Functionalized esters as bis-electrophiles in a silicon-induced domino synthesis of annulated carbocycles

Article abstract of DOI:10.1016/j.tet.2009.01.119

The reaction of silyl-substituted carbanion 1b with arene-1,2-dicarboxylates 6, 15 yields indenone derivatives 11, 16 in a domino process involving silyl C→O migration and elimination. However, in a competing pathway, the initial addition of 1b leads to l

Full text of DOI:10.1016/j.tet.2009.01.119

Tetrahedron 65 (2009) 5577–5587
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Functionalized esters as bis-electrophiles in a silicon-induced domino synthesis
of annulated carbocycles
,
b
c
Florian Genrich a, Guido Harms a, Ernst Schaumann a , Mimoza Gjikaj , Gunadi Adiwidjaja
*
a Institut fu¨r Organische Chemie, Technische Universita¨t Clausthal, Leibnizstraße 6, 38678 Clausthal-Zellerfeld, Germany
b Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Clausthal, Paul-Ernst-Straße 4, 38678 Clausthal-Zellerfeld, Germany
c
¨
Mineralogisch-Petrographisches Institut, Universitat Hamburg, Grindelallee 48, 20146 Hamburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of silyl-substituted carbanion 1b with arene-1,2-dicarboxylates 6, 15 yields indenone de-
rivatives 11, 16 in a domino process involving silyl C/O migration and elimination. However, in
a competing pathway, the initial addition of 1b leads to lactone formation (8, 17). Substrates 26, 38
containing an ester group and a bromine substituent react with 1b under substitution of the halogen not
allowing silyl migration. But desilylation with TBAF gives reactive carbanions providing benzo-annulated
cycloalkanones 29, 40.
Received 30 October 2008
Received in revised form 30 January 2009
Accepted 31 January 2009
Available online 17 April 2009
Keywords:
Silylated thioacetals
Carbanions
Ó 2009 Elsevier Ltd. All rights reserved.
Esters
Carbocycles
Domino reaction
1. Introduction
O
OSi
O
Si
R1
R2
OTs
n
The silicon-induced domino reaction which we have developed
has proven to be a versatile synthetic method for the preparation of
various functionalized 4- to 7-ring carbocycles.1 In this one-pot
reaction, a reversible C/O silyl migration (Brook rearrangement)2
is the key step. In Scheme 1, the method is illustrated for a silyl-
substituted carbanion to react with an epoxy-tosylate as bis-
electrophile.
~Si
OTs
OTs
n
n
Si
R2
R1
R1
R2
SNi
OTs
t
: SiM
Si
e3, SiMe2Ph, SiMePh2, SiMe2 Bu
R1: SiMe3, SiMe2Ph, SMe
R2: SMe, SPh
Besides epoxy-tosylates, also bis-epoxides,3 vinyl-epoxides,4 or
epoxy-aziridines5 have been used in the domino process. In all these
cases, the epoxy oxygen is the acceptor for the migrating silyl resi-
due. We nowconsidered other oxygen-containing functional groups
as silicon acceptor and here report our results on the ester group.
R1,R2: S-(CH2)3-S
n = 0-3
OSi
n
R1
R2
Scheme 1. The silicon-induced domino process with epoxy-tosylates leads to func-
tionalized 4–7-ring carbocycles by a [1,4]-Brook rearrangement.
2. Results and discussion
THF with 1.1 equiv of n-BuLi for 30 min at ꢀ78 ꢁC and subsequent
quenching with D2O showed only 28% of deuteration to product 1c,
as determined by 1H NMR spectroscopy. In extending literature
information by Seebach et al.,7 we found that addition of 1.1 equiv
of n-BuLi to a 0.5 M solution of the precursor 1a in dry THF at
ꢀ78 ꢁC, stirring for 30 min, then dipping the flask for 30 min into
ice/water, followed by 15 min stirring at room temp are optimal
conditions for quantitative lithiation to 1b; the carbanion solution
is then immediately used for reactions (Scheme 2).
To exclude problems resulting from carbanion generation, in the
first step of our investigations we did deuteration experiments to
make sure that the C1-building block 1a, which can easily be syn-
thesized from formaldehyde dimethylmercaptal,6,7 is quantita-
tively deprotonated to carbanion 1b. Stirring precursor 1a in dry
* Corresponding author. Tel.: þ49 5323 72 2519; fax: þ49 5323 72 2858.
E-mail address: ernst.schaumann@tu-clausthal.de (E. Schaumann).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.119

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F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
Me3Si
Me3Si
CO2Et
CO2Et
Me3Si
a)
b)
c)
SMe
SMe
SMe
SMe
MeS
SMe
SiMe3
1a
SMe
SMe
MeS
SMe
D
88 %
1b
6
1b
1c
Scheme 2. (a) n-BuLi (1.1 equiv), Me3SiCl (2.0 equiv), THF, ꢀ70 to 0 ꢁC, overnight; (b)
n-BuLi (1.1 equiv), THF, 30 min at ꢀ78 ꢁC, then 30 min at 0 ꢁC, finally 15 min at room
temp; (c) D2O.
O OEt
Me3SiO OEt
SiMe3
SMe
SMe
SMe
~ SiMe3
SMe
CO2Et
CO2Et
7a
7b
Initial experiments showed that CH-acidic or a,b-unsaturated
esters cannot be used in the process since the basic conditions fa-
vour competing reactions.6 In case of dimethyl succinate (2), the
carbanion 1b undergoes no nucleophilic attack on the ester, instead
SMe
Me3Si
Me3SiO
SMe
OEt
OEt
SMe
SMe
the a-carbon is deprotonated, and ester condensation is observed
yielding product 4. Interestingly, the formation of a cyclization
product as it is otherwise common for the action of bases on suc-
cinates8 is not observed. To prevent deprotonation chemistry, the
unsaturated ester diethyl maleate (3) was used and shows Michael
addition to give succinate 5 (Scheme 3).
O
O
O
9
8, 24 %
m-CPBA
SO2Me
H
SO2Me
OEt
OEt
O
O
O
CO2Me
SMe
SMe
CO2Me
SMe
O
CO2Me
MeO2C
CO2Me
4, 87 %
2
11, 18 %
O
O
12
SiMe3
MeS
MeS
10, 93 %
Scheme 4. Competing reaction pathways in the reaction of phthalate
carbanion 1b.
6 with
SiMe3
1b
MeS
MeS
CO2Et
CO2Et
CO2Et
CO2Et
5, 82 %
-unsaturated esters cannot be used for the silicon-induced
3
Scheme 3. CH-acidic or
a
,
b
domino process.
For non-enolizable aromatic esters, such as phthalates, silicon
migration should be possible and eventually lead to annulated
rings. Therefore these esters are promising starting materials for
the synthesis of new carbocyclic products by a [1,3]-Brook
rearrangement.
Starting from diethyl phthalate (6), the desired nucleophilic
addition of the silyl-substituted carbanion 1b onto the ester func-
tion is indeed observed. However, this reaction yields two different
products: g
-lactone 8 is isolated besides indenone 11.6 So at the
stage of intermediate 7a, lactonization competes with the C/O
silyl shift to 7b. Nevertheless, isolation of indenone 11 demon-
strates that silyl migration to 7b must have taken place, followed by
ring-closure, providing intermediate 9, which could not be isolated
nor the expected product 12. Instead, indenone 11 is formed as
result of an uncommon elimination (Scheme 4). Thioacetal 8 was
oxidized to sulfone 10, which gave single crystals and allowed
structural proof by X-ray analysis (Fig. 1).
The unusual formal elimination of a silyl methanesulfenate
leading to indenone 11 called for a rigorous proof of structure.
Unfortunately, product 11 is an oil and derivatization to the corre-
sponding sulfone or 2,4-dinitrophenylhydrazone gave no suitable
crystals for X-ray study. So in an independent synthesis (Scheme 5)
1,3-indandione (13) is first converted into 2,2-(bismethylthio)-1,3-
indandione (12). The thioacetal function is then reduced by
a method of Grossert and Dubey,9 using ethanethiol and an excess
of sodium hydride. From this reaction after acidification, sulfide 14
is isolated. Finally acid-catalyzed ethoxylation with triethyl ortho-
formate as water scavenger in dry ethanol10 affords the previously
obtained product 11 confirming the suggested structure.
Figure 1. X-ray structure of
g
-lactone 10.6
O
O
O
O
O
a)
b)
SMe
H
SMe
SMe
38 %
94 %
O
13
12
14
OEt
O
c)
SMe
3 %
11
Scheme 5. Independent synthesis of indenone 11: (a) NaH (2.1 equiv), MeSSO2Me
(2.1 equiv), THF, reflux, 7 h; (b) EtSH (3.0 equiv), NaH (4.0 equiv), THF, 0 ꢁC to room
temp, 3 h, then HCl, H2O; (c) p-TsOH (5 mol %), (EtO)3CH (3.0 equiv), EtOH, reflux, 12 h.

F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
5579
Dimethyl phthalate as starting material gave no better yields
O
O
than ester 6. Warming to room temp and longer stirring times
neither result in higher conversions nor a better product yield.
Additives such as DMPU, TMEDA or 12-crown-4 ether that have
been reported to facilitate silyl migration1b,11 did not improve the
outcome of the reactions.
Furthermore, variations on the diester backbone seemed
promising. Employing diethyl naphthalene-2,3-dicarboxylate (15)
in the domino process, by analogy with the results for phthalate
6, the reaction delivers carbocycle 16 along with lactone 17
(Scheme 6).
a)
b)
OH
OH
O
O
70 %
83 %
22
23
24
c), d) 47 %
52 %
O
O
OMe
OTs
OMe
OTs
25
21
MeS
Me3Si
SMe
OEt
Scheme 8. Ester-tosylates. Synthesis of an ester-tosylate as C5-building block, starting
from isochromane: (a) SeO2 (2.0 equiv), xylene, reflux, 42 h; (b) KOH (3.6 equiv), Et2O,
room temp, 36 h, then HCl, H2O; (c) TMSCHN2 (1.3 equiv), MeOH/THF (1:1), room
temp, 15 min; (d) TsCl (2 equiv), pyridine (3 equiv), CHCl3, 0 ꢁC to room temp, 14 h.
OEt
CO2Et
CO2Et
a)
O
SMe
15
O
O
16, 8 %b (10 %)c
17, 22 %b (28 %)c
Scheme 6. Diethyl naphthalene-2,3-dicarboxylate: (a) 1b (1.3 equiv), THF, ꢀ78 to
ꢀ50 ꢁC, overnight; (b) isolated yield; (c) isolated yield based on conversion, as judged
by the amount of recovered starting material.
Additional promising targets for carbanion 1b appeared to be
hetarene-1,2-dicarboxylates. But in a complex reaction mixture
a tendency for reaction at the hetarene ring rather than at the ester
unit is seen in the reaction of pyridine derivative 18, which with
carbanion 1b gives a nucleophilic aromatic substitution reaction at
carbon 6 providing thioacetal 19. The hydride, which must be
formed at the same time partially reduces the thioacetal to sulfide
20, which is isolated as well (Scheme 7).
Figure 2. X-ray structure of ester tosylate 25.
