Highly Regioselective Remote Lithiation of Functionalized 1,3-bis-Silylated Arenes

Article abstract of DOI:10.1002/anie.201812742

Substituted arenes flanked by two bulky triethylsilyl groups were regiospecifically lithiated at the 5-position with nBuLi?PMDTA at 25 °C. The resulting aryllithiums reacted with a broad range of electrophiles such as ketones, isocyanates, Weinreb amides, allyl bromides, and CO₂ at 25 °C. These bis-silylated arenes were then converted in simple reaction sequences into silyl-free tetrasubstituted arenes. This remote lithiation was extended to 2,6-bis(triethylsilyl)pyridine as well as 3,3′-bis(triethylsilyl)biphenyl.

Full text of DOI:10.1002/anie.201812742

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Accepted Article
Title: Highly Regioselective Remote Lithiation of Functionalized 1,3-bis-
Silylated Arenes
Authors: Andreas Bernd Bellan and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812742
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Highly Regioselective Remote Lithiation of Functionalized 1,3-bis-
Silylated Arenes
Andreas B. Bellan and Paul Knochel*
Abstract: Substituted arenes flanked by two bulky triethylsilyl groups
First, we have investigated metalation conditions for the lithiation
are regiospecifically lithiated in 5-position with nBuLi•PMDTA at 25 °C. of 2,6-bis(triethylsilyl)fluorobenzene (1a) as test substrate. The
The resulting aryllithiums reacted with a broad range of electrophiles
such as ketones, isocyanates, Weinreb-amides, allyl bromides or CO2
at 25 °C. These bis-silylated arenes were converted in simple reaction
sequences to silyl-free tetrasubstituted arenes. This remote lithiation
was extended to 2,6-bis(triethylsilyl)pyridine as well as a 3,3’-
bis(triethylsilyl)biphenyl.
formation of the lithiated arene 2a was determined by quenching
reaction aliquots with MeSSMe leading to the thioether 3a. No
lithiation was observed with standard lithium bases (Table 1,
entries 1-4). The addition of N,N,N’,N’-tetramethylethylene-
diamine (TMEDA), a reactivity enhancing agent of alkyllithium
reagents, had no effect (entries 5-6).[11] However, addition of
N,N,N’,N’’,N’’-pentamethyldiethylenetriamine (PMDTA)[12] to
either nBuLi or sBuLi afforded the expected metalation product 2a
in 43% and 29% yield respectively,[13] indicating that nBuLi is for
these systems the superior alkyllithium base (entries 7-8). To
improve the incomplete metalation, the base amount was
increased from 1.5 equiv. to 3.0 equiv. raising the yield to 58%
(entry 9). Surprisingly Schlosser’s base (nBuLi•KOtBu)[14] led to a
drastic product decrease (entry 10). To our delight changing from
ethereal solvents to non-coordinating hexane improved the
lithiation considerably and the reaction of 1a with nBuLi•PMDTA
led, after quench with MeSSMe, to an increased yield of 65%
isolated product of 3a (entry 11).[15,16]
The metalation of arenes and heteroarenes is an important
functionalization method of these ring systems.[1] Usually, a
functional group is required to direct such metalations in ortho-
position.[2] However, metalation in meta- or para-positions are
rather seldom. Recently, Mulvey and O’Hara described selective
meta-functionalizations using mixed alkali-metal-mediated
metalations allowing the double functionalization of various
aromatics in ortho-meta’ or even in meta-meta’-positions.[3] Also,
Gaunt reported
a copper-catalyzed oxidative C-H-coupling
leading to a meta-arylation of aniline derivatives.[4] Using
removable nitrile containing tethers, Yu[5] and Tan[6] were able to
perform meta C-H activations using palladium-catalyzed Heck
reactions. Yu performed an oxidative Pd-catalyzed Catellani-
reaction, changing the regioselectivity of the C-H activation from
ortho to the meta position.[7] Ackermann reported a meta-selective
ruthenium-catalyzed C-H alkylation using secondary alkyl
halides.[8] Maiti observed a para-selective oxidative acylation of
arenes employing enol ethers as acylating reagents.[9] Pioneering
work of Schlosser showed that a bulky silyl-substituent between
two chlorides on a benzene ring results in a buttress effect, which
kinetically favors the meta-metalation relative to the halides.[10]
This led us to envision the use of the direct sterical bulk of two
silyl groups for achieving a remote metalation. Herein, we report
a convenient, more general, 5-lithiation of arenes of type 1,
leading to para-substituted aryllithiums of type 2 (Scheme 1).
