Preparation and regioselective metalation of Bis(trimethylsilyl)methyl- substituted aryl derivatives

Article abstract of DOI:10.1002/chem.201402531

A range of bis(trimethylsilyl)methyl-substituted aryl derivatives was prepared by using a Kumada-Corriu cross-coupling reaction. The regioselective metalation of the resulting bis(trimethylsilyl)methyl-substituted aryl derivatives bearing this bulky silyl group allowed the generation of functionalized aromatics. A regioselective switch in the presence or in the absence of the bis(trimethylsilyl)methyl group has been demonstrated. Furthermore, this silyl group was converted into a formyl group or a styryl group, enhancing the scope of application of such bis(trimethylsilyl)methyl- substituted arenes.

Full text of DOI:10.1002/chem.201402531

DOI: 10.1002/chem.201402531
Communication
&
Metalation
Preparation and Regioselective Metalation of
Bis(trimethylsilyl)methyl-Substituted Aryl Derivatives
Veronika Werner,[a] Thomas Klatt,[a] Masaya Fujii,[c] Jenifer Markiewicz,[a] Yitzhak Apeloig,[b]
and Paul Knochel*[a]
allows regioselective magnesiation or lithiation of these func-
Abstract: A range of bis(trimethylsilyl)methyl-substituted
aryl derivatives was prepared by using a Kumada–Corriu
tionalized aromatics. In some cases, a regioselective switch was
demonstrated (in the presence or absence of the BTSM group).
cross-coupling reaction. The regioselective metalation of
In addition, several transformations of the BTSM group were
the resulting bis(trimethylsilyl)methyl-substituted aryl de-
performed.
rivatives bearing this bulky silyl group allowed the genera-
Thus, (Me3Si)2CHMgBr·LiCl was prepared by the reaction of
(Me3Si)2CHBr (3, 1.0 equiv) with magnesium turnings
(1.25 equiv) in the presence of LiCl (1.25 equiv), furnishing the
tion of functionalized aromatics. A regioselective switch in
the presence or in the absence of the bis(trimethylsilyl)-
methyl group has been demonstrated. Furthermore, this
desired Grignard reagent 2 within 30 min at 08C. Titration of
the organomagnesium reagent with iodine in THF indicated
silyl group was converted into a formyl group or a styryl
group, enhancing the scope of application of such bis(tri-
a concentration of 0.6m (80% yield).
In preliminary experiments, (Me3Si)2CHMgBr·LiCl (2) under-
methylsilyl)methyl-substituted arenes.
went a smooth Kumada–Corriu cross-coupling reaction with
tert-butyl 3-bromobenzoate (4a, 0.9 equiv, 508C, 2 h) by using
2% Pd(OAc)2 and 4% SPhos.[12] The BTSM-substituted benzoic
The regioselective metalation of aromatics is an important syn-
thetic task as functionalized arenes are essential building
blocks for pharmaceuticals and agrochemicals.[1] Additionally,
functionalized silyl substituents have found an increasing ap-
plication in organic chemistry.[2] Numerous strategies have
been elaborated for performing regioselective lithiations,[3] and
the use of the (Me3Si)2CH group (BTSM)[4] was pioneered by
Snieckus and was shown to trigger the directed lithiation of
benzamides with great efficiency.[5] In addition, this bulky sili-
con group has been successfully used as a remote control in
the synthesis of isolable atropisomeric amides by Xia and Xu.[6]
Recently, the bis(silyl)methyl moiety has also been used for
Wittig rearrangements and Prins cyclization.[7] Also, we have
shown that the pyrazine scaffold can be fully functionalized
starting from a BTSM-substituted pyrazine[8] by using the mag-
nesium base TMP2Mg·2LiCl (1; TMP=2,2,6,6-tetramethylpiper-
idyl).[9] Herein, we report a simple way to introduce the BTSM
substituent onto an aromatic system by using a Kumada–
Corriu cross-coupling reaction[10] between (Me3Si)2CHMgBr·LiCl
(2)[11] and various aryl bromides. We show that the BTSM group
ester (5a) was obtained in 97% yield (Scheme 1).
Scheme 1. Preparation of 5a and subsequent cross-coupling reaction.
This cross-coupling procedure could be extended to a range
of aromatic bromides bearing either electron-donating or elec-
tron-withdrawing substituents. Thus, the meta-substituted aryl
bromides 4b–4 f underwent the cross-coupling reaction with
the Grignard reagent 2 and the corresponding BTSM-function-
alized aromatic derivatives (5b–5 f) were isolated in 88–95%
yield (Table 1, entries 1–5). Also, the para-substituted methyl 4-
bromobenzoate (4g) was converted into the corresponding
cross-coupling product 5g in 89% yield (entry 6). Even a keto
function could be tolerated in this cross-coupling and the bro-
mobenzophenone 4h was converted to 5h in 72% yield
(entry 7). Also, the unprotected aniline derivative 4i furnished
the corresponding cross-coupling product 5i by using 3 equiv-
alents of the Grignard reagent 2 and toluene as co-solvent
(THF/toluene=2:1, 808C, 24 h). The resulting aniline 5i was
isolated in 60% yield (entry 8).
