β,β-disilylated sulfones as versatile building blocks in organic chemistry - A new sulfonyl carbanion transmetalation

Article abstract of DOI:10.1055/s-0030-1258772

1,3-Bis(trimethylsilyl)propyl phenyl sulfone undergoes, in contrast to all reported sulfones bearing α-hydrogen atoms, an initial ortho metalation to an aryllithium at low temperature, which transmetalates quantitatively to the corresponding α-sulfonyl or

Full text of DOI:10.1055/s-0030-1258772

LETTER
2579
b,b-Disilylated Sulfones as Versatile Building Blocks in Organic Chemistry –
A New Sulfonyl Carbanion Transmetalation
S
ulfonyl Carbani
er
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo namesti 2,
16610 Prague 6, Czech Republic
Fax +420220183578; E-mail: jahn@uochb.cas.cz
Received 2 August 2010
TMS
EtO2C
X
Wittig
Abstract: 1,3-Bis(trimethylsilyl)propyl phenyl sulfone undergoes,
in contrast to all reported sulfones bearing a-hydrogen atoms, an
initial ortho metalation to an aryllithium at low temperature, which
transmetalates quantitatively to the corresponding a-sulfonyl orga-
nolithium intermediate. Both organolithiums react selectively with
aldehydes to give the corresponding products in good to excellent
yields with high selectivity.
reaction
TMS
X = H
PPh3
A
B
X = TMS
O
Julia olefination
TMS
TMS
Key words: carbanions, transmetalation, silanes, sulfones, Julia
olefination
TMS
TMS
R
Ph
S
2
O
1
TMS
TMS
TMS
R
S
The formation of carbon–carbon double bonds is one of
the most important reactions in organic synthesis, since
olefins are prevalent in many naturally occurring and bio-
logically active molecules, polymer precursors, and or-
ganic materials. Numerous methods ranging from Wittig
and related reactions, through Peterson- or Tebbe-type
olefinations to cross-metathesis were developed over the
years. Among those, the Julia olefination and its variants1
represents one of the most powerful tools of organic
chemistry, since it is known to be E-selective, well con-
trolled, and easy to perform.
In a recent total synthesis of dihydronepetalactone,2 a
Wittig reaction using phosphorane A was applied to con-
struct the pivotal trisubstituted allylsilane cyclization pre-
cursor B (Scheme 1, X = H). This reaction was plagued
by low yield and the formation of side products. Thus, an
alternative selective approach to allylsilanes of type B
(X = H) or 2 (X = TMS) was highly needed. Since known
methods3 to access compounds of type 2 were not appli-
cable with respect to functional-group tolerance and ease
of precursor synthesis, we aimed for the development of a
Julia olefination using unknown silylated sulfones 1.
TMSO
R
O2
3
4
Scheme 1
tion conditions. This reactivity diversity is based on a new
sulfonyl carbanion transmetalation.
Bis(trimethylsilylmethyl)methyl phenyl sulfone (1) was
prepared by successive alkylation of methyl phenyl sul-
fone with (chloromethyl)trimethylsilane in the presence
of TMEDA in excellent yield in a one-pot process
(Scheme 2). It is worth underlining that a single addition
of two equivalents of n-BuLi and (chloromethyl)trimeth-
ylsilane does not lead to compound 1, but gives only the
monoalkylated product even after long reaction time at el-
evated temperature.
TMS
n-BuLi, TMEDA, THF, ClCH2TMS
PhSO2Me
TMS
then n-BuLi, ClCH2TMS
PhSO2
1 89%
We present herein, initial results of a reactivity study of
the so far unknown bissilylated sulfone 1 (Scheme 1).
This sulfone proves to be a true synthetic chameleon be-
cause of its distinct behavior under defined metalation
conditions, but also since the resulting anions can be rec-
ognized easily visually by their colors. Not less than three
classes of so far more or less explored compound classes,
compounds 2–4 can be synthesized with a good substrate
scope in good to excellent yield applying defined metala-
Scheme 2
Initial experiments of 1 with benzaldehyde using standard
Julia olefination conditions (n-BuLi, –78 °C) furnished
ortho-substituted 3a instead of the expected olefination
product (Scheme 3). Addition of TMEDA leads to the
same result. This was surprising, since directed ortho met-
alation was never observed before as the initial event for
sulfones bearing a-hydrogens.4,5 On the other hand, allylic
silyl ether 4a was obtained as the only product using
HMPA as an additive.
SYNLETT 2010, No. 17, pp 2579–2582
x
x
.x
x
.2
0
1
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Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258772; Art ID: G25110ST
© Georg Thieme Verlag Stuttgart · New York
These results indicated that the ortho- or the a-carbanions
1a-Li or 1b-Li were either selectively generated or that a