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
a)
MeS
MeS
O
O
N
N
N
b)
c)
a)
SMe
OMe
OTs
OMe
Br
18
19, 11 %
20, 4 %
68 %
Scheme 7. Reactions of hetarenes: (a) 1b (1.3 equiv), THF, ꢀ78 to ꢀ50 ꢁC.
25
26
O
O
In addition to bis-esters as bis-electrophiles, we employed ester
tosylates by analogy to epoxy-tosylates, which have already shown
successful applications in the domino process (Scheme 1). The
unknown methyl 2-(tosyloxymethyl)benzoate (21) appeared to be
a promising candidate, but we were unable to tosylate the alcohol
precursor methyl 2-(hydroxymethyl)benzoate due to competing
phthalide formation.13
We were more successful in the synthesis of homologue 25,
a C5-building block, which would eventually lead to annulated
cyclohexanes (C5þC1/C6) by the silicon-induced domino reaction.
Starting from isochromane (22) we obtained 1-isochromanone (23)
after oxidation with selenium dioxide on a multigram-scale.14 Sa-
OMe
OMe
SiMe3
SMe
SMe
28
27
O
O
SMe
SMe
OMe
27
29
24 % (2 steps)
26 % (2 steps)
ponification of d-lactone 23, followed by cautious acidification and
conscientious exclusion of heat (to avoid recyclization)15 affords
hydroxy acid 24. Methylation of the ester by TMS-diazomethane12
and subsequent tosylation16 of the crude product gives ester tosy-
d) 86 %
O
OMe
late 25, aside from recyclization to d-lactone 23, which could not be
SMe
O
avoided (Scheme 8). Single crystals of the new bis-electrophile 25
allowed an X-ray structural analysis (Fig. 2).
SO2Me
SO2Me
SMe
31
The reaction of 1b with ester tosylate 25 gave only minor
conversion and no well-defined products. So as before the ester
function shows low reactivity towards carbanion 1b. Substitution
of the tosyloxy group by chloride did not show better results. So
bromide 26 was synthesized from the tosylate. In the reaction of
1b with ester-bromide 26 we observed substitution of the
30
Scheme 9. C5þC1 annulation protocol: (a) LiBr (1.9 equiv), acetone, reflux, 12 h; (b) 1b
(1.3 equiv), THF, ꢀ78 ꢁC to room temp, overnight (products 27, 28 not separable); (c)
anhydrous TBAF, THF, ꢀ78 ꢁC to room temp, overnight (use of standard TBAF con-
taining H2O leads to desilylated product 31; (d) m-CPBA (6.4 equiv), CHCl3, room temp,
4 days.

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F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
Figure 4. X-ray structure of 2,2-bis(methylsulfonyl)-1-benzosuberone (41).
Figure 3. X-ray structure of 2,2-bis(methylsulfonyl)-1-tetralone (30).
to get alcohol 36 from diacid 33. Acid 33 is commercially available,
but rather expensive; so we started one step back from the
cheaper 2-carboxycinnamic acid (32). A method of Arterburn
et al.19 was adopted to reduce the double bond where saturated
compound 33 is quantitatively obtained by a palladium-catalyzed
hydrogenation using formic acid as hydride donor. Carboxylic acid
33 is selectively converted into the mono methyl ester by esteri-
fication in methanol at room temp. The ester is reduced to the
corresponding alcohol by lithium borohydride in dioxane.18a We
then combined two steps, not esterifying the benzoic acid 35 as
described, but methylating it with TMS-diazomethane,12 con-
tinuing the reaction simply after having evaporated the solvents
in vacuo. Subsequent tosylation of the alcohol 36 afforded the
novel ester tosylate 37. This tosylate is more stable than its con-
gener 25.
bromide affording silylated compound 28 in an inseparable mix-
ture with elimination product 27 (Scheme 9). In this substitution
reaction of the bromide, silyl migration is not possible; so the
ring-closure reaction was attempted via desilylation. Using dry
TBAF17 the new carbocycle 29 could successfully be isolated.
Elimination product 27 and tetralone derivative 29 could now be
separated. Analogous use of commercial TBAF gives only desily-
lated product 31. Thioacetal 29 was oxidized to the corresponding
sulfone 30. The stability of compound 30 at room temp is limited,
but single crystals could be grown for an X-ray structural analysis
(Fig. 3).
As to the corresponding C6-building block (Scheme 10), a lit-
erature report by Meise et al.18a revealed a multi-step procedure
Neither ester tosylate 37 nor the corresponding chloride reacted
in the domino process with carbanion 1b just as we had experi-
enced with the analogous C5-building block 25 and its chloride. The
tosyloxy function can be displaced by bromide as well, using lith-
ium bromide in acetone yielding bromo-ester 38. The reaction of 38
with carbanion 1b shows quantitative substitution of the bromide
affording silylated product 39. Treatment of 39 with anhydrous
TBAF17 gives a novel carbocycle, benzosuberone derivative 40. With
commercial TBAF, desilylated compound 42 is isolated, which could
not be forced to cyclize neither by n-BuLi nor t-BuLi. Thioacetal 40
was oxidized to the corresponding sulfone 41 for an X-ray struc-
tural analysis (Scheme 10 and Fig. 4).
CO2H
CO2H
33
CO2H
CO2Me
34
CO2H
CO2H
32
a)
b)
99 %
95 %
CO2Me
CO2H
d), e)
47 %
c)
79 %
OR
OH
36: R = H; 37: R = Ts
35
CO2Me
CO2Me
SiMe3
f)
g)
Br
95 %
99 %
SMe
SMe
3. Conclusion
38
39
O
O
SMe
SO2Me
SO2Me
The isolation of indenone derivatives 11, 16 confirms that ad-
dition of silyl-substituted carbanion 1b to one ester moiety in
phthalate 6 or naphthalene-2,3-dicarboxylate 15 may be followed
by C/O silyl migration to give a new carbanion, ring-closure and
finally, by a noteworthy 1,2-elimination step, carbocycles 11, 16
(Schemes 4 and 6). This corresponds to a four-step domino process
(Scheme 4). However, we were not able to suppress the competing
cyclization to lactones 10, 17 after the initial addition of carbanion
1b. Furthermore, the reactions did not go to completion. The re-
luctance of the ester unit to add carbanion 1b is also seen in the lack
of ester reactivity in esters 26, 38 with an additional bromine
substituent. Here, the bromine is displaced and cyclization occurs
only after TBAF-induced desilylation. However, products 29, 40 are
identical with the products, which would be formed by reaction of
1b with the ester, silyl migration, cyclization and finally hydrolysis.
Lack of ester reactivity is furthermore seen in the reaction of
hetarene 18 with carbanion 1b. Also the desilylated derivates 31, 42
of 28, 39 do not cyclize after deprotonation with alkyl lithiums. A
special role of the tetrabutylamonium cation is apparent, which has
also been seen in other work.20
SMe
h)
i)
90 %
73 %
40
41
j)
O
OMe SMe
SMe
42
Scheme 10. C6þC1 annulation protocol: (a) PdCl2 (10 mol %), HCOOH (4 equiv), NaOH/
H2O, 65 ꢁC, 24 h; (b) H2SO4 (cat.), MeOH, room temp, 30 min; (c) LiBH4 (2.5 equiv),
dioxane, 100 ꢁC, 20 min, then HCl, H2O; (d) TMSCHN2 (1.7 equiv), MeOH/THF (1:1),
0
ꢁC, 15 min; (e) TsCl (2 equiv), pyridine (3 equiv), CHCl3, 0 ꢁC to room temp, 14 h; (f)
LiBr (2.0 equiv), acetone, reflux, 17 h; (g) 1b (1.3 equiv), THF, ꢀ78 ꢁC to room temp,
overnight; (h) anhydrous TBAF, THF, ꢀ78 ꢁC to room temp, overnight; (i) m-CPBA
(10 equiv), CHCl3, room temp, 4 days; (j) desilylated product 42 cannot be cyclized to
40 neither using n-BuLi nor t-BuLi.

F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
5581
4. Experimental
4.1. General
1.3 equiv of 1a and 1.4 equiv n-BuLi as described above) is added
dropwise via cannula or syringe. After complete addition, the
temperature is slowly raised and the mixture stirred at ꢀ50 ꢁC
overnight. The reaction is quenched at ꢀ50 ꢁC by water and the
mixture is allowed to warm to room temp. After multiple extrac-
tions with Et2O or CH2Cl2, the combined organic layers are dried
over Na2SO4 and the solvents are removed on a rotary evaporator
followed by purification of the crude product by flash
chromatography.
1H NMR and 13C NMR spectra were recorded on Bruker DPX-200
and AMX-400 instruments in the solvents CDCl3, DMSO-d6 or
MeOD as indicated. Chemical shifts are reported in
d (ppm) and
coupling constants J in hertz. Unless otherwise stated, for NMR
spectra the solvent peak (1H NMR: CDCl3¼7.26, DMSO¼2.50,
MeOD¼3.34; 13C NMR: CDCl3¼77.4, DMSO¼40.4, MeOD¼49.9) was
used as reference. The degree of substitution (C, CH, CH2, CH3) was
determined by the DEPT-135 method. Melting points are un-
corrected. IR spectra were recorded on a Bruker Vektor 22 FTIR
spectrometer in the range of 400 to 4000 cmꢀ1. Elemental analyses
were performed by the Institut fu¨r Pharmazeutische Chemie,
Technische Universita¨t Braunschweig. The GC–MS spectra (EI) were
recorded either with a GC Hewlett-Packard 5980, Serie II/MS
Hewlett Packard 5989 B, or a Varian GC3900 with SAT2100T mass
spectrometer. The ESI mass spectra were measured with an Agilent
LCMSD Series HP1100 with APIES. Samples were sprayed from
methanol at a fragmentor voltage of 0 V, unless otherwise noted.
HRMS spectra were measured at the Institut fu¨r Organische Chemie,
4.2.4. Trimethyl 3-oxopentane-1,2,5-tricarboxylate (4)6
Under nitrogen at room temp, a solution of thioacetal 1a
(192 mg, 1.06 mmol, 1.0 equiv) in abs THF (7 mL) was treated
dropwise with n-BuLi (1.6 M in hexane, 0.70 mL, 1.12 mmol,
1.1 equiv). After 5 min the solution was cooled to ꢀ80 ꢁC, and
DMPU (0.08 mL, 0.62 mmol, 0.6 equiv) was added. The obtained
solution was then added to a solution of dimethyl succinate (2,
156 mg, 1.06 mmol, 1.0 equiv) in abs THF (27 mL) at ꢀ80 ꢁC. The
mixture was allowed to warm to ꢀ30 ꢁC, observing a brightly yel-
low colour. After completion, the reaction was quenched with
water, extracted with CH2Cl2, the combined organic layers dried
over Na2SO4 and the solvents evaporated on a rotary evaporator.