[a] V. Werner, T. Klatt, J. Markiewicz, Prof. Dr. P. Knochel
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen
Butenandtstrasse 5-13, Haus F, 81377 Mꢁnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
[b] Prof. Dr. Y. Apeloig
Schulich Faculty of Chemistry and the Lise Meitner-Minerva Center for
Computational Quantum Chemistry, Technion-Israel Institute of Technology
Technion-City, Haifa 32000 (Israel)
[c] M. Fujii
Graduate School of Pharmaceutical Sciences, University of Tokyo
7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
The prepared BTSM-substituted aromatics of type 5 were
submitted to metalation reactions employing various Li or Mg
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402531.
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dibenzylideneacetone) and 4% tfp (tfp=tri(2-furyl)phos-
phine)[14] led to the corresponding biphenyls 9a and b in 88
and 93% yield, respectively. The cross-coupling reaction with
4-bromobenzonitrile (8c) with 2% Pd(OAc)2 and 4% SPhos as
the catalytic system (508C, 12 h), furnished the nitrile 9c in
88% yield (entry 3). In the presence of CuCN·2LiCl (1.6 equiv),
reaction with ethyl (2-bromomethyl)acrylate[15] (8d) gave the
allylated product 9d in 92% yield (entry 4). The less sensitive
substrate 5b was conveniently lithiated with TMPLi (2 equiv) in
THF (À608C, 1 h), leading to the aryllithium reagent 6b
(Scheme 2). Transmetalation with ZnCl2 (2.1 equiv) and subse-
quent cross-coupling reaction with the aryl bromide 8e led to
the expected product 9e in 95% yield (entry 5). Moreover, the
cross-coupling reaction with 2-iodothiophene (8 f) furnished
the biaryl 9 f in 96% yield (entry 6). For the metalation of 5c,
sBuLi (1.5 equiv) and TMEDA (tetramethylethylenediamine,
1.5 equiv) in hexane[16] (À308C, 1.5 h) were used, leading to
the ortho-lithiated species 6c, which underwent, after trans-
metalation with ZnCl2 (1.5 equiv), a copper-catalyzed allylation
with 8d to give the allylated product 9g in 57% yield
(entry 7). The aryllithium species 6c reacted directly with the
sulfur electrophile 8g to afford the thioether 9h in 60% yield
(entry 8). Transmetalation to the magnesium species (with
1.6 equiv MgCl2) and subsequent reaction with N,N-dimethyl-
enemethaniminium trifluoroacetate (8h)[17] furnished the corre-
sponding benzylamine 9i in 62% yield (entry 9). Transmetala-
tion of 6c with ZnCl2 and subsequent Pd-catalyzed cross-cou-
pling reactions with aryl halides 8i and 8j gave the biphenyls
9j and 9k in 64–77% yield (entries 10 and 11).
Table 1. Products of type 5 obtained by Kumada–Corriu cross-coupling
reaction of various aryl bromides with 2.
Entry
Electrophile
Product[a]
1
2
3
4
5
4b: R=F
5b: 92%
5c: 91%
5d: 91%
5e: 95%
5 f: 88%
4c: R=CF3
4d: R=CO2Et
4e: R=OMe
4 f: R=NMe2
6
7
4g: R=CO2Me
4h: R=COPh
5g: 89%
5h: 72%
8
4i
5i: 60%[b]
[a] Yields of isolated, analytically pure product. [b] The cross-coupling re-
action was performed by using 2.5 equivalents of 2 in a 2:1 mixture of
THF/toluene at 808C for 24 h.
The presence or absence of the BTSM group allowed switch-
ing of the metalation regioselectivity. Thus, an aryl bromide of
type 4 (FG is an electron-withdrawing substituent) is preferen-
tially metalated in position 2, leading to products of type 10
after quenching with an electrophile E (Scheme 3). On the
other hand, the metalation of substrate 5 proceeds at the least
sterically hindered position, 6, leading to products of type 9
after quenching with an electrophile. In this sequence, the
final group, R, present in 9 or 10 is either a BTSM group or
a formyl group (CHO).
Thus, ester 4a was smoothly metalated by TMPMgCl·LiCl[9]
(1.5 equiv) in THF (08C, 45 min; Scheme 4). Direct addition to
4-chlorobenzaldehyde furnished the lactone 11 a in 75% yield.