Table 1: Optimization of the lithiation of bis-silylated fluorobenzene (1a).
Entry
Li reagent
Additive
Equiv.
Solvent
Yield [%][a]
1
nBuLi
sBuLi
tBuLi
-
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
Et2O
Et2O
Et2O
THF
0
2
-
0
3
-
0
4
TMPLi
nBuLi
sBuLi
nBuLi
sBuLi
nBuLi
nBuLi
nBuLi
-
0
5
TMEDA
TMEDA
PMDTA
PMDTA
PMDTA
PMDTA/KOtBu
PMDTA
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
nhexane
0
6
0
7
43
8
29
9
58
10
11
9
71 (65)[b]
[a] Yield of 2a determined by GC analysis of reaction aliquots quenched with
MeSSMe. [b] Yield of analytically pure isolated product.; TMP: 2,2,6,6-
tetramethylpiperidyl.
The aryllithium 2a generated under these optimized conditions
was treated with various electrophiles leading regiospecifically to
para-substituted fluorobenzenes 3a-l in 61-89% yield (Scheme
2).[15,17,18]
Scheme 1: Schlosser’s buttress remote lithiation and an extension of sterically
hindered bis-silylated arenes of type 1.
[*]
A. B. Bellan, Prof. Dr. P. Knochel, Ludwig-Maximilians-Universität
München, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
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the corresponding thioethers 9-12 were obtained in 38-48% yield.
Quenching of 2b with various electrophiles (including aldehyde,
ketone, Weinreb amide, isocyanate) provided the expected
products 8b-8n in 62-96% yield (Scheme 4).[15]
Scheme 2: Remote lithiation of fluorobenzene 1a, leading to functionalized
arenes of type 3. [a] Yield of analytically pure isolated product. [b] ZnCl2 (3.0
equiv.) was added. [c] CuCN•2LiCl (10 mol%) was added.
To demonstrate the utility of bis-silyl derivatives of type 3, we have
converted 3b into silyl-free tetrasubstituted fluorobenzenes of
type 4 (Scheme 3). Thus, iodination of 3b with ICl provides aryl
iodide 5 in 90% yield.[19] A selective I/Mg-exchange on 5
(iPrMgCl•LiCl, –40 °C, 15 min) furnished
a
magnesium
intermediate, which was quenched with a range of electrophiles
(E1–X), to give the mono-silanes 6a-g in 71-94% yield.[20]
Treatment of arenes 6 with ICl afforded the silyl-free arenes 7a-b
in 91-94% yield. A subsequent I/Mg-exchange on iodoketone 7a
and quenching with a second electrophile (E2-X) led to the
tetrasubstituted fluorobenzenes 4a-c in 73-82% yield.
Scheme 4: Remote lithiation of various functionalized arenes of type 1, leading
to functionalized arenes of type 8-12. [a] nBuLi•PMDTA, 25 °C, 6 h. [b] MeSSMe,
–20 °C, 1 h. [c] The metalation temperature was –10 °C. [d] Yield of analytically
pure isolated product. [e] ZnCl2 (3.0 equiv.) was added. [f] This reaction was
performed on a 30 mmol scale with no yield decrease. [g] CuCN•2LiCl
(10 mol%) was added.
The oxazolyl arenes of type 8 were converted into various silyl
free amides and lactones via a short reaction sequence. Thus, in
a one-pot procedure, oxazolyl arene 8c was methylated with
Me3OBF4 (1.05 equiv., 0 °C, 2 h) followed by a new reductive ring
opening with LiEt3BH (1.2 equiv., 0 °C, 4 h), affording benzamide
13 in 86% yield (Scheme 5). Treatment of 13 with ICl provided
iodoarene 14 in 89% yield. Methylation of 14 with MeLi•LiBr
(1.05 equiv., –78 °C, 1 h) furnished the 2-methylated arene 15 in
[21]
91% yield.
Subsequent iodo-desilylation with ICl afforded
iodoarene 16 in 96% yield. Finally, a I/Mg-exchange followed by
reactions with various electrophiles gave the desired
polyfunctional arenes 17a-e in 61-86% yield.