Purification of the crude product by flash chromatography (petro-
leum ether/EtOAc¼10:1) afforded compound 4 (120 mg, 87%) as
a colourless oil. C11H16O7; 260.24 g/mol. 1H NMR (200 MHz, CDCl3):
¨
Leibniz Universitat Hannover. X-ray structural analysis of compound
10 was performed at Mineralogisch-Petrographisches Institut, Uni-
¨
¨
versitat Hamburg; and of compounds 25, 30 and 41 at the Institut fur
¨
Anorganische und Analytische Chemie, Technische Universitat Claus-
d
¼4.04 (dd, J¼7.7, 6.8 Hz, 1H, CH), 3.76 (s, 3H, OCH3), 3.67 (s, 3H,
OCH3), 3.66 (s, 3H, OCH3), 3.14–2.80 (m, 4H, CH2), 2.62 (t, J¼6.6 Hz,
2H, CH2). 13C NMR (50 MHz, CDCl3):
thal. TLC was performed on Merck 60 F254 precoated silica plates,
spots were detected either by UV (254 nm, 366 nm) or dipping into
a permanganate [KMnO4 (3 g), K2CO3 (20 g), NaOH (5 mL, 5% in
H2O), H2O (300 mL)] or an anisaldehyde solution [3% p-methoxy-
benzaldehyde and 1% H2SO4 in MeOH] and heating. Flash chro-
d
¼202.7 (1C, C]O), 173.1 (1C,
CO2Me), 172.1 (1C, CO2Me), 169.0 (1C, CO2Me), 54.1 (1C, CH), 53.3
(1C, OCH3), 52.5 (1C, OCH3), 52.2 (1C, OCH3), 37.7 (1C, CH2), 32.5
(1C, CH2), 28.1 (1C, CH2). IR (film): nmax¼2957, 1739, 1438, 1167, 913,
745 cmꢀ1. MS (ESIþ): m/z¼283 [MþNa]þ. Elemental analysis: found
C 51.42%, H 6.42%, calcd C 50.77%, H 6.20%.
matography was performed with silica gel 60 (Merck, 40–63 mm);
the given mass is for the amount of silica gel used. Boiling range of
petroleum ether: 60–70 ꢁC. Absolute solvents (abs) were dried by
standard laboratory methods and kept under nitrogen.
4.2.5. Diethyl 2-(bis(methylthio)(trimethylsilyl)methyl)-
succinate (5)6
4.2. Synthesis and analytics
Under nitrogen at 0 ꢁC, a solution of thioacetal 1a (100 mg,
0.55 mmol, 1.1 equiv) in abs THF (4 mL) was treated with n-BuLi
(1.6 M in hexane, 0.41 mL, 0.66 mmol, 1.3 equiv). After 30 min
DMPU (0.08 mL, 0.62 mmol, 1.2 equiv) was added, the solution
stirred at 0 ꢁC for further 60 min and cooled to ꢀ78 ꢁC. This solution
was then added dropwise to a solution of diethyl maleate (3, 86 mg,
0.50 mmol, 1.0 equiv) in abs THF (5 mL) at ꢀ60 ꢁC, the mixture
turning yellow, then becoming darker. The reaction mixture was
allowed to come to room temp, quenched with water and extracted
with CH2Cl2. The combined organic layers were dried over Na2SO4,
and the solvents evaporated on a rotary evaporator. Purification of
the crude product by flash chromatography (petroleum ether/
EtOAc¼30:1) afforded compound 5 (144 mg, 82%) as a colourless
4.2.1. Lithio-bis(methylthio)(trimethylsilyl)methane (1b):
optimized procedure for quantitative deprotonation
In an oven-dried Schlenk flask compound 1a6,7 (1.0 equiv) is
placed under an inert and dry atmosphere, generated by at least
three short evacuations (volatile compound!) with an oil pump,
alternately ventilating with nitrogen; then dissolving in abs THF
(0.5 M). To this solution n-BuLi (1.1 equiv) is added dropwise via
syringe at ꢀ78 ꢁC. The solution is stirred at ꢀ78 ꢁC for 30 min, then
30 min at 0 ꢁC and finally 15 min at room temp. The pale yellow
solution of the carbanion is then immediately used for reactions.
4.2.2. Deutero-bis(methylthio)(trimethylsilyl)methane (1c)
oil. C14H28O4S2Si; 352.59 g/mol. 1H NMR (200 MHz, CDCl3):
d
¼4.17
A solution of carbanion 1b (obtained using 100 mg, 0.55 mmol,
of 1a) was quenched by D2O (1 mL). The mixture was diluted with
Et2O and washed with water. The organic layer was dried over
Na2SO4 and the solvents removed in vacuo obtaining 1c (89 mg,
89%) as a colourless liquid. C6H15DS2Si; 181.41 g/mol. 1H NMR
(q, J¼7.0 Hz, 2H, OCH2), 4.11 (q, J¼7.1 Hz, 2H, OCH2), 3.27 (dd, J¼7.6,
6.5 Hz, 1H, CH), 3.18–2.95 (m, 2H, CH2), 2.14 (s, 3H, SCH3), 2.09 (s,
3H, SCH3), 1.29 (t, J¼7.1 Hz, 3H, CH3), 1.24 (t, J¼7.1 Hz, 3H, CH3), 0.26
(s, 9H, SiMe3). 13C NMR (50 MHz, CDCl3):
d
¼173.1 (1C, C]O), 172.5
(1C, C]O), 61.4 (1C, OCH2), 61.1 (1C, OCH2), 49.1 (1C, CH), 48.3 (1C,
C), 35.8 (1C, CH2), 14.5 (1C, CH3), 14.4 (1C, CH3), 13.5 (1C, CH3), 12.2
(1C, CH3), 0.9 (3C, SiMe3). IR (film): nmax¼2982, 2360, 1735, 1249,
(200 MHz, CDCl3):
d
¼2.16 (s, 6H, SCH3), 0.17 (s, 9H, SiMe3). 13C NMR
(50 MHz, CDCl3):
(3C, SiMe3).
d
¼41.4 (t, J¼21 Hz, 1C, CD), 15.2 (2C, SCH3), ꢀ1.3
913, 743 cmꢀ1
.
MS (ESIþ): m/z¼375 [MþNa]þ. HRMS (ESIþ):
[MþNa]þ found 375.1093, calcd 375.1096.
4.2.3. General procedure for reactions of carbanion 1b with bis-
electrophiles
4.2.6. 3-(Bis(methylthio)(trimethylsilyl)methyl)-3-ethoxy-
The bis-electrophile (1.0 equiv) is placed in an oven-dried,
rubber septum sealed Schlenk flask, evacuated by an oil pump and
alternately ventilated with nitrogen at least 3ꢂ. Then abs THF is
added to give a 0.25 M solution, which is cooled to ꢀ78 ꢁC. A si-
multaneously prepared solution of carbanion 1b (0.5 M, using
phthalide (8) and 3-ethoxy-2-(methylthio)-1-indenone (11)
Addition of carbanion 1b [obtained using 1a (529 mg,
2.93 mmol, 1.3 equiv), abs THF (6 mL), n-BuLi (1.6 M in hexane,
2.0 mL, 3.2 mmol, 1.4 equiv)] to a solution of diethyl phthalate (6,
500 mg, 2.25 mmol, 1.0 equiv) in abs THF (9 mL) showed

5582
F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
incomplete conversion and gave 780 mg of a red liquid as crude
product. Purification by flash chromatography (78 g, petroleum
ether/EtOAc¼20:1) afforded excess of 1a in an inseparable mixture
with further nonpolar undefined side products; a mixture of 8 and
11 as a red oil (315 mg) and the recovered phthalate 6 (185 mg,
37%). Separation of 8 and 11 was achieved by a second flash chro-
c¼14.131(1) Å,
b
¼147.03(1)ꢁ, V¼1543.7(2) Å3, Z¼4, dcalcd
¼
1.499 g cmꢀ3, F(000)¼728 using 3449 independent reflections and
220 parameters. R1¼0.0498, wR2¼0.1208 [I>2
s(I)], goodness of fit
on F2¼1.074, residual electron density¼0.399 and ꢀ0.330 e Åꢀ3
.
Further details of the crystal structure investigations have been
deposited with the Cambridge Crystallographic Data Center,
CCDC-699488. Copies of this information may be obtained free of
charge from The Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44(1223) 336 033; e-mail: fileserv@ccdc.ac.uk;
www.ccdc.cam.ac.uk).
matography (25 g, toluene/CH2Cl2¼1:1) delivering lactone
8
(196 mg, 24%) as a slightly orange oil, and carbocycle 11 (90 mg,
18%) as a slowly solidifying orange oil. Lactone 8: C16H24O3S2Si;
356.58 g/mol. Mp 35–40 ꢁC. 1H NMR (200 MHz, CDCl3):
d¼8.10–
8.02 (m, 1H, Har.), 7.95–7.86 (m, 1H, Har.), 7.67–7.54 (m, 2H, Har.),
3.44–3.02 (m, 2H, OCH2), 2.36 (s, 3H, SCH3), 1.27 (s, 3H, SCH3), 1.17
(t, J¼7.0 Hz, 3H, CH3), 0.38 (s, 9H, SiMe3). 13C NMR (50 MHz, CDCl3):
4.2.9. 2,2-Bis(methylthio)-1,3-indandione (12)
Under nitrogen, a solution of 1,3-indandione (13, 500 mg,
3.42 mmol,1.0 equiv) and S-methyl methanethiosulfonate (906 mg,
7.18 mmol, 2.1 equiv) in abs THF (10 mL) was added to a suspension
of sodium hydride (60% in mineral oil, 287 mg, 7.18 mmol,
2.1 equiv) in abs THF (10 mL). A spontaneous black-violet tinct was
observed. After heating at reflux for 7 h and stirring for additional
16 h at room temp, the dark reaction mixture was poured into
water and extracted 3ꢂ with CH2Cl2 (red aqueous phase). The
combined organic layers were dried over Na2SO4, filtrated and the
solvents removed on a rotary evaporator. Purification of the oily
brown residue by flash chromatography (70 g, petroleum ether/
EtOAc¼5:1) afforded thioacetal 12 (310 mg, 38%) as a beige solid.
C11H10O2S2; 238.33 g/mol. Mp 74–76 ꢁC. 1H NMR (200 MHz, CDCl3):
d¼167.9 (1C, C]O), 145.0 (1C, Car.), 133.1 (1C, CHar.), 131.1 (1C, CHar.),
130.2 (1C, Car.), 126.4 (1C, CHar.), 125.3 (1C, CHar.), 115.8 (1C, Cacetal),
60.7 (1C, OCH2), 50.9 (1C, C), 16.7 (1C, SCH3), 15.3 (1C, SCH3), 12.1
(1C, CH3), 1.5 (3C, SiMe3). IR (KBr): nmax¼2979, 2923, 1777, 1466,
1260, 1128, 1105, 919, 845 cmꢀ1. GC–MS (EI): m/z¼356 [100%, Mþ],
341 [20%], 311 [72%], 179 [32%]. HRMS (EI): [Mþ] found 356.0935,
calcd 356.0934. Indenone 11: C12H12O2S; 220.29 g/mol. 1H NMR
(200 MHz, CDCl3):
d
¼7.44–7.22 (m, 4H, Har.), 4.98 (q, J¼7.0 Hz, 2H,
OCH2), 2.32 (s, 3H, SCH3), 1.51 (t, J¼7.2 Hz, 3H, CH3). 13C NMR
(50 MHz, CDCl3):
d
¼194.0 (1C, C]O), 175.6 (1C, COEt), 140.6 (1C,
Car.), 132.9 (1C, CHar.), 132.5 (1C, Car.), 130.5 (1C, CHar.), 121.4 (1C,
CHar.), 119.2 (1C, CHar.), 102.6 (1C, CSMe), 68.9 (1C, OCH2), 19.6 (1C,
SCH3), 15.8 (1C, CH3). IR (KBr): nmax¼2981, 2923, 1712, 1613, 1553,
d
¼8.03–7.84 (m, 4H, Har.), 2.34 (s, 6H, SCH3). 13C NMR (50 MHz,
1467, 1377, 1350, 1296, 1156, 1079, 1007, 875, 769, 712, 691 cmꢀ1
.
