64.18, H 6.09; found: C 63.61, H 6.04.
X-ray crystallographic study of 27d: Formula: (C14H16O6, H2O); M=
298.28. Bruker-AXS APEXII Kappa-CCD diffractometer, MoKa radia-
tion (l=0.71073 Š), T=100 K; monoclinic, P21/a; a=9.5218(8), b=
14.6638(12), c=10.1078(8) Š, b=95.891(5)8; V=1403.9(2) Š3; Z=4; d=
1.411 gcmÀ3, m=0.114 mmÀ1. The structure was solved by direct methods
using the SIR97 program,[34] and then refined with full-matrix least-
square methods based on F2 (SHELX-97)[35] with the aid of the
WINGX[36] program. All non-hydrogen atoms were refined with aniso-
tropic thermal parameters. Hydrogen atoms were finally included in their
calculated positions. A final refinement on F2 with 3202 unique intensi-
ties and 199 parameters converged at wR
2292 observed reflections with I>2s(I)).
(F2)=0.096 (R(F)=0.045 for
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A
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Received: April 23, 2007
Published online: June 20, 2007
7384
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 7374 – 7384