Generation of organolithium compounds bearing super silyl ester and their application to Matteson rearrangement

Article abstract of DOI:10.1002/anie.201304225

It's super-silyl-fragilithyl-ester-aryl-docious: The super silyl group is a strong protecting group for carboxylic acids and provides a method for direct lithiation that is compatible with the ester moiety. Organolithium compounds bearing a super silyl ester react with a variety of electrophiles in high yields (see scheme). The reaction of lithiated super silyl chloroacetate with a boron compound gives α-functionalization of the ester moiety by Matteson rearrangement. Copyright

Full text of DOI:10.1002/anie.201304225

Angewandte
Chemie
Communications
Synthetic Methods
S. Oda, H. Yamamoto*
&&&& — &&&&
Generation of Organolithium
Compounds bearing Super Silyl Ester and
their Application to Matteson
Rearrangement
It’s super-silyl-fragilithyl-ester-aryl-doc-
ious: Super silyl group is a strong pro-
tecting group for carboxylic acids and
provides a method for direct lithiation
that is compatible with the ester moiety.
Organolithium compounds bearing
super silyl ester react with a variety of
electrophiles in high yields (see scheme).
The reaction of lithiated super silyl chlor-
oacetate with a boron compound gives a-
functionalization of the ester moiety by
Matteson rearrangement.
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DOI: 10.1002/anie.201304225
Synthetic Methods
Generation of Organolithium Compounds bearing Super Silyl Ester
and their Application to Matteson Rearrangement**
Susumu Oda and Hisashi Yamamoto*
Organolithium compounds are versatile intermediates in
organic synthesis. Since they are highly reactive and readily
available from organohalides by lithium/halogen exchange,
their reaction with various electrophiles is one of the most
reactive organometallic reagents, such as organozinc[3] and
organomagnesium[4] reagents. Knochel et al. reported the
turbo Grignard reagent (iPrMgBr·LiCl) undergoes metal/
halogen exchange with aryl halides and the resulting aryl-
magnesium reagents demonstrate high tolerance toward
electrophilic functional groups. Despite the advance of
these alternative methods, a general strategy for direct
lithiation in a macrobatch reactor that is compatible with
the ester functional group has not been accomplished. Toward
this end, the utilization of an unaffected ester under
highly nucleophilic conditions would be straightfor-
ward and advantageous. Even the sterically demand-
ing tert-butyl ester, however, requires extremely low
temperature to suppress the self-condensation.[5]
Therefore, the development of a robust protecting
group for carboxylic acids, which can be easily
masked and removed, is desirable.
powerful methods for C C bond formation.[1] However, their
À
synthetic utility has been restricted by limited functional
group compatibility. For example, organolithium compounds
bearing an ester group suffer significantly from self-conden-
sation (Figure 1a). Since direct transformation of ester
Tris(trialkylsilyl)silyl groups, such as Si(TMS)3
and Si(TES)3, which are called “super silyl” groups,
demonstrate unique reactivity owing to their steric
bulk and electronic properties. Our group reported
Mukaiyama aldol reactions using super silyl enol
ethers to afford the mono, double, and triple cross-
aldol products with excellent diastereoselectivity.[6]
Halogenated super silyl enol ethers were also used
to construct the halogenated polyketide-like struc-
tures. Recently, we have developed super silyl esters
as a new class of protected carboxylic acids and
applied them to diastereoselective aldol and Mannich
reactions.[7] Therein, the super silyl group plays a crucial role
not only as a stereodirecting group to attain high diastereo-
selectivity, but as a perfect protecting group to stabilize the
lithium enolate intermediate. Further, its protection/depro-
tection process is completed under mild conditions. Encour-
aged by these results, we envisioned the super silyl group
would prevent the organolithium intermediate bearing ester
from self-condensation and provide facile synthetic trans-
formations (Figure 1b).
Figure 1. Organolithium compounds bearing ester moieties.