CDCl3):
d
¼193.4 (2C, C]O), 138.8 (2C, Car.), 136.8 (2C, CHar.), 124.8
GC–MS (EI): m/z¼220 [100%, Mþ]. HRMS (EI): [Mþ] found 220.0559,
(2C, CHar.), 60.4 (1C, SCS), 12.6 (2C, SCH3). IR (KBr): nmax¼2919, 1741,
1704, 1589, 1417, 1351, 1328, 1252, 1157, 1087, 1024, 943, 865, 845,
765, 649, 614, 531 cmꢀ1. GC–MS (EI): m/z¼238 [100%, Mþ], 191
[42%]. HRMS (EI): [Mþ] found 238.0123, calcd 238.0122.
calcd 220.0558.
4.2.7. 3-(Bis(methylsulfonyl)methyl)-3-ethoxy-phthalide (10)
Lactone 8 (100 mg, 0.28 mmol, 1.0 equiv) and m-CPBA (70%,
760 mg, 3.08 mmol,11 equiv) were stirred in CHCl3 (20 mL) at room
temp for 12 h. An aqueous solution of Na2S2O3 was added to de-
stroy excess m-CPBA. The mixture was extracted with CH2Cl2
(3ꢂ20 mL), the combined organic layers were washed with satd
NaHCO3 (2ꢂ10 mL) and water (20 mL), dried over Na2SO4 and the
solvents removed on a rotary evaporator. Purification of the residue
by flash chromatography (petroleum ether/EtOAc¼1:1) afforded
sulfone 10 (91 mg, 93%) as a colourless solid. C13H16O7S2; 348.39 g/
4.2.10. 2-(Methylthio)-1,3-indandione (14)
NaH (60% in mineral oil, 504 mg, 12.6 mmol, 4.0 equiv) was
suspended in abs THF (20 mL) under nitrogen and cooled by ice/
water. Ethanethiol (0.70 mL, 9.45 mmol, 3.0 equiv) was added
dropwise, and the mixture was stirred until the formation of gas
ceased (5 min). Then
a solution of thioacetal 12 (750 mg,
3.15 mmol, 1.0 equiv) in abs THF (20 mL) was added slowly via sy-
ringe, obtaining an ochre reaction mixture. The ice was removed,
followed by additional stirring at room temp for 3 h. The suspen-
sion was poured into water (30 mL), and the resulting red mixture
acidified by 1 M HCl (30 mL), observing a change of colour to or-
ange. It was extracted with Et2O (3ꢂ50 mL) until complete decol-
ouration of the aqueous layer was reached. The combined organic
layers were dried over Na2SO4 and the solvents removed on a rotary
evaporator, obtaining a brown residue. Washing with petroleum
ether (3ꢂ2 mL) and subsequent drying in vacuo gave 14 (568 mg,
94%) as a pale yellow powder. C10H8O2S; 192.23 g/mol. Mp 133–
mol. Mp 134 ꢁC. 1H NMR (200 MHz, DMSO):
d
¼8.10–7.56 (m, 4H,
Har.), 6.65 (s, 1H, CH), 3.36 (s, 3H, SO2CH3), 3.33 (s, 3H, SO2CH3),
3.30–2.87 (m, 2H, OCH2), 1.10 (t, J¼7.0 Hz, 3H, CH3). 13C NMR
(50 MHz, DMSO):
d
¼167.3 (1C, C]O), 143.2 (1C, Car.), 135.5 (1C,
CHar.), 132.5 (1C, CHar.), 128.8 (1C, Car.), 125.8 (1C, CHar.), 125.5
(1C, CHar.), 105.7 (1C, Cacetal), 82.8 (1C, CH), 59.8 (1C, OCH2), 49.7
(1C, SO2CH3), 46.7 (1C, SO2CH3),15.1 (1C, CH3). IR (film): nmax¼3419,
2936, 2916, 1770, 1330, 1135, 928, 784, 719 cmꢀ1. MS (ESIþ): m/z¼
371 [MþNa]þ.
135 ꢁC. 1H NMR (200 MHz, CDCl3):
(s, 1H, CH), 2.22 (s, 3H, SCH3). 13C NMR (50 MHz, CDCl3):
d¼8.06–7.84 (m, 4H, Har.), 3.85
4.2.8. X-ray analysis of 106
d
¼196.3
A suitable single crystal of the title compound was selected
under a polarization microscope and mounted in a glass capillary
(d¼0.5 mm). The crystal structure was determined by X-ray dif-
fraction analysis. Single crystal intensity data were collected by use
of an Enraf-Nonius Kappa CCD equipped with a rotating anode
(2C, C]O), 142.0 (2C, Car.), 136.6 (2C, CHar.), 124.1 (2C, CHar.), 52.2
(1C, CH), 14.5 (1C, SCH3). IR (KBr): nmax¼2905, 1707, 1582, 1429,
1246, 1160, 780, 754, 655, 492 cmꢀ1
.
MS (ESIþ): m/z¼407
[2 MþNa]þ, 215 [MþNa]þ. HRMS (ESIþ): [MþH]þ found 193.0328,
calcd: 193.0323; no analytical data in the references.22
(MoK
a
radiation,
l
¼0.71073 Å) [T¼293(2) K]. The crystal structure
was solved by Direct Methods using SHELXS-9721a and refined
using alternating cycles of least squares refinements against F2
(SHELXL-97).21a All non-H atoms were located in Difference Fourier
maps and were refined with anisotropic displacement parameters.
The H positions were determined by a final Difference Fourier
Synthesis. For the presentation of the structure drawings the pro-
grams ORTEP21b and POV-Ray21c were applied. C13H16O7S2;
M¼348.39 g molꢀ1 crystallized in the monoclinic space group P21/c
4.2.11. 3-Ethoxy-2-(methylthio)-1-indenone (11): independent
synthesis
Sulfide 14 (100 mg, 0.52 mmol, 1.0 equiv) and p-TsOH$H2O
(5 mg, 0.03 mmol, 5 mol %) were dissolved in abs EtOH (5 mL) un-
der nitrogen. Triethyl orthoformate (0.26 mL, 1.56 mmol, 3.0 equiv)
was added and the mixture heated at reflux for 12 h. The red re-
action mixture was diluted with Et2O (50 mL) in spite of incomplete
conversion. The mixture was washed 3ꢂ with satd NaHCO3, the
yellow organic layer dried over Na2SO4 and the solvents were
with
lattice
parameters
a¼9.005(1) Å,
b¼22.292(1) Å,

F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
5583
removed on a rotary evaporator. Purification of the crude product
(9 mg) by flash chromatography (1 g, petroleum ether/EtOAc¼11:1)
afforded indenone 11 (3 mg, 3%) as a red oil (for analytical data see
above).
d
¼8.65 (d, J¼2.1 Hz, 1H, Har.), 8.10 (d, J¼2.2 Hz, 1H, Har.), 3.99 (s, 3H,
OCH3), 3.93 (s, 3H, OCH3), 3.71 (s, 2H, CH2), 2.00 (s, 3H, SCH3). 13
NMR (50 MHz, CDCl3):
C
d
¼166.7 (1C, C]O), 166.2 (1C, C]O), 152.1
(1C, CHar.), 149.2 (1C, Car.), 137.9 (1C, CHar.), 136.8 (1C, Car.), 127.2 (1C,
Car.), 53.5 (1C, OCH3), 53.4 (1C, OCH3), 35.2 (1C, CH2), 15.3 (1C,
SCH3). IR (film): nmax¼2954, 1731, 1562, 1435, 1298, 1137, 1078, 963,
795 cmꢀ1. GC–MS (EI): m/z¼255 [16%, Mþ], 224 [54%], 180 [100%,
MþꢀOCH3ꢀCO2CH3], 139 [93%]. MS (ESIþ): m/z¼278 [MþNa]þ.
HRMS (ESIþ): [MþH]þ found 256.0643, calcd 256.0644.
4.2.12. 3-Ethoxy-2-(methylthio)-1H-cyclopenta[b]-naphthalen-1-
one (16) and 3-(bis(methylthio)(trimethylsilyl)methyl)-3-
ethoxynaphtho[2,3-c]furan-1(3H)-one (17)
Addition of carbanion 1b [obtained using 1a (87 mg, 0.48 mmol,
1.3 equiv), abs THF (1 mL), n-BuLi (2.4 M in hexane, 0.22 mL,
0.52 mmol, 1.4 equiv)] to a solution of diethyl ester 15 (100 mg,
0.37 mmol, 1.0 equiv) in abs THF (1.5 mL) showed incomplete
conversion and gave 140 mg of a red oil as crude product. Purifi-
cation by flash chromatography (14 g, petroleum ether/
EtOAc¼30:1) afforded lactone 17 (32 mg, 22%) as an orange oil,
carbocycle 16 as an orange solid (8 mg, 8%); and recovered ester 15
(40 mg, 41%). Carbocycle 16: C16H14O2S; 270.35 g/mol. Mp 45–73 ꢁC.
4.2.14. 1-Isochromanone (23)14
Isochromane (6.37 g, 47.5 mmol, 1.0 equiv) and selenium di-
oxide (5.27 g, 47.5 mmol, 1.0 equiv) were stirred in xylene (50 mL,
isomers) under reflux for 20 h. The black mixture was allowed to
cool, and a second portion of selenium dioxide (5.27 g, 47.5 mmol,
1.0 equiv) was added. The mixture was heated at reflux for addi-
tional 22 h, then filtrated and the xylene was removed on a rotary
evaporator. Purification of the red residue by flash chromatography
1H NMR (200 MHz, CDCl3):
J¼7.0 Hz, 2H, OCH2), 2.40 (s, 3H, SCH3), 1.55 (t, J¼7.0 Hz, 3H, CH3).
13C NMR (100 MHz, CDCl3):
d¼8.47–7.45 (m, 6H, Har.), 5.02 (q,
(240 g, petroleum ether/EtOAc¼5:1) afforded
70%) as a pale red liquid. C9H8O2; 148.16 g/mol. 1H NMR (200 MHz,
CDCl3):
¼8.11–8.07 (m, 1H, Har.), 7.58–7.50 (m, 1H, Har.), 7.43–7.35
d-lactone 23 (4.91 g,
d
¼192.7 (1C, C]O), 175.3 (1C, COEt),
135.9 (1C, Car.), 135.7 (1C, Car.), 134.5 (1C, Car.), 133.7 (1C, Car.), 130.8
(1C, CHar.), 129.6 (1C, CHar.), 128.7 (1C, CHar.), 127.8 (1C, CHar.), 122.2
(1C, CHar.), 118.8 (1C, CHar.), 108.5 (1C, CSMe), 69.0 (1C, OCH2), 19.1
(1C, SCH3), 15.9 (1C, CH3). IR (film): nmax¼2924, 1698, 1545, 1459,
1302, 1199, 1120, 895, 779 cmꢀ1. GC–MS (EI): m/z¼270 [100%, Mþ].