2580
B. Puget, U. Jahn
LETTER
HO
Table 1 Rearrangement of Carbanions 1-Li
Ph
TMS
TMS
n-BuLi, (TMEDA), THF, –78 °C
then PhCHO
Entry Base
Additive Solvent
1a/1b
–78 °C –40 °C 0 °C 20 °C
S
O2
1
1
2
3
4
5
6
n-BuLi
n-BuLi
n-BuLi
n-BuLi
LDA
–
THF
2.3:1 2.1:1
9.6:1 2.8:1
1:5.6 1:24
1:4.9 1:20
1:20 1:49
1:99 1:99
3a 84%
TMS
TMSO
Ph
TMEDA THF
n-BuLi, THF–HMPA, –78 °C
then PhCHO
TMEDA DME 13.2:1 5.6:1
4a 64%
HMPA
THF
THF
THF
1:5.6 1:49
3.6:1 1.5:1
Scheme 3
–
–
1:9
–
1:11.5
KHMDS
–
–
–
rearrangement between them took place (Scheme 4). To
distinguish these options, the deprotonation of 1 using dif-
ferent bases and additives was monitored by keeping the
reaction mixtures for 30 minutes at the given tempera-
tures, taking aliquots, quenching them by D2O, and ana-
OH
R1
R2
n-BuLi, TMEDA
then R1COR2
TMS
TMS
TMS
TMS
1
THF, –78 °C
S
S
lyzing the products by H NMR (Scheme 4, Table 1).
O2
O2
Using n-BuLi as a base in THF at –78 °C, 1a-D and 1b-D
were formed in a 2.3:1 ratio (entry 1). Warming succes-
sively to –40 °C, 0 °C, and 20 °C leads to a reversed ratio
of 1a-D/1b-D of 1:24. The course of the transmetalation
of the ortho- to the a-carbanion can be monitored even vi-
sually, since 1a-Li is pale yellow while 1b-Li appears red
in solution. The initial 1a-Li/1b-Li selectivity is better
with TMEDA (entry 2) and especially in DME (entry 3).
Immediate a-deprotonation to 1b-Li was predominant
with HMPA even at –78 °C (entry 4). LDA deprotonated
1 less selectively to 1a-Li at –78 °C, but rearrangement to
1b-Li took place smoothly (entry 5). The conversion was
quantitative for all entries. In contrast, widely used
KHMDS was completely ineffective as a base (entry 6).
1
3a–f
Scheme 5
Table 2 Scope of Aryllithium Addition to Aldehydes and Ketones
Entry
Product
3a
R1
R2
H
H
H
H
Yield (%)
1
2
3
4
5
6
Ph
91
92
88
88
85
83
3b
i-Pr
3c
EtCH=CH
PhCH2CH2
3d
3e
-(CH2)5-
3f
Ph
Ph
TMS
TMS
Li
TMS
TMS
base,
(additive)
1
Ph
cohols 6 resulted (Scheme 6). To circumvent isolation of
6, benzoyl chloride6 was added immediately after con-
sumption of the aldehyde providing the more stable b-
benzoyloxy sulfones 7a–e in good yields (Table 3). The
reagent used for the subsequent conversion of 7a–e to al-
lylic bissilanes 2a–e in high yields was SmI2 (0.1 M in
THF; entries 1–5). Some isomerization was observed dur-
ing reduction of 7b (E/Z ratio = 4:1, entry 2). Even bromi-
nated compound 2e was obtained in excellent yield (entry
5).
solvent
S
S
Li
O2
O2
1b-Li
1a-Li
D2O after
D2O after
30 min at T
30 min at T
TMS
TMS
D
TMS
TMS
Ph
S
S
D
O2
O2
1a-D
1b-D
Scheme 4
TMS
TMS
n-BuLi, DME
TMEDA
With reliable conditions in hand to generate anions 1a-Li
and 1b-Li selectively, the scope of their reactivity toward
aldehydes was explored. Deprotonation of 1 with n-BuLi/
TMEDA in THF at –78 °C for 30 minutes, followed by
addition of aldehydes gave ortho-(hydroxyalkyl)phenyl
sulfones 3a–d in excellent yield (Scheme 5, Table 2, en-
tries 1–4). This method is also applicable to ketones such
as cyclohexanone or benzophenone to provide alcohols
3e–f (entries 5 and 6).
TMS
TMS
LiO
R
HO
R
H2O
1
–78 °C to r.t.
then RCHO
O2SPh
O2SPh
5
6
PhCOCl
TMS
TMS
TMS
TMS
PhOCO
R
SmI2, THF
DMPU, 0 °C
R
O2SPh
7a–e
2a–e
When the reaction mixture of 1, n-BuLi, and TMEDA was
allowed to warm to room temperature followed by addi-
tion of structurally different aldehydes, very unstable al-
Scheme 6
Synlett 2010, No. 17, 2579–2582 © Thieme Stuttgart · New York