Alternatively, transmetalation of the magnesiated species with
ZnCl2 (1.6 equiv) and subsequent Pd-catalyzed cross-coupling
reactions with 4-iodo-anisole (8b) or ethyl 4-iodobenzoate (8a)
gave the biphenyls 11 b and 11 c, respectively, in 61–
bases. In all cases, a regioselective metalation at the least hin-
dered position of the aromatic substrate 5 was observed, lead-
ing to the lithiated or magnesiated species 6 and not to the
more sterically hindered organometallic species 7 (Scheme 2).
For the metalation of benzoate 5a, bearing a sensitive ester
function, the use of TMPMgCl·LiCl did not lead to complete
conversion. Therefore, the stronger base TMP2Mg·2LiCl was ap-
plied for a selective metalation. Thus, treatment of 5a with
TMP2Mg·2LiCl (1, 1.5 equiv) in THF (258C, 2 h) led to the
Grignard reagent 6a. After transmetalation with ZnCl2
(1.6 equiv), a Pd-catalyzed Negishi cross-coupling[13] reaction
with ethyl 4-iodobenzoate (8a) or 4-iodoanisole (8b; Table 2,
entries 1–2) in THF (508C, 12 h) by using 2% Pd(dba)2 (dba=
72% yield. A Kumada cross-coupling reaction of the
ortho-substituted substrates 11a–c with Grignard re-
agent 2 required harsher conditions (808C, 12 h) and
the BTSM products 10a–c were isolated in 32–47%
yield. The resulting products 10a–c have a comple-
mentary regioisomeric substitution pattern compared
to the BTSM-substituted arenes 9a–d already de-
scribed in Table 2 (entries 1–4).
A similar regioselectivity switch was found with
the 3-substituted aryl fluorides 4b and 5b
(Scheme 5). Thus, treatment of 4b with
Scheme 2. Regioselective metalation of aromatics of type 5 by using various Li or Mg
bases.
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Table 2. Products of type 9 obtained by metalation of 5 followed by
Table 2. (Continued)
reaction with different electrophiles.
Entry Substrate
Electrophile
Product[a]
9j: 77%[g,d]
Entry Substrate
Electrophile
Product[a]
5c
8i
1
11
5a
8a
8b
9a: 88%[b,c]
5c
8j
9k: 64%[g,c]
[a] Yields of isolated, analytically pure product. [b] Metalation conditions:
TMP2Mg·2LiCl (1.5 equiv), 258C, 2 h. [c] Cross-coupling conditions: ZnCl2,
2% Pd(dba)2, 4% tfp, 508C, 12 h. [d] Cross-coupling conditions: ZnCl2, 2%
Pd(OAc)2, 4% SPhos, 508C, 12 h. [e] CuCN·2LiCl (1.6 equiv) was added.
[f] Metalation conditions: TMPLi (2 equiv), À608C, 1 h. [g] Metalation con-
ditions: sBuLi (1.5 equiv), TMEDA (1.5 equiv), hexane, À308C, 1.5 h.
[h] MgCl2 (1.6 equiv) was added.
2
5a
9b: 93%[b,c]
3
5a
8c
9c: 88%[b,d]
4
5a
8d
9d: 92%[b,e]
5
5b
8e
8 f
8d
9e: 95%[f,d]
9 f: 96%[f,c]
9g: 57%[g,e]
6
Scheme 3. Regioselective metalation of substrates of type 4 and 5.
5b
7
TMP2Mg·2LiCl (1.1 equiv, À208C, 1 h) led to a 2-magnesiated
intermediate that, after transmetalation with ZnCl2 (1.2 equiv),
underwent a Pd-catalyzed cross-coupling reaction with 3-iodo-
anisole (8k) to furnish the biphenyl 10d in 78% yield. A Br/Li
exchange was then performed on the arene 10d with nBuLi
(1.1 equiv) in THF (À788C, 30 min) to afford a lithiated species,
which was trapped with DMF (2 equiv) to give the benzalde-
hyde 13 in 76% yield. Complementarily, the metalation of 5b
with TMPLi (2 equiv, À608C, 1 h) followed by transmetalation
with ZnCl2 (2.1 equiv) and subsequent Negishi cross-coupling
with 8k, afforded the biphenyl 9l in 95% yield. Oxidation of 9l
with CAN (ceric ammonium nitrate, 5 equiv, 08C) according to
the methodology developed by Palomo et al.[18] in a 3:1 mix-
ture of methanol/acetonitrile (08C, 10 min) furnished the benz-
aldehyde derivative 12a in 88% yield.