HRMS (EI): [Mþ] found 270.0715, calcd 270.0715. Lactone 17:
d
(m, 1H, Har.), 7.28–7.24 (m, 1H, Har.), 4.53 (t, J¼6.0 Hz, 2H, OCH2),
3.06 (t, J¼6.0 Hz, 2H, CH2). 13C NMR (50 MHz, CDCl3):
¼165.5 (1C,
d
C]O), 139.9 (1C, Car.), 134.0 (1C, CHar.), 130.8 (1C, CHar.), 128.0
(1C, CHar.),127.6 (1C, CHar.),125.7 (1C, Car.), 67.7 (1C, OCH2), 28.2 (1C,
CH2).
C20H26O3S2Si; 406.63 g/mol. 1H NMR (200 MHz, CDCl3):
d¼8.48 (s,
1H, Har.), 8.45 (s, 1H, Har.), 8.07–8.00 (m, 2H, Har.), 7.72–7.58 (m, 2H,
Har.), 3.46–3.10 (m, 2H, OCH2), 2.40 (s, 3H, SCH3), 1.18 (s, 3H, SCH3),
1.18 (t, J¼7.0 Hz, 3H, CH3), 0.41 (s, 9H, SiMe3). 13C NMR (50 MHz,
4.2.15. 2-(2-Hydroxyethyl)benzoic acid (24)15
Powdered KOH (4.9 g, 87 mmol, 2 equiv) was added to a solu-
tion of 1-isochromanone (23, 6.45 g, 43.5 mmol, 1.0 equiv) in Et2O
(120 mL) and the suspension was stirred at room temp for 12 h. A
second portion of powdered KOH (4.0 g, 71 mmol, 1.6 equiv) was
added and the mixture stirred at room temp for additional 24 h.
After complete conversion (TLC) the ethereal solution was dec-
anted, the residue was washed with additional ether, dissolved in
water (70 mL) and cooled by ice/water. The aqueous solution was
acidified with 1 M HCl (130 mL), then extracted 3ꢂ with Et2O. The
combined ethereal layers were shortly dried over Na2SO4 and the
solvents removed in vacuo without any heat. Hydroxy acid 24
(5.97 g, 83%) was obtained as a beige solid. C9H10O3; 166.17 g/mol.
Mp 79–81 ꢁC (lit. white crystals, which slowly turn into lactone when
CDCl3):
d
¼168.0 (1C, C]O), 138.9 (1C, Car.), 135.6 (1C, Car.), 134.3
(1C, Car.),130.1 (1C, CHar.), 129.5 (1C, CHar.), 129.3 (1C, CHar.), 128.0
(1C, CHar.), 127.5 (1C, Car.), 126.3 (1C, CHar.), 125.6 (1C, CHar.), 116.0
(1C, Cacetal), 60.7 (1C, OCH2), 51.1 (1C, C), 16.7 (1C, SCH3), 15.4 (1C,
CH3), 12.3 (1C, SCH3), 1.6 (3C, SiMe3). IR (film): nmax¼2979, 2925,
1771, 1635, 1511, 1450, 1337, 1253, 1187, 1129, 1041, 920, 859,
751 cmꢀ1. GC–MS (EI): m/z¼406 [85%, Mþ], 391 [11%], 377 [23%],
359 [65%], 271 [100%, MþꢀSi(CH3)3ꢀSCH3ꢀCH3], 227 [65%], 73
[44%]. HRMS (EI): [Mþ] found 406.1094, calcd 406.1093.
4.2.13. Dimethyl 6-(bis(methylthio)methyl)-pyridine-2,3-
dicarboxylate (19) and dimethyl 6-(methylthiomethyl)-
pyridine-2,3-dicarboxylate (20)
exposed to air, mp 87 ꢁC). 1H NMR (200 MHz, DMSO):
H, CO2H), 7.78–7.74 (m, 1 H, Har.), 7.49–7.41 (m, 1 H, Har.), 7.33–7.24
d¼12.84 (s, 1
Addition of carbanion 1b [obtained using 1a (265 mg,
1.47 mmol, 1.3 equiv), abs THF (3 mL), n-BuLi (2.4 M in hexane,
0.66 mL, 1.58 mmol, 1.4 equiv)] to a solution of dimethyl ester 18
(225 mg, 1.13 mmol, 1.0 equiv) in abs THF (4.5 mL) showed com-
plete conversion and gave 380 mg of a yellow oil as crude product.
A first flash chromatography (25 g, petroleum ether/EtOAc¼4:1)
afforded excess of 1a in an inseparable mixture with non-polar
undefined side products, impure 19 (70 mg) as a viscous orange to
brown oil and impure 20 (100 mg) as an orange oil. Further flash
chromatography of each compound afforded 19 (35 mg, 11%) as
a yellow oil by (7 g, toluene/CH2Cl2¼1:1) and 20 (13 mg, 4%) as
(m, 2 H, Har.), 4.65 (s, 1 H, OH), 3.58 (t, J¼7.0 Hz, 2 H, OCH2), 3.07 (t,
J¼7.0 Hz, 2 H, CH2). 13C NMR (50 MHz, MeOD):
¼172.0 (1 C, C]O),
d
142.4 (1 C, Car.), 133.8 (2 C, CHar.), 132.8 (1 C, Car.), 132.7 (1 C, CHar.),
128.2 (1 C, CHar.), 65.0 (1 C, OCH2), 39.4 (1 C, CH2).
4.2.16. Methyl 2-(2-tosyloxyethyl)benzoate (25)
Acid 24 (6.07 g, 36.5 mmol, 1.0 equiv) was dissolved in abs THF/
abs MeOH (1:1, 60 mL) under nitrogen and cooled to 0 ꢁC.
TMSCHN2 (2.0 M in Et2O, 24 mL, 48 mmol, 1.3 equiv) was added
within 15 min via syringe until a persistent yellowish colour was
observed and the development of gas ceased. The volatile com-
pounds were removed on a rotary evaporator without any heating
(!) and the colourless oily residue was dissolved in abs CHCl3
(65 mL) under nitrogen. At 0 ꢁC, first a solution of TsCl (13.8 g,
72 mmol, 2 equiv) in abs CHCl3 (20 mL) was added via syringe,
immediately followed by the addition of abs pyridine (9 mL,
108 mmol, 3 equiv). The cooling bath was removed and the solution
stirred at room temp for 14 h. More CHCl3 was added and the
mixture was washed with 0.1 M HCl (200 mL). The aqueous phase
was tested for acidity (slightly acidic), then it was extracted 2ꢂ with
CHCl3. The combined organic layers were washed 2ꢂ with satd
NaHCO3 (!), dried over Na2SO4, filtrated and the solvents removed
on a rotary evaporator at 30 ꢁC. Purification of the crude product
a
yellowish oil by (10 g, toluene/Et2O¼5:1). Thioacetal 19:
C12H15NO4S2; 301.38 g/mol. 1H NMR (200 MHz, CDCl3):
d
¼8.21 (d,
J¼8.3 Hz, 1H, Har.), 7.69 (d, J¼8.3 Hz, 1H, Har.), 4.95 (s, 1H, CH), 3.99
(s, 3H, OCH3), 3.92 (s, 3H, OCH3), 2.15 (s, 6H, SCH3). 13C NMR
(50 MHz, CDCl3):
d¼167.0 (1C, C]O), 165.6 (1C, C]O), 163.2 (1C,
Car.),151.0 (1C, Car.),139.1 (1C, CHar.), 124.7 (1C, Car.),123.1 (1C, CHar.),
57.6 (1C, CH), 53.5 (1C, OCH3), 53.3 (1C, OCH3), 15.2 (2C, SCH3). IR
(film): nmax¼2953, 2919, 1732, 1586, 1434, 1394, 1292, 1229, 1148,
1074, 959, 911, 827, 758 cmꢀ1. GC–MS (EI): m/z¼302 [10%, Mþ], 270
[11%], 255 [100%, MþꢀSCH3], 223 [16%]. MS (ESIþ): m/z¼324
[MþNa]þ. HRMS (ESIþ): [MþNa]þ found 324.0343, calcd 324.0340.
Sulfide 20: C11H13NO4S; 255.29 g/mol. 1H NMR (200 MHz, CDCl3):

5584
F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
(14.3 g yellow oil) by flash chromatography (250 g, petroleum
ether/EtOAc¼gradient, 6:1 to 2:1) afforded tosylate 25 (5.74 g, 47%)
as a slowly solidifying oil, giving a waxy beige solid (mp 54–56 ꢁC)
as well as lactone 23 (2.84 g, 52%, analytics see above) as a yellow oil.
Tosylate 25 was partially crystallized from petroleum ether/EtOAc
in the cold, giving a snow-white solid (mp 60–61 ꢁC). Especially in
CHCl3 its stability is limited. Single crystals (mp 60–61 ꢁC) for X-ray
analysis were grown from petroleum ether/CH2Cl2. Tosylate 25:
3.25 mmol, 1.0 equiv) in abs THF (13 mL) with the reaction tem-
perature of the pale pink solution after 30 min at ꢀ78 ꢁC slowly
being raised to room temp in a Dewar overnight (16 h, conversion
not detectable by TLC, petroleum ether/EtOAc, same Rf for starting
material and product) gave 1.22 g of a yellow liquid as crude
product. Excess of 1a was separated by flash chromatography
(120 g, petroleum ether/EtOAc¼500:1) obtaining an inseparable
mixture of 27 and 28 (680 mg, yellow oil). Methyl 2-vinylbenzoate
24
C17H18O5S; 334.39 g/mol. 1H NMR (200 MHz, CDCl3):
d
¼7.88 (dd,
(27):
C
H10O2; 162.19 g/mol. 1H NMR (200 MHz, CDCl3):
d
¼7.91–
10
J¼7.7, 1.5 Hz, 1H, Har.), 7.67–7.63 (m, 2H, Har.), 7.42 (ddd, J¼7.4,
7.86 (m, 1H, Har.), 7.61–7.40 (m, 3H, Har.), 7.32–7.28 (m, 1H, Hvinyl),
1.6 Hz, 1H, Har.), 7.33–7.22 (m, 4H, Har.), 4.29 (t, J¼6.5 Hz, 2H, CH2),
5.65 (dd, J¼17.4, 1.8 Hz, 1H, Hvinyl), 5.36 (dd, J¼10.9, 1.3 Hz, 1H,
3.83 (s, 3H, OCH3), 3.31 (t, J¼6.5 Hz, 2H, CH2), 2.42 (s, 3H, CHT3s). 13
C
Hvinyl), 3.90 (s, 3H, OCH3). 13C NMR (50 MHz, CDCl3):
d¼168.2 (1C,
NMR (50 MHz, CDCl3):
d
¼167.8 (1C, C]O), 144.8 (1C, Car.), 138.6
C]O), 139.9 (1C, Car.), 136.2 (1C, CH), 132.5 (1C, CHar.), 130.7
(1C, CHar.), 128.9 (1C, Car.), 127.8 (1C, CHar.), 127.6 (1C, CHar.), 116.8
(1C, CH2), 52.5 (1C, OCH3). Silylated product 28: C16H26O2S2Si;
(1C, Car.), 133.3 (1C, Car.), 132.7 (1C, CHar.), 132.6 (1C, CHar.), 131.4 (1C,
CHar.), 130.0 (2C, CHar.), 129.6 (1C, Car.), 128.2 (2C, CHar.), 127.4 (1C,
CHar.), 71.0(1C,CH2OTs), 52.4 (1C, OCH3), 34.7(1C, CH2), 22.0(1C, CH3).