derivatives provides a concise synthetic route to numerous
organic compounds, great efforts have been made to solve this
long-standing problem. One way to utilize such an unstable
intermediate is the use of a microflow system described by
Yoshida et al.[2] They found the microflow reactor allows the
direct lithiation of aryl halides bearing an ester group and the
subsequent reaction with electrophiles.[2] On the other hand,
a wide range of functional groups are compatible with less-
A series of super silyl esters were synthesized quantita-
tively by our reported method[7] from carboxylic acid and
tris(triethylsilyl)silane, and the lithiation of super silyl hal-
obenzoate was investigated (Table 1). Treatment of super silyl
para-iodobenzoate 1a with tert-butyllithium in THFat À788C
led to para-lithiobenzoate intermediate and the subsequent
addition of benzaldehyde gave the product 2a in 80% yield
(entry 1). The use of para-bromobenzoate resulted in slightly
higher yield (entry 2). The microflow system has relatively
low efficiency for lithiation of aryl bromides owing to the
sluggish Br/Li exchange[2a] and the present method is com-
plementary in regard to the scope of application. The reaction
[*] S. Oda, Prof. Dr. H. Yamamoto
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
E-mail: yamamoto@uchicago.edu
Prof. Dr. H. Yamamoto
Molecular Catalyst, Research Center, Chubu University
1200 Matsumoto, Kasugai, Aichi 487-8501 (Japan)
[**] This work was supported by the NIH (P50GM086145-01). We would
like to thank Dr. Antoni Jurkiewicz and Dr. Jin Qin for their expertise
in NMR spectroscopy and mass spectrometry, respectively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304225.
2
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Table 1: Lithiation of super silyl halobenzoate.[a]
Table 2: Scope of electrophiles.[a]
Entry Super silyl haloben-
zoate
X
Product
Yield
[%][b]
Entry
1
Electrophile
MeI
Product
Yield [%][b]
84
3a
3b
1
2
3
I
Br
Cl
80
2a 87
0
2
3
4
acetophenone
DMF
85
66
31
4
5
Br
Br
2b 84
3c
3d
2c 83
DMA
[a] All reactions were performed at 0.2 mmol scale. [b] Yield of isolated
product.
5
6
CO2
3e
3 f
49
64
failed with para-chlorobenzoate because of the difficulty of
the Cl/Li exchange (entry 3).[8] Lithiation of meta- and ortho-
bromobenzoate took place successfully and furnished the
desired product in high yield (entries 4 and 5). No self-
condensation product was detected. As expected, an aryl-
lithium bearing a super silyl ester is highly stable at low
temperature.[9] While reaction of tert-butyl ortho-lithioben-
zoate with benzaldehyde afforded the corresponding lactone
through intramolecular cyclization, the super silyl ester gave
the products without any of these side reactions.
Next, we screened the scope of electrophiles. As high-
lighted in Table 2, super silyl para-lithiobenzoate was able to
react with a variety of electrophiles, such as methyl iodide,
ketone, amide, carbon dioxide, and borate in moderate to
high yields. Formylation and acylation were achieved by using
dimethylformamide (DMF) and dimethylacetamide (DMA)
(Table 2, entries 3 and 4). The reaction with carbon dioxide
gave the carboxylated product 3e (entry 5). The use of
triethylborate led to the boronic acid 3 f (entry 6).
B(OEt)3
[a] All reactions were performed at 0.2 mmol scale. [b] Yield of isolated
product.
Table 3: Lithiation of heteroaromatic super silyl esters[a].
Entry HetAr-X
1[b]
Product[b]
Yield [%][e]
5a 71
Our method can be applied to heteroaromatic rings:[10]
results of lithiation of super silyl heteroaryl esters are shown
in Table 3. Thiophene- and furan-derived super silyl esters
participated in a-lithiation by using n-butyllithium. The
reaction of 2-thiophenecarboxylate with benzaldehyde gave
the product 5a in 71% yield (Table 3, entry 1). Notably, 3-
thiophenecarboxylate 4b was selectively functionalized at the
sterically congested 2-position, which indicates the super silyl
ester has a directing effect analogous to the conventional ester
(entry 2). The use of super silyl furyl esters 4c and 4d worked
as well to give 5c and 5d in good yield (entries 3 and 4). Super
silyl 5-bromopyridine-3-carboxylate 4e was converted into
the product 5e in 48% yield (entry 5). The Li/Br exchange
reaction proceeded smoothly without the protection of the
nitrogen atom. Indole-derived super silyl ester 4 f was also
applied to afford the product 5 f by using three equivalents of
tert-butyllithium (entry 6).
2[b]
3[b]
4[b]
5b 81
5c 77
5d 82
5[c]
5e 48
5 f 78
6[d]
[a] All reactions were performed at 0.2 mmol scale. [b] nBuLi (1.0 equiv)
was used. [c] tBuLi (2.0 equiv) was used. [d] tBuLi (3.0 equiv) was used.
[e] Yield of isolated product.