5c
8
5c
8g
8h
9h: 60%[g]
9
5c
9i: 62%[g,h]
10
Finally, to show the utility of the BTSM group, we have con-
verted several polyfunctional BTSM-substituted arenes to the
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corresponding aldehydes by using the oxidation
method of Palomo. Thus, the biphenyls 9c and 9k
provided, after treatment with CAN (5 equiv), the cor-
responding aldehydes 12a and b in 76 and 92%
yield, respectively (Scheme 6).
Additionally, we have performed Peterson olefina-
tions[19] of the biphenyls 9a, 9e, and 9j by using
benzaldehyde (14a), 3,4,5-trimethoxybenzaldehyde
(14b), or thiophene-2-carbaldehyde (14c, 1.2 equiv)
in the presence of 10% tetra-n-butylammonium fluo-
ride (TBAF)[20] in THF (À208C, 15 min), leading to the
stilbene derivatives 15a–c (>99% E) in 62–98% yield
(Scheme 7).
In summary, we have developed a simple proce-
dure for the preparation of BTSM-functionalized
arenes by using a Kumada–Corriu cross-coupling re-
action. A range of functional groups, such as esters,
ketones, and amino groups were tolerated in the
cross-coupling reactions. The bulky BTSM group
allows the regioselective metalation of various sub-
strates as well as the synthesis of orthogonally func-
tionalized compounds. Transfor-
Scheme 4. Orthogonal functionalization of 4a and 5a by a regioselective magnesiation
by using TMPMgCl·LiCl or TMP2Mg·2LiCl.
mation of the BTSM group into
aldehydes or E-stilbenes has
been performed, confirming that
the BTSM group is a versatile
substituent of aromatics that
allows highly regioselective lith-
iation or magnesiation. Exten-
sion of this methodology for the
metalation of heterocycles is cur-
rently underway in our laborato-
ries.
Experimental Section
tert-Butyl 3-(bis(trimethylsilyl)-
methyl)benzoate (5a)
tert-Butyl 3-bromobenzoate (4a,
257 mg, 1.00 mmol), Pd(OAc)2
(4.5 mg, 0.02 mmol, 2 mol%), and
Scheme 5. Generation of orthogonal-functionalized benzaldehydes 12 and 13.
SPhos
(16.4 mg,
0.04 mmol,
4 mol%) were suspended in dry
THF (3.50 mL) in
a
dry, argon-flushed Schlenk flask. Then,
(TMS)2CHMgBr·LiCl (2, 1.83 mL, 1.10 mmol, 0.6m in THF) was added
and the reaction mixture was stirred for 2 h at 508C. After full con-
version was detected by GC analysis of quenched reaction aliquots,
sat. aq NH4Cl (10 mL) was added and the aqueous layer was ex-
tracted with EtOAc (3ꢁ10 mL). The combined organic phases were
dried (Na2SO4). Evaporation of the solvents in vacuo and purifica-
tion by column chromatography (silica gel, ihexane/Et2O=50:1) af-
forded the desired product 5a (326 mg, 97%) as colorless oil.
Acknowledgements
We thank the German–Israel project cooperation (DIP) for fi-
nancial support. We also thank BASF SE (Ludwigshafen), W. C.
Scheme 6. Oxidation of 9c and 9k into the corresponding aldehydes 12b
and 12c.
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Brook, J. J. Chrusciel, Organometallics 1984, 3, 1317; c) M. Lautens, R. N.
Ben, P. H. M. Delanghe, Angew. Chem. 1994, 106, 2557; Angew. Chem.
Int. Ed. Engl. 1994, 33, 2448; d) D. M. Hodgson, S. F. Barker, L. H. Mace,
J. R. Moran, Chem. Commun. 2001, 153; for its use in metalation reac-
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Received: March 10, 2014
Published online on && &&, 0000
Chem. Eur. J. 2014, 20, 1 – 6
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
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Metalation
V. Werner, T. Klatt, M. Fujii, J. Markiewicz,
Y. Apeloig, P. Knochel*
&& – &&
Metalation with bulky groups: A range
of bis(trimethylsilyl)methyl-substituted
aryl derivatives was prepared by using
a Kumada–Corriu cross-coupling. The re-
gioselective metalation of the resulting
arenes bearing this bulky silyl group al-
lowed the generation of functionalized
aromatics. A regioselective switch in the
presence or in the absence of this silyl
group has been demonstrated. Further-
more, the bis(trimethylsilyl)methyl
group was converted into a formyl
group or a styryl group.
Preparation and Regioselective
Metalation of
Bis(trimethylsilyl)methyl-Substituted
Aryl Derivatives
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Chem. Eur. J. 2014, 20, 1 – 6
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!