IR (film): nmax¼2953, 1719, 1599, 1577, 1492, 1435, 1359, 1266,
1176, 1090, 964, 907, 817, 777, 708, 664, 555, 434 cmꢀ1. GC–MS
(EI): m/z¼303 [1%, MþꢀOCH3], 149 [100%, MþꢀCH2OTs], 118 [37%],
91 [31%]. HRMS (ESIþ): [MþNa]þ found 357.0775, calcd 357.0773.
342.59 g/mol. 1H NMR (400 MHz, CDCl3):
d
¼7.89–7.22 (m, 4H, Har.),
3.90 (s, 3H, OCH3), 3.21–3.16 (m, 2H, CH2), 2.09 (s, 6H, SCH3), 2.08–
2.03 (m, 2H, CH2), 0.28 (s, 9H, SiMe3). 13C NMR (100 MHz, CDCl3):
d
¼168.4 (1C, C]O), 144.1 (1C, Car.), 132.4 (1C, CHar.), 131.3 (1C,
CHar.), 131.0 (1C, CHar.), 130.1 (1C, Car.), 126.4 (1C, CHar.), 52.5 (1C,
OCH3), 47.9 (1C, C), 40.2 (1C, CH2), 31.9 (1C, CH2), 11.7 (2C, SCH3),
ꢀ0.5 (3C, SiMe3). IR (film): nmax¼2952, 2919, 1723, 1685, 1601, 1575,
1484, 1434, 1257, 1133, 1083, 843, 755, 714 cmꢀ1. GC–MS (EI): m/z¼
327 [100%, MþꢀMe], 223 [59%], 91 [78%]. MS (ESIþ): m/z¼365
[MþNa]þ. HRMS (ESIþ): [MþNa]þ found 365.1041, calcd 365.1041.
4.2.17. X-ray analysis of 25
A suitable single crystal of the title compound was selected
under a polarization microscope and mounted in a glass capillary
(d¼0.3 mm). The crystal structure was determined by X-ray dif-
fraction analysis using graphite monochromated MoKa radiation
(0.71073 Å), whereas the scattering intensities were collected with
a single crystal diffractometer (STOE IPDS II). The crystal structure
was solved by Direct Methods using SHELXS-9721a and refined
using alternating cycles of least squares refinements against F2
(SHELXL-97).21a All non-H atoms were located in Difference Fourier
maps and were refined with anisotropic displacement parameters.
The H positions were determined by a final Difference Fourier
Synthesis. For the presentation of the structure drawings the pro-
grams ORTEP21b and POV-Ray21c were applied. C17H18O5S,
M¼334.39 g molꢀ1 crystallized in the triclinic space group P-1 with
lattice parameters a¼7.638(1) Å, b¼8.410(1) Å, c¼14.338(3) Å,
4.2.20. 2,2-Bis(methylthio)-1-tetralone (29)
TBAF$3H2O (2.88 g, 9.1 mmol, 4.6 equiv) was placed in a Schlenk
flask under nitrogen, and was dissolved in abs THF (28 mL). After
cooling to 0 ꢁC, hexamethyldisilazane (HMDS, 8.5 mL, 41 mmol,
20.7 equiv) was added, the cooling bath removed and the mixture
stirred at room temp for 16 h. Under intense stirring, the volatile
compounds were then condensed into a cooling trap (liquid N2)
with an oil pump vacuum. The vacuum was held for several hours
until a solid brownish residue was obtained. After ventilation with
nitrogen, the solid was broken into small pieces by spattle in a ni-
trogen counter current, and the solid again conscientiously dried in
vacuum until an optically dry beige solid was obtained (about 6 h).
The flask was ventilated with nitrogen, the solid dissolved in abs THF
(21 mL) and cooled to ꢀ78 ꢁC. Then a solution of silylated compound
28 (inseparable mixture from the prior reaction, 680 mg, <1.98 mmol,
<1 equiv) in abs THF (35 mL) was slowly added via syringe. The
reaction temperature was slowly allowed to rise to room temp
overnight. The orange solution was quenched with water (100 mL)
after 16 h, observing decolouration. The mixture was extracted with
CH2Cl2 (4ꢂ60 mL), the combined organic layers dried over Na2SO4
and the solvents removed on a rotary evaporator. Purification of the
crude product (640 mg, brown oil) by flash chromatography (60 g,
petroleum ether/EtOAc¼500:1) afforded styrene 27 (210 mg, 24%
over two steps, for analytical data see above) as a yellowish liquid; and
tetralone 29 (205 mg, 26% over two steps) as a colourless oil.
a
¼74.14(1)ꢁ,
b
¼84.17(1)ꢁ,
g
¼64.58(1)ꢁ, V¼800.0(2) Å3, Z¼2,
dcalcd¼1.388 g cmꢀ3
,
F(000)¼352 using 2767 independent re-
flections and 280 parameters. R1¼0.0358, wR2¼0.0819 [I>2
s(I)],
goodness of fit on F2¼1.055, residual electron density¼0.253 and
ꢀ0.326 e Åꢀ3. Further details of the crystal structure investigation
have been deposited with the Cambridge Crystallographic Data
Center, CCDC-699489. Copies of this information may be obtained
free of charge from The Director, CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44(1223) 336 033; e-mail: fileserv@ccdc.ac.uk;
www.ccdc.cam.ac.uk).
4.2.18. Methyl 2-(2-bromoethyl)benzoate (26)23
Under nitrogen, tosylate 25 (206 mg, 0.62 mmol, 1.0 equiv) and
LiBr (104 mg, 1.9 mmol, 1.9 equiv) were stirred in abs acetone
(10 mL) at reflux for 12 h. The solvents were removed by a rotary
evaporator. Purification by flash chromatography (10 g, petroleum
ether/EtOAc¼50:1) afforded bromide 26 (103 mg, 68%) as a col-
ourless oil. C10H11BrO2; 243.10 g/mol. 1H NMR (200 MHz, CDCl3):
C12H14OS2; 238.37 g/mol. 1H NMR (200 MHz, CDCl3):
(m,1H, Har.), 7.52–7.44 (m,1H, Har.), 7.37–7.29 (m,1H, Har.), 7.23–7.19
d
¼8.15–8.11
(m, 1H, Har.), 3.08 (t, J¼6.3 Hz, 2H, CH2), 2.60 (t, J¼6.3 Hz, 2H, CH2),
2.06 (s, 6H, SCH3). 13C NMR (50 MHz, CDCl3):
d
¼188.8 (1C, C]O),
d
¼7.98–7.94 (m, 1H, Har.), 7.52–7.44 (m, 1H, Har.), 7.38–7.28 (m, 2H,
Har.), 3.91 (s, 3H, OCH3), 3.69–3.61 (m, 2H, CH2), 3.55–3.46 (m, 2H,
CH2). 13C NMR (50 MHz, CDCl3):
142.4 (1C, Car.), 133.8 (1C, CHar.), 130.6 (1C, Car.), 129.2 (1C, CHar.),
128.8 (1C, CHar.), 127.3 (1C, CHar.), 65.1 (1C, C), 35.8 (1C, CH2), 26.8
(1C, CH2), 11.6 (2C, SCH3). IR (film): nmax¼2917, 1673, 1600, 1454,
d
¼167.8 (1C, C]O), 140.9 (1C, Car.),
132.6 (1C, CHar.), 132.3 (1C, CHar.), 131.5 (1C, CHar.), 129.7 (1C, Car.),
127.5 (1C, CHar.), 52.5 (1C, OCH3), 38.5 (1C, CH2), 33.4 (1C, CH2).
1426,1355,1292,1220,1157,1124,1025, 965, 889, 815, 747, 636 cmꢀ1
.
GC–MS (EI): m/z¼238 [10%, Mþ], 191 [100%, MþꢀSCH3], 163 [24%].
HRMS (EI): [Mþ] found 238.0486, calcd 238.0486.
4.2.19. Methyl 2-(3,3-bis(methylthio)-3-(trimethylsilyl)-
propyl)benzoate (28)
4.2.21. 2,2-Bis(methylsulfonyl)-1-tetralone (30)
Addition of carbanion 1b [obtained using 1a (762 mg,
4.23 mmol, 1.3 equiv), abs THF (8.5 mL), n-BuLi (2.4 M in hexane,
1.9 mL, 4.55 mmol, 1.4 equiv)] to a solution of bromide 26 (790 mg,
A solution of thioacetal 29 (50 mg, 0.21 mmol, 1.0 equiv) and m-
CPBA (77%, 300 mg, 1.34 mmol, 6.4 equiv) in CHCl3 (20 mL) was
stirred at room temp for 4 days. The mixture was diluted with Et2O,

F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
5585
washed with 10% Na2S2O3, 2ꢂsatd NaHCO3, and water. The organic
layer was dried over Na2SO4 and the solvents were removed on
a rotary evaporator. Purification of the crude product by flash
chromatography (15 g, petroleum ether/EtOAc¼5:1) afforded sul-
fone 30 (53 mg, 86%) as a colourless solid. Single crystals for X-ray
analysis were grown from petroleum ether/CH2Cl2. C12H14O5S2;
302.37 g/mol. Mp 147–153 ꢁC (decomposition). 1H NMR (200 MHz,
d
¼7.96–7.91 (m, 1H, Har.), 7.52–7.44 (m, 1H, Har.), 7.37–7.27 (m, 2H,
Har.), 3.28 (t, J¼8.0 Hz, 2H, CH2), 2.64 (t, J¼8.0 Hz, 2H, CH2). 13C NMR
(50 MHz, DMSO):
Car.), 132.7 (1C, CHar.), 131.7 (1C, CHar.), 131.4 (1C, Car.), 131.2 (1C,
CHar.), 127.2 (1C, CHar.), 36.3 (1C, CH2), 30.0 (1C, CH2).
d
¼174.7 (1C, CO2H), 169.6 (1C, CO2H), 142.8 (1C,
4.2.25. 2-(2-Methoxycarbonylethyl)benzoic acid (34)18a
CDCl3):
d
¼8.11–8.07 (m, 1H, Har.), 7.63–7.55 (m, 1H, Har.), 7.42–7.34
Acid 33 (4.98 g, 25.6 mmol, 1.0 equiv) was dissolved in MeOH
(150 mL), concd H2SO4 (2.5 mL) was added and the solution stirred
at room temp for 30 min. The solution was concentrated on a rotary
evaporator at 30 ꢁC to about 1/10 of the original volume. The resi-
due was dissolved in water (60 mL), and 1 M NaOH (60 mL) was
added while stirring. The pH value was cautiously brought to 8–9
by addition of satd NaHCO3 and more 1 M NaOH. The aqueous so-
lution was washed with Et2O (2ꢂ100 mL) and the ethereal layers
were discarded. The stirred aqueous layer was cautiously acidified
with concd HCl (pH¼1–2) and the milky acidic product extracted
4ꢂ with Et2O. The combined organic layers were dried over Na2SO4
and the solvents removed by a rotary evaporator at 30 ꢁC. After
further drying in vacuo, ester 34 (5.04 g, 95%) was obtained as
a colourless solid. C11H12O4; 208.21 g/mol. Mp 79–81 ꢁC (lit. 78–
(m, 1H, Har.), 7.30–7.26 (m, 1H, Har.), 3.44 (s, 6H, SO2CH3), 3.36 (t,
J¼6.4 Hz, 2H, CH2), 3.09 (t, J¼6.2 Hz, 2H, CH2). 13C NMR (50 MHz,
CDCl3):
d
¼184.1 (1C, C]O), 142.9 (1C, Car.), 135.9 (1C, CHar.), 132.1
(1C, Car.), 129.3 (1C, CHar.), 129.0 (1C, CHar.), 128.0 (1C, CHar.), 88.5
(1C, C), 41.4 (2C, SO2CH3), 25.4 (1C, CH2), 25.3 (1C, CH2). IR (KBr):
nmax¼3023, 2930, 1677, 1597, 1463, 1311, 1237, 1200, 1133, 954, 881,
782, 741 cmꢀ1. GC–MS (EI): m/z¼302 [5%, Mþ], 223 [39%], 144
[100%, MþꢀSO2CH3], 115 [50%].
