New in situ trapping metalations of functionalized arenes and heteroarenes with TMPLi in the presence of ZnCl2 and other metal salts

Article abstract of DOI:10.1002/anie.201403688

The addition of TMPLi to a mixture of an aromatic or heteroaromatic substrate with a metal salt such as MgCl₂, ZnCl₂, or CuCN at -78 °C first leads to lithiation of the arene followed by transmetalation with the metal salt to afford functionalized organometallic compounds of Mg, Zn, or Cu. This in situ trapping method allows an expedited metalation (-78 °C, 5 min) of a range of sensitive pyridines (bearing a nitro, ester, or cyano group) and allows the preparation of kinetic regioisomers of functionalized aromatic compounds or heterocycles not otherwise available by standard metalating agents, such as TMPMgCl·LiCl or TMPZnCl·LiCl. Fast, faster, the fastest: Aromatic and heterocyclic substrates, when treated with TMPLi (TMP=2,2,6,6-tetramethylpiperidyl), undergo a kinetic lithiation and then a transmetalation with a metal salt such as MgCl₂, ZnCl ₂, or CuCN. This allows an expedited metalation of sensitive pyridines bearing a nitro, ester, or cyano group and allows the preparation of kinetic regioisomers of functionalized aromatic compounds or heterocycles.