Scheme 3: Polyfunctional arenes of type 4 prepared by selective iodo-
desilylations, followed by I/Mg-exchange and electrophile quenchings. [a] Yield
of analytically pure isolated product. [b] CuCN•2LiCl (10 mol%) was added. [c]
ZnCl2 (1.1 equiv.), Pd(dba)2 (2 mol%) and P(o-furyl)3 (4 mol%) were added. [d]
CuCN•2LiCl (1.1 equiv.) was added.
We were confident that the fluoro-substituent of the bis-silyl arene
1a was essential for a fast metalation. However, after preparing
analogs of 1a such as 1b-f, we realized that other factors than the
substituent electronegativity were important for such remote
lithiations. Thus, the oxazolyl derivative 1b was smoothly
metalated with nBuLi•PMDTA (3.0 equiv., 25 °C, 6 h) to provide
the lithiated arene 2b (Scheme 4). Quenching 2b with MeSSMe
led to the corresponding thioether 8a in 89% isolated yield,[15]
suggesting that complexation of nBuLi•PMDTA by the oxazolyl
group was essential for an efficient metalation. Related
coordinating functionalities, such as a methoxy 1c, an amido 1d
or a carbamate 1e, proved to be less powerful directing groups
and led to lithiations with comparable efficiency than the
unsubstituted substrate 1f. After quenching 2c-f with MeSSMe,
Scheme 5: Polyfunctional benzamides and lactones of type 17 prepared by
reductive ring opening and selective iodo-desilylations, followed by I/Mg-
exchange and electrophilic quench. [a] Yield of analytically pure isolated product.
[b] CuCN•2LiCl (10 mol%) was added. [c] ZnCl2 (1.1 equiv.), Pd(dba)2 (2 mol%)
and P(o-furyl)3 (4 mol%) were added. [d] The crude benzylic alcohol was
refluxed in 1,4-dioxane.[15]
Remarkably, this remote metalation can be extended to the
pyridine scaffold.[22] Thus, 2,6-bis(triethylsilyl)pyridine (18) was
treated with nBuLi•PMDTA (1.1 equiv., 25 °C, 3 h) leading to the
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4-lithiated bis-silyl pyridine 19, which was quenched with a variety
of electrophiles affording the 4-functionalized pyridines 20a-m in
60-96% yield (Scheme 6).[15,23]
In summary, we have found that the nBuLi•PMDTA complex is an
exceptionally active base for the regioselective remote lithiation of
various 1,3-bis(triethylsilyl)arenes, including the bis-silylated
pyridine 18. We have converted the resulting para-functionalized
arenes into a variety of tetrasubstituted arenes, demonstrating the
utility of our procedure for remote lithiations. Further extensions
of this method are currently being studied in our laboratories.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (DFG) for
financial support. We thank Albemarle (Frankfurt, Germany) for
the generous gift of chemicals. We thank Dr. Johannes Nickel for
preliminary experiments.
Scheme 6: Remote lithiation of pyridine 18, leading to functionalized pyridines
of type 20. [a] Yield of analytically pure isolated product. [b] NEt3 was used
during column chromatographical purification. [c] ZnCl2 (1.1 equiv.) and
CuCN•2LiCl (10 mol%) were added. [d] ZnCl2 (1.1 equiv.) and Pd(PPh3)4
(2 mol%) were added. [e] MgCl2 (1.0 equiv.) was added.
Keywords: lithiation • pyridines • remote metalation • silanes
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TBAF: tetrabutylammonium fluoride
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Scheme 8: Remote lithiation of biphenyl 24, leading to thioether 26. [a] Yield of
analytically pure isolated product.
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[15] For more details, see the Supporting Information.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Andreas B. Bellan, and Paul Knochel*
Page No. – Page No.
Highly Regioselective Remote
Lithiation of Functionalized 1,3-bis-
Silylated Arenes
Lithiation in para-position: The regiospecific remote lithiation of easily prepared
o,o’-bis(triethylsilyl)arenes and heteroarenes using nBuLi•PMDTA (PMDTA =
MeN(CH2CH2NMe2)2) is reported. These lithiated (hetero)arenes react with a broad
range of electrophiles leading after further functionalizations to silyl-free
tetrasubstituted products.
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