4.2.22. X-ray analysis of 30
Procedure analogous to X-ray study of compound 25.
C12H14O5S2, M¼302.37 g molꢀ1 crystallized in the monoclinic space
group
P21/c
with
lattice
parameters
a¼14.627(3) Å,
b¼6.0043(7) Å, c¼15.082(4) Å,
b
¼99.45(2)ꢁ, V¼1306.6(4) Å3, Z¼4,
80 ꢁC). 1H NMR (200 MHz, DMSO):
d
¼12.92 (s, 1H, CO2H), 7.83–7.78
dcalcd¼1.537 g cmꢀ3
,
F(000)¼632 using 2211 independent re-
(m, 1H, Har.), 7.51–7.43 (m, 1H, Har.), 7.35–7.27 (m, 2H, Har.), 3.57 (s,
flections and 229 parameters. R1¼0.0433, wR2¼0.0866 [I>2
s(I)],
3H, OCH3), 3.16 (t, J¼7.8 Hz, 2H, CH2), 2.60 (t, J¼7.8 Hz, 2H, CH2). 13
C
goodness of fit on F2¼1.076, residual electron density¼0.300 and
ꢀ0.327 e Åꢀ3. Further details of the crystal structure investigation
have been deposited with the Cambridge Crystallographic Data
Center, CCDC-699486. Copies of this information may be obtained
free of charge from The Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK (fax: þ44(1223) 336 033; e-mail: fileserv@ccdc.ac.uk;
www.ccdc.cam.ac.uk).
NMR (50 MHz, DMSO):
d
¼173.6 (1C, C]O), 169.5 (1C, C]O), 142.5
(1C, Car.), 132.8 (1C, CHar.), 131.8 (1C, CHar.), 131.3 (1C, CHar.), 131.3
(1C, Car.), 127.4 (1C, CHar.), 52.2 (1C, OCH3), 36.0 (1C, CH2), 30.0 (1C,
CH2).
4.2.26. 2-(3-Hydroxypropyl)benzoic acid (35)18a
Under nitrogen, LiBH4 (1.14 g, 52.5 mmol, 2.5 equiv) was sus-
pended in abs dioxane (60 mL). To this suspension, a solution of
ester 34 (4.37 g, 21.0 mmol, 1.0 equiv) in abs dioxane (40 mL) was
added dropwise via cannula (nitrogen current). When the addition
was complete, the reaction mixture was heated for 20 min at
100 ꢁC, then poured into a beaker with ice (120 g) (foaming!). The
mixture was cautiously acidified to pH¼1 with 1 M HCl (85 mL),
preventing it from foaming too much. The aqueous solution was
saturated with NaCl and extracted with Et2O (5ꢂ100 mL). The
combined ethereal layers were concentrated under reduced pres-
sure and the oily residue dissolved in 1 M NaOH (80 mL). The al-
kaline aqueous phase was washed 3ꢂ with CH2Cl2 and 1ꢂ with
Et2O, and the organic layers were discarded. The aqueous phase
was acidified with 1 M HCl (120 mL) and extracted 3ꢂ with Et2O.
The combined ethereal layers were dried over Na2SO4 and the
solvents removed in vacuo. Alcohol 35 (3.00 g, 79%) was obtained
as a colourless solid. C10H12O3; 180.20 g/mol. Mp 55–65 ꢁC (lit. 63–
4.2.23. Methyl 2-(3,3-bis(methylthio)propyl)benzoate (31)
Desilylated product 31 (10 mg, 0.04 mmol) was obtained as
a colourless oil after flash chromatography (petroleum ether/
EtOAc¼500:1), from a reaction analogous to the preparation of 29
using not conscientiously dried TBAF, but working with an oily
residue. C13H18O2S2; 270.41 g/mol. 1H NMR (200 MHz, CDCl3):
d
¼7.90–7.87 (m, 1H, Har.), 7.49–7.39 (m, 1H, Har.), 7.31–7.22 (m, 2H,
Har.), 3.90 (s, 3H, OCH3), 3.66 (t, J¼7.2 Hz, 1H, CH), 3.22–3.14 (m, 2H,
CH2), 2.11 (s, 6H, SCH3), 2.09–2.02 (m, 2H, CH2). 13C NMR (50 MHz,
CDCl3):
d
¼168.3 (1C, C]O), 143.5 (1C, Car.), 132.4 (1C, CHar.), 131.6
(1C, CHar.), 131.2 (1C, CHar.), 129.9 (1C, Car.), 126.6 (1C, CHar.), 54.6
(1C, CH), 52.4 (1C, OCH3), 36.8 (1C, CH2), 33.0 (1C, CH2), 13.0 (2C,
SCH3). IR (film): nmax¼2917, 1721, 1434, 1260, 1123, 1082, 756,
710 cmꢀ1. MS (ESIþ): m/z¼309 [MþOþNa]þ (thioacetal 31 is readily
oxidized to the corresponding sulfoxide on exposition to air.), 293
[MþNa]þ; HRMS (ESIþ): [MþOþNa]þ found 309.0598, calcd
309.0595.
65 ꢁC). 1H NMR (200 MHz, DMSO):
(m, 1H, Har.), 7.49–7.41 (m, 1H, Har.), 7.31–7.16 (m, 2H, Har.), 4.46 (s,
1H, OH), 3.44 (t, J¼6.6 Hz, 2H, CH2), 2.95 (t, J¼7.7 Hz, 2H, CH2), 1.79–
1.68 (m, 2H, CH2).
d
¼12.72 (s, 1H, CO2H), 7.77–7.73
4.2.24. 2-(2-Carboxyethyl)benzoic acid (33)18b
PdCl2 (461 mg, 2.6 mmol,10 mol %) was added to a solution of 2-
carboxycinnamic acid (32, 5.00 g, 26.0 mmol, 1.0 equiv) in 2.5 M
aqueous NaOH (400 mL). Formic acid (3.9 mL, 104 mmol, 4.0 equiv)
was added, the flask equipped with an air cooler, and the mixture
stirred at 65 ꢁC for 24 h. The black palladium particles were re-
moved by filtration, and the basic solution washed 2ꢂ with Et2O.
The aqueous phase was acidified to pH 1–2 with concd HCl,
obtaining a fluffy white precipitate, which was dissolved by the
addition of EtOAc. The mixture was extracted 4ꢂ with EtOAc, the
combined organic layers dried over Na2SO4 and the solvents re-
moved in vacuo. Saturated acid 33 (4.98 g, 99%) was obtained as
a colourless crystalline solid. Use of 5 mol % PdCl2 under identical
reaction conditions resulted in incomplete reduction! Acids 32 and 33
are distinguishable by TLC (CH2Cl2/MeOH¼1:1). C10H10O4; 194.18 g/
mol. Mp 167–169 ꢁC (lit. 166–168 ꢁC). 1H NMR (200 MHz, MeOD):
4.2.27. Methyl 2-(3-tosyloxypropyl)benzoate (37)
Reaction analogous to the preparation of tosylate 25. Methyla-
tion: compound 35 (3.60 g, 20 mmol, 1.0 equiv), abs MeOH/abs THF
(35 mL each), TMSCHN2 (2.0 M in Et2O, 17 mL, 34 mmol, 1.7 equiv).
Tosylation: crude product 36 (colourless oil) in abs CHCl3 (30 mL),
TsCl (7.60 g, 40 mmol, 2 equiv) in abs CHCl3 (20 mL), abs pyridine
(5 mL, 60 mmol, 3 equiv), and purification of the crude product by
flash chromatography (250 g, petroleum ether/EtOAc¼gradient,
6:1 to 2:1) afforded tosylate 37 (3.27 g, 47% over two steps) as
a colourless oil. C18H20O5S; 348.41 g/mol. 1H NMR (200 MHz,
CDCl3):
d
¼7.91–7.78 (m, 3H, Har.), 7.42–7.12 (m, 5H, Har.), 4.06 (t,
J¼6.3 Hz, 2H, CH2), 3.86 (s, 3H, OCH3), 2.98 (t, J¼7.9 Hz, 2H, CH2),
2.45 (s, 3H, CH3), 2.01–1.90 (m, 2H, CH2). 13C NMR (50 MHz, CDCl3):
d¼168.0 (1C, C]O), 145.0 (1C, Car.), 142.8 (1C, Car.), 133.4 (1C, Car.),

5586
F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
132.4 (1C CHar.), 131.5 (1C, CHar.), 131.3 (1C, CHar.), 130.1 (2C, CHar.),
129.5 (1C, Car.), 128.2 (2C, CHar.), 126.6 (1C, CHar.), 70.4 (1C, OCH2),
52.2 (1C, OCH3), 30.8 (1C, CH2), 30.7 (1C, CH2), 21.9 (1C, CHT3s). IR
(film): nmax¼2953, 1720, 1599, 1435, 1360, 1260, 1177, 1136, 1095,
1000, 966, 928, 816, 752, 710, 664, 573, 555, 443 cmꢀ1. GC–MS (EI):
m/z¼317 [23%, MþꢀOCH3], 177 [76%], 148 [100%, MþꢀOTsꢀOCH3],
117 [21%]. HRMS (ESIþ): [MþH]þ found 349.1107, calcd 349.1110;
[MþNaþMeCN]þ found 412.1189, calcd 412.1195.
petroleum ether/EtOAc¼500:1) afforded benzosuberone 40
(272 mg, 73%) as a colourless oil, which solidified in the cold,
obtaining a waxy colourless solid. C13H16OS2; 252.40 g/mol. Mp 39–
43 ꢁC. 1H NMR (400 MHz, CDCl3):
d
¼7.40–7.35 (m, 2H, Har.), 7.29
(dd, J¼7.3, 1.1 Hz, 1H, Har.), 7.12 (dd, J¼7.1, 0.3 Hz, 1H, Har.), 2.86 (t,
J¼6.9 Hz, 2H, CH2), 2.08 (s, 6H, SCH3), 2.02–1.95 (m, 2H, CH2), 1.90–
1.86 (m, 2H, CH2). 13C NMR (100 MHz, CDCl3):
d
¼199.4 (1C, C]O),
139.1 (1C, Car.), 137.1 (1C, Car.), 131.3 (1C, CHar.), 128.6 (1C, CHar.),
128.2 (1C, CHar.), 126.9 (1C, CHar.), 68.7 (1C, C), 31.8 (1C, CH2), 31.5
(1C, CH2), 23.0 (1C, CH2), 12.2 (2C, SCH3). IR (film): nmax¼2918, 1681,
1600, 1451, 1246, 959, 762, 675, 635 cmꢀ1. GC–MS (EI): m/z¼252
[3%, Mþ], 205 [72%], 177 [100%, MþꢀSCH3ꢀCO], 133 [52%]. MS
(ESIþ): m/z¼527 [2 MþNa]þ, 275 [MþNa]þ. HRMS (EI): [Mþ] found
252.0643, calcd 252.0643.