In our prior studies, we found that lithiation of super silyl
propionate provides the stable lithium enolate for aldol and
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Mannich reactions.[7] Taking advantage of the inactive Cl/Li
exchange, we envisioned lithiation of super silyl a-chloroace-
tate would give a-chloro lithium enolate, which can be used
for a Matteson rearrangement[11] to attain a-functionalization
of the ester moiety.[12] a-Arylation is, in particular, a valuable
method to give access to a-aryl carboxylic acids, an important
structural class for pharmaceuticals. While a number of
transition-metal-catalyzed a-arylations has been reported,[13]
the direct reaction of easy accessible boron and organolithium
compounds is still attractive. Aggarwal et al. accomplished
a great achievement in the asymmetric homologation of
boron compounds by using lithiated carbamates.[14]
Super silyl chloroacetate 6 was treated with lithium
bis(trimethylsilyl)amide (LiHMDS) to form a-chloro lithium
enolate, followed by the addition of trialkyl borane (BR3). a-
Alkylation of super silyl chloroacetate is summarized in
Scheme 1. Super silyl butyrate 7a was obtained in 83% yield
Scheme 3. a-Arylation of super silyl chloroacetate by Matteson rear-
rangement. All reactions were performed at 0.2 mmol scale. The yields
are of isolated products.
bond due to steric repulsion between 9-BBN and the super
silyl group (see Scheme 4B).[14f]
To our delight, aryl migration took place with the use of
aryl propanediol boronate.[15] For these reactions, potassium
bis(trimethylsilyl)amide (KHMDS) was found to be suitable
and a-arylation of super silyl chloroacetate proceeds
smoothly (Scheme 3). The reaction demonstrated high toler-
ance to the substituent of aromatic ring at the ortho, meta, and
para positions. Electron-rich aryl boronates resulted in higher
yield than electron-deficient aryl boronates. The reaction with
haloaryl boronates left the halogen atom intact, proving an
opportunity for further transformations. The rearrangement
occurred with the use of sterically hindered naphthyl boro-
nate and vinyl-derived cinnamyl boronate to provide 9i and
9j. Although the use of 2-thienyl boronate gave 9k in low
yield, 3-thienyl boronate afforded 9l effectively, indicating
the coordination of the thiophene ring has negative effect on
the migration. 3-Furylboronate also worked to furnish 9m in
63% yield.
Scheme 1. a-Alkylation of super silyl chloroacetate by Matteson rear-
rangement. All reactions were performed at 0.2 mmol scale. The yields
are of isolated products.
by using triethyl borane. Secondary alkyl boranes, such as
cyclohexyl and norbornyl borane were also applicable. While
the reaction with triallylborane gave a complex mixture of
side-products, 2-phenethyl and hydrocinnamyl borane fur-
nished 7e and 7 f in good yields. No product was observed
with the use of triphenyl borane. Surprisingly, when lithiated 6
was treated with
a
9-BBN (9-BBN = 9-borabicyclo-
[3.3.1]nonane) derived phenylborane, the alkyl-migration
product 8 was obtained (Scheme 2). Although it has been
demonstrated to give aryl-migration product in Aggarwalꢀs
report,[14b] the cyclooctyl group migrated presumably because
À
it positions anti-periplanar against the s* orbital of the C Cl
A proposed mechanism is shown in Scheme 4. Super silyl
chloroacetate is deprotonated by base (LiHMDS or
KHMDS) to generate metal enolate A, and the reaction
with a boron compound leads to the formation of boron ate
complex B. 1,2-Metallate rearrangement occurs to give the
boron enolate C. Finally, the desired product D is obtained
after being quenched with NH4Cl aqueous solution. The super
silyl group is indispensable to protect the intermediates A and
C and inhibit their self-condensation. While LiHMDS suc-
ceeded for a-alkylation, the decomposition of intermediate B
was observed with warming up to 08C for a-arylation. Thus,
Scheme 2. The reaction of super silyl chloroacetate with 9-BBN derived
phenyl borane.
4
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Scheme 4. Proposed mechanism for Matteson rearrangement of super
silyl chloroacetate.
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In summary, super silyl haloesters and heteroaromatic
super silyl esters were synthesized in high yields. By treating
with an alkyllithium reagent, the lithium/halogen exchange or
deprotonation reaction gave the organolithium reagents
bearing a super silyl ester group. They were found to react
with a variety of electrophiles, such as aldehyde, ketone,
amide, carbon dioxide, and borate. Moreover, a-functional-
ization of super silyl chloroacetate was successful by a Matte-
son rearrangement. Thus, the super silyl group is a strong and
robust protecting group even against highly reactive anionic
species. Further application of super silyl ester is under
investigation.
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Received: May 16, 2013
Published online: && &&, &&&&
Keywords: arylation · matteson rearrangement ·
.
organolithium reagents · super silyl · synthetic methods
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