LETTER
Sulfonyl Carbanion Transmetalation
2581
Table 3 Scope of the Julia Olefination to 2
n-BuLi, THF, –78 °C,
D
5 min, then D2O
Entry
R
Product Yield (%) Product Yield (%)
S
S
O2
O2
1
2
3
4
5
Ph
7a
7b
7c
7d
7e
79
82
76
80
85
2a
2b
2c
2d
2e
89
8
8a 91% (96% D)
EtCH=CH
PhCH=CH
n-C5H11
4-BrC6H4
84a
90
n-BuLi, THF, –78 °C,
5 min, then D2O
t-Bu
t-Bu
t-Bu
t-Bu
D
S
S
64b
91
O2
O2
9
9a 96% (65% D)
Scheme 8
a Product is a 4:1 E/Z diastereomeric mixture.
b Product is volatile.
How general is the sulfonyl anion transmetalation? It is
known that deprotonation of isopropyl phenyl sulfone 8
occurs exclusively in a-position at room temperature
(Scheme 8).10 To shed more light on a potentially similar
initial metalation selectivity, orienting deprotonation/deu-
teration experiments were performed with 8 and phenyl
(2,2,6,6-tetramethylhept-4-yl)phenyl sulfone (9), the car-
bon analogue of 1. For 8, exclusive but common a-depro-
tonation was found at –78 °C even after short
deprotonation times. Compound 9, which was obtained by
twofold alkylation of methyl phenyl sulfone with neopen-
tyl iodide (see the Supporting Information), gave ortho-
deuterated product 9a exclusively after five minutes
deprotonation time. The lower D incorporation of 65%
into 9 may be due to incomplete deprotonation of this
even more hindered sulfone after the short metalation
time. This result demonstrates that the initial ortho depro-
tonation and the subsequent rearrangement may be a more
general process even when more acidic a-protons are
available. The results of 8 and 9 vs. 1 point to steric rea-
sons being responsible for the divergent deprotonation be-
havior. A potential kinetically destabilizing b-silyl
carbanion effect11 can be excluded based on the common
reactivity of 1 and 9. Future studies must determine how
far the steric hindrance of the sulfones can be reduced to
still allow initial ortho deprotonation. Other factors such
as whether the transmetalation is inter- or intramolecular
must be studied in detail.
Deprotonation of 1 in the presence of HMPA as an addi-
tive and subsequent reaction with aldehydes at low tem-
perature furnished the allylic silyl ethers 4a–f in good
yield (Scheme 7, Table 4). These compounds are very
valuable as substituted allylic silane nucleophiles7 or tri-
methylene methane precursors after conversion of the
silyl ether unit to a triflate.8
SiMe3
n-BuLi
TMSO
TMS
TMS
LiO
THF–HMPA
1
–78 to –40 °C
then RCHO
– PhSO2Li
R
R
O2S Ph
4a–f
5
Scheme 7
Table 4 Scope of the Synthesis of Allylic Silyl Ethers 4
Entry
R
Product
4a
Yield (%)
1
2
3
4
5
6
Ph
74
71
68
72
72
70
n-C5H11
c-C6H11
EtCH=CH
PhCH=CH
PhCH2CH2
4b
4c
4d
4e
4f
In summary, a new sulfonyl carbanion transmetalation
was discovered. It seems to be based on the limited acces-
sibility of the a-proton in sulfones such as 1 or 9. A selec-
tive rich reactivity of bissilylated sulfone 1 based on its
carbanion chemistry was uncovered. Directed ortho met-
alation/nucleophilic additions, Julia olefinations and
Brook rearrangements can be selectively addressed. All
products 2–4 are synthetically interesting in their own
right. Especially the bis(allylic) silanes 2 will be interest-
ing functional dinucleophiles and radical acceptors for fu-
ture applications. Compounds 4 represent nucleophiles,
which are applicable in Sakurai reactions or as substituted
trimethylenemethane synthons after conversion of the si-
lyl ether to a triflate. The synthetic potential and structural
prerequisites of the new transmetalation must be explored
in future studies. On this basis, many applications of 1 and
other similar compound classes can be foreseen. Research
along these lines is under way in this laboratory.
This divergent reactivity can be rationalized as follows at
the current stage: Initial ortho deprotonation of 1 with n-
BuLi is strongly kinetically favored at low temperature.
The resulting anion 1a-Li is stable at low temperature and
reacts selectively with electrophiles to benzylic alcohols
3. On warming, the aryllithium transmetalates to thermo-
dynamically favored a-sulfonyllithium 1b-Li and pro-
vides Julia olefination products 2. Immediate a-
deprotonation to 1b-Li seems to prevail in the presence of
HMPA, suggesting that good ligands for the lithium ion
prevent precoordination of BuLi to the sulfone necessary
for the formation of 1a-Li more effectively. This fact to-
gether with the synergistic facilitation of the Brook
rearrangement9 leads to silyl ethers 4 and contributes fa-
vorably to the diversity of the reactivity of 1.
Synlett 2010, No. 17, 2579–2582 © Thieme Stuttgart · New York

2582
B. Puget, U. Jahn
LETTER
(5) In a single example of a ortho metalation, but after a-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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(b) Gais, H.-J.; Ball, W. A.; Bund, J. Tetrahedron Lett. 1988,
29, 781.
Acknowledgment
We gratefully acknowledge generous funding by a grant of the Aca-
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J. Am. Chem. Soc. 2009, 131, 17548.
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