4.2.28. Methyl 2-(3-bromopropyl)benzoate (38)25
Under nitrogen, tosylate 37 (820 mg, 2.35 mmol, 1.0 equiv) and
LiBr (408 mg, 4.70 mmol, 2.0 equiv) were refluxed in abs acetone
(20 mL) for 17 h. The solvents were removed on a rotary evaporator
followed by purification of the residue by flash chromatography
(50 g, petroleum ether/EtOAc¼50:1) to afford bromide 38 (575 mg,
95%) as a colourless liquid. C11H13BrO2; 257.12 g/mol. 1H NMR
4.2.31. 2,2-Bis(methylsulfonyl)-1-benzosuberone (41)
(200 MHz, CDCl3):
d
¼7.93–7.89 (m, 1H, Har.), 7.49–7.40 (m, 1H, Har.),
A solution of thioacetal 40 (50 mg, 0.20 mmol, 1.0 equiv) and m-
CPBA (77%, 448 mg, 2.0 mmol, 10 equiv) in CHCl3 (10 mL) was
stirred at room temp for 4 days. The mixture was diluted with Et2O,
washed with 10% Na2S2O3, 2ꢂsatd NaHCO3, and water. The organic
layer was dried over Na2SO4 and the solvents removed on a rotary
evaporator. Purification of the colourless crude product by flash
chromatography (15 g, petroleum ether/EtOAc¼6:1) afforded sul-
fone 41 (57 mg, 0.18 mmol, 90%) as a colourless solid (mp 175–
180 ꢁC). Single crystals for X-ray analysis were grown from petro-
leum ether/CH2Cl2 (mp 192–193 ꢁC). C13H16O5S2; 316.39 g/mol. 1H
7.31–7.23 (m, 2H, Har.), 3.90 (s, 3H, OCH3), 3.44 (t, J¼6.6 Hz, 2H,
CH2), 3.11 (t, J¼7.6 Hz, 2H, CH2), 2.25–2.11 (m, 2H, CH2). 13C NMR
(50 MHz, CDCl3):
d¼168.2 (1C, C]O), 143.0 (1C, Car.), 132.5 (1C,
CHar.), 131.6 (1C, CHar.), 131.3 (1C, CHar.), 129.7 (1C, Car.), 126.7
(1C, CHar.), 52.4 (1C, OCH3), 34.7 (1C, CH2Br), 33.9 (1C, CH2), 33.3
(1C, CH2).
4.2.29. Methyl 2-(4,4-bis(methylthio)-4-(trimethylsilyl)-
butyl)benzoate (39)
Addition of carbanion 1b [obtained using 1a (346 mg,
1.90 mmol, 1.3 equiv), abs THF (3 mL), n-BuLi (2.4 M in hexane,
0.86 mL, 2.10 mmol,1.4 equiv)] to a solution of bromide 38 (380 mg,
1.48 mmol, 1.0 equiv) in abs THF (8 mL) with the reaction temper-
ature after 30 min at ꢀ78 ꢁC slowly being raised to room temp in
a Dewar overnight, showed complete conversion after 16 h. From
the pale yellow solution, 620 mg of a pale yellow liquid was
obtained as crude product. Purification by flash chromatography
(23 g, petroleum ether/EtOAc¼500:1) afforded silylated compound
39 (527 mg, 99%) as a colourless oil. C17H28O2S2Si; 356.62 g/mol. 1H
NMR (400 MHz, CDCl3):
d
¼7.47 (ddd, J¼7.4, 1.8 Hz, 1H, Har.), 7.38–
7.31 (m, 2H, Har.), 7.15 (d, J¼7.2 Hz, 1H, Har.), 3.40 (s, 6H, SO2CH3),
3.06 (t, J¼7.1 Hz, 2H, CH2), 2.69 (t, J¼6.7 Hz, 2H, CH2), 2.24 (qui,
J¼6.9 Hz, 2H, CH2). 13C NMR (100 MHz, CDCl3):
¼196.5 (1C, C]O),
d
139.3 (1C, Car.), 137.4 (1C, Car.), 133.4 (1C, CHar.), 129.3 (1C, CHar.),
129.0 (1C, CHar.), 127.7 (1C, CHar.), 92.2 (1C, C), 41.4 (2C, SO2CH3),
29.9 (1C, CH2), 24.2 (1C, CH2), 22.3 (1C, CH2). IR (KBr): nmax¼3034,
2926, 1694, 1596, 1448, 1420, 1336, 1304, 1247, 1135, 944, 883, 802,
775, 749, 604, 551, 528, 504, 483, 465 cmꢀ1. GC–MS (EI): m/z¼317
[6%, Mþ], 237 [100%, MþꢀSO2CH3], 158 [59%].
NMR (200 MHz, CDCl3):
d
¼7.87–7.83 (m, 1H, Har.), 7.46–7.38 (m, 1H,
Har.), 7.28–7.20 (m, 2H, Har.), 3.88 (s, 3H, OCH3), 2.97–2.90 (m, 2H,
CH2), 2.00 (s, 6H, SCH3), 1.84–1.80 (m, 4H, CH2), 0.14 (s, 9H, SiMe3).
4.2.32. X-ray analysis of 41
Procedure analogous to X-ray study of compound 25. C13H16O5S2,
M¼316.39 g molꢀ1 crystallized in the orthorhombic space group Pbca
with lattice parameters a¼12.036(1) Å, b¼13.692(1) Å, c¼16.679(1) Å,
V¼2748.5(3) Å3, Z¼8, dcalcd¼1.529 g cmꢀ3, F(000)¼1328 using 2435
independent reflections and 246 parameters. R1¼0.0339, wR2¼0.0837
13C NMR (50 MHz, CDCl3):
d¼168.4 (1C, C]O), 144.1 (1C, Car.), 132.3
(1C, CHar.), 131.3 (1C, CHar.), 131.0 (1C, CHar.), 129.9 (1C, Car.), 126.3
(1C, CHar.), 52.3 (1C, OCH3), 47.7 (1C, C), 37.9 (1C, CH2), 35.1 (1C,
CH2), 29.1 (1C, CH2), 11.5 (2C, SCH3), ꢀ0.6 (3C, SiMe3). IR (film):
nmax¼2951, 1723, 1601, 1575, 1488, 1434, 1251, 1134, 1088, 965, 842,
753, 710, 625, 427 cmꢀ1. GC–MS (EI): m/z¼341 [100%, MþꢀMe], 309
[20%], 251 [37%], 163 [28%], 149 [41%], 91 [84%]. MS (ESIþ): m/z¼379
[MþNa]þ. HRMS (ESIþ): [MþNa]þ found 379.1194, calcd 379.1191.
[I>2
s
(I)], goodness of fit on F2¼1.145, residual electron density¼0.371
and ꢀ0.270 e Åꢀ3. Further details of the crystal structure investigations
have been deposited with the Cambridge Crystallographic Data
Center, CCDC-699487. Copies of this information may be obtained free
of charge from The Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44(1223) 336 033; e-mail: fileserv@ccdc.ac.uk; www.
ccdc.cam.ac.uk).
4.2.30. 2,2-Bis(methylthio)-1-benzosuberone (40)
TBAF$3H2O (1.31 g, 4.1 mmol, 2.8 equiv) was placed in a Schlenk
flask under nitrogen, and was dissolved in abs THF (15 mL). After
cooling to 0 ꢁC, hexamethyldisilazane (3.9 mL, 18.6 mmol,
12.6 equiv) was added, the cooling removed and the mixture stirred
at room temp for 15 h. Under intense stirring, the volatile com-
pounds were then condensed into a cooling trap (liquid N2) with an
oil pump vacuum. The vacuum was held for 6 h until an optically
dry beige solid was obtained. The flask was ventilated with nitro-
gen, the solid dissolved in abs THF (10 mL) and cooled to ꢀ78 ꢁC.
Then a solution of silylated compound 39 (527 mg, 1.48 mmol,
1.0 equiv) in abs THF (20 mL) was slowly added via syringe. The
reaction temperature was allowed to slowly rise to room temp
overnight in a Dewar. The red solution was quenched with water
after 20 h, observing decolouration. The mixture was extracted 4ꢂ
with CH2Cl2, the combined organic layers were dried over Na2SO4
and the solvents removed on a rotary evaporator. Purification of the
crude product (400 mg, brown oil) by flash chromatography (50 g,
4.2.33. Methyl 2-(4,4-bis(methylthio)butyl)benzoate (42)
Desilylated product 42 (64 mg, 68%) was obtained as a colour-
less oil after flash chromatography (10 g, petroleum ether/
EtOAc¼500:1), from the reaction of 39 (120 mg, 0.34 mmol) with
TBAF, analogous to the preparation of 40 using not conscientiously
dried TBAF, but working with an oily residue. C14H20O2S2; 284.44 g/
mol. 1H NMR (200 MHz, CDCl3):
d¼7.89–7.84 (m, 1H, Har.), 7.46–7.38
(m, 1H, Har.), 7.28–7.20 (m, 2H, Har.), 3.89 (s, 3H, OCH3), 3.70–3.63
(m,1H, CH), 3.02–2.92 (m, 2H, CH2), 2.08 (s, 6H, SCH3),1.89–1.78 (m,
4H, CH2). 13C NMR (50 MHz, CDCl3):
d¼168.4 (1C, C]O), 144.2 (1C,
Car.), 132.3 (1C, CHar.), 131.2 (1C, CHar.), 131.1 (1C, CHar.), 129.8 (1C,
Car.), 126.3 (1C, CHar.), 54.6 (1C, CH), 52.3 (1C, OCH3), 34.8 (1C, CH2),
34.1 (1C, CH2), 29.9 (1C, CH2), 12.9 (2C, SCH3). IR (film): nmax¼2917,
1723, 1601, 1575, 1488, 1434, 1261, 1189, 1121, 1084, 964, 751,
710 cmꢀ1. GC–MS (EI): m/z¼237 [34%, MþꢀSCH3], 206 [100%,

F. Genrich et al. / Tetrahedron 65 (2009) 5577–5587
5587
MþꢀSCH3ꢀOCH3], 190 [66%]. MS (ESIþ): m/z¼307 [MþNa]þ. HRMS
(ESIþ): [MþMeCNþK]þ found 364.0812, calcd 364.0807.
11. (a) Smith, A. B., III; Boldi, A. M. J. Am. Chem. Soc. 1997, 119, 6925; (b) Mukho-
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Support of our work by the Deutsche Forschungsgemeinschaft
(Scha 231/11) is gratefully acknowledged.
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