Full text of DOI:10.1002/anie.201403688

Angewandte
Chemie
DOI: 10.1002/anie.201403688
Regioselective Metalations
New In Situ Trapping Metalations of Functionalized Arenes and
Heteroarenes with TMPLi in the Presence of ZnCl2 and Other Metal
Salts**
Annette Frischmuth, Maitane Fernꢀndez, Nadja M. Barl, Florian Achrainer, Hendrik Zipse,
Guillaume Berionni, Herbert Mayr, Konstantin Karaghiosoff, and Paul Knochel*
Abstract: The addition of TMPLi to a mixture of an aromatic
or heteroaromatic substrate with a metal salt such as MgCl2,
ZnCl2, or CuCN at À788C first leads to lithiation of the arene
followed by transmetalation with the metal salt to afford
functionalized organometallic compounds of Mg, Zn, or Cu.
This in situ trapping method allows an expedited metalation
(À788C, 5 min) of a range of sensitive pyridines (bearing
a nitro, ester, or cyano group) and allows the preparation of
kinetic regioisomers of functionalized aromatic compounds or
heterocycles not otherwise available by standard metalating
agents, such as TMPMgCl·LiCl or TMPZnCl·LiCl.
a practical access to organometallic Mg, Zn, or Cu com-
pounds.
The lithiation of functionalized carbocycles or heterocy-
clic arenes of type 1 with TMPLi would provide the unstable
lithiated species 2. The performance of this lithiation in the
presence of ZnCl2 (or MgCl2 and CuCN) may result in an
in situ trapping of the lithiated arene 2 to yield the zinc
reagent 3, which now has an excellent thermal stability and
can be readily trapped with electrophiles, thereby leading to
various products of type 4. To be successful, such a method
requires that the metalation of 1 with TMPLi is faster than the
transmetalation of TMPLi to TMPZnCl·LiCl. It should be
noted that TMPZnCl·LiCl is unreactive toward the metal-
ation of 1 at À788C (Scheme 1). Herein, we report the
T
he lithiation of arenes and heteroarenes constitutes a pow-
erful method[1] which is of great importance for various
applications. TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl)[2]
has been used for the selective lithiation of arenes. Never-
theless, the scope of the lithiation of complex molecules with
TMPLi is limited; highly reactive lithium derivatives are
produced which often have little compatibility with sensitive
functional groups (esters, cyano, or nitro groups), especially
when attached to electron-deficient N heterocycles. A range
of less-reactive bases of Mg and Zn have recently been
developed to improve the reaction scope.[3] LiCl-complexed[4]
metal amides, such as TMPMgCl·LiCl,[5] TMP2Mg·2LiCl,[6]
TMPZnCl·LiCl,[7] and TMP2Zn·2MgCl2·2LiCl,[8] have proved
to be especially useful.[9] Interestingly, it has been demon-
strated that these powerful bases are compatible with several
Lewis acids, which further increases their metalation scope.[10]
Since lithium bases have been used in the presence of
electrophiles such as boronic esters or Me3SiCl (in situ
trapping methods),[11] we envisioned metalations of function-
alized N-heteroarenes and acceptor-substituted benzenes by
the concomitant use of TMPLi and various metal salts such as
MgCl2, ZnCl2, or CuCN. This new method would give
Scheme 1. Reaction of a mixture of ZnCl2 and an aromatic or a hetero-
cyclic substrate 1 with TMPLi at À788C leads to zinc reagents of type
3 through a lithiation-transmetalation sequence.
realization of this in situ trapping method and demonstrate
the advantages of this lithiation-transmetalation procedure
for generating highly functionalized organozinc compounds
that are otherwise difficult to prepare. We also show that
these lithiations can be used to provide metalated intermedi-
ates with a different regioselectivity to the one produced with
TMPZnCl·LiCl or TMP2Zn·2LiCl. This synthetic approach
can be extended from ZnCl2 to MgCl2 or CuCN to produce
valuable magnesium or copper intermediates.
[*] M. Sc. A. Frischmuth, Dr. M. Fernꢀndez, M. Sc. N. M. Barl,
M. Sc. F. Achrainer, Prof. Dr. H. Zipse, Dr. G. Berionni,
Prof. Dr. H. Mayr, Prof. Dr. K. Karaghiosoff, Prof. Dr. P. Knochel
Ludwig Maximilians-Universitꢁt Mꢂnchen, Department Chemie
Butenandtstrasse 5-13, Haus F, 81377 Mꢂnchen (Germany)
E-mail: paul.knochel@cup.uni-muenchen.de
First, we examined the metalation of 2,4-dichlorobenzo-
nitrile (1a; Scheme 2). A calculation of the relative acidity of
H3, H5, and H6 shows that H3 is about 106 times more acidic
than H5 and H6.[12] Thus, the reaction of 1a with a moderately
powerful base such as TMPZnCl·LiCl only allows metalation
at position 3, thus leading exclusively, after iodolysis, to the 3-
iodinated benzonitrile 5a in 78% yield.
[**] This research has received funding from the Deutsche For-
schungsgesellschaft (SFB749, B2). We also thank BASF AG (Lud-
wigshafen) and Rockwood Lithium GmbH (Frankfurt) for the
generous gift of chemicals. TMP=2,2,6,6-tetramethylpiperidyl.
Since the cyano group is a good ortho-directing group,[13]
a kinetic metalation of 1a at position 6 is expected when using
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403688.
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Scheme 3. Regioselectivity switch in the metalation of 1b by TMPLi in
the presence of metal salts or TMPMgCl·LiCl. [a] Calculated pKa values
for H2, H4, H5, and H6.
Scheme 2. Regioselectivity switch in the metalation of 1a by TMPLi in
the presence of metal salts or TMPZnCl·LiCl. [a] Calculated pKa values
for H3, H5, and H6.
adjacent to the most powerful directing group (the ethyl ester
moiety). The metalation of 1b is complete after 5 min at
À788C, and furnishes, after iodolysis, the aryl iodide 4e
accompanied by about 20% of the iodide 5b. These aryl
iodides can be readily separated to provide the pure iodide 4e
in 54% yield. The use of ZnCl2·2LiCl for the in situ trapping
allows functionalization of position 6 by subsequent Negishi
cross-coupling reactions; after chromatographic separation
from small quantities of regioisomers, the pure 6-arylated
products 4 f and 4g were isolated in 84 and 87% yield,
respectively. Similarly, a CuCN·2LiCl catalyzed allylation
with 3-bromocyclohexene (0.7 equiv) provides the 3-cyano-
benzoate 4h in 79% yield (Scheme 3).[15]
a very strong lithium base. Thus, a mixture of 1a and
ZnCl2·2LiCl (1.1 equiv) was treated with a solution of TMPLi
(1.5 equiv, ca. 0.6m) in THF at À788C. After 5 min, the
metalation of 1a is complete, and iodolysis furnishes the 6-
iodobenzonitrile 4a in 74% yield. The complexation of ZnCl2
with LiCl enhances the solubility and often increases the
reaction yields by about 10–20%. The regioselectivity of the
metalation is excellent (ca. 95:5) and is complementary to the
metalation with TMPZnCl·LiCl, which proceeds at position 3.
Independently
generated
TMP2Zn·2LiCl
or
“(TMP)3ZnLi·2LiCl”[14] either does not metalate 1a at
À788C or metalates with low regioselectivity (C3/C6 = 4:1)
and with only 29% conversion after 10 min. Competition
experiments show that the reaction of TMPLi with 1a is more
than six times faster than the reaction of TMPLi with
ZnCl2·2LiCl (see the Supporting Information). Besides
iodolysis, the resulting arylzinc compound derived from 1a
was submitted to a Negishi cross-coupling with 1-chloro-4-
iodobenzene (0.9 equiv), which afforded the biphenyl 4b in
68% yield. All of the in situ trapping reactions favor the
metalation at position 6.
The new in situ quench procedure has also been applied to
the metalation of heterocyclic ring positions, which are
notoriously difficult to metalate. Thus, as expected, thiophene
derivative 1c undergoes a smooth magnesiation at position 5
with TMPMgCl·LiCl (Scheme 4). Metalation at this position
Although this new in situ trapping is very satisfactory
using ZnCl2·2LiCl, we have extended our method to the
preparation of some other useful organometallic intermedi-
ates. Thus, mixing 1a with MgCl2·2LiCl (1.1 equiv) and
adding TMPLi (1.5 equiv, À788C, 5 min) produces the
corresponding magnesium reagent, which on reaction with
ArSSO2Ph (Ar= p-FC6H4) affords the thioether 4c in 75%
yield. An in situ quench with CuCN·2LiCl is also possible and
produces valuable copper intermediates. Thus, performing
the metalation of 1a with TMPLi in the presence of
CuCN·2LiCl (1.1 equiv) provides the corresponding cop-
per(I) intermediate, which reacts smoothly with 3-bromocy-
clohexene (0.9 equiv) to afford 4d in 89% yield.
Scheme 4. Regioselectivity switch in the metalation of 1c by TMPLi in
the presence of metal salts or TMPMgCl·LiCl and metalation of 1d
with TMPLi in the presence of metal salts. [a] Calculated pKa values for
H3, H4, and H5.
Analogous switches of regioselectivity were observed for
several aromatic systems. The calculated pKa values of the
different positions of ethyl 3-cyanobenzoate (1b) show that
H2 is the most acidic proton (Scheme 3). A deprotonation
with TMPMgCl·LiCl leads, after iodolysis, to the 2-iodinated
ethyl benzoate 5b in 46% yield. Treatment of 1b with TMPLi
in the presence of ZnCl2·2LiCl allows lithiation at the
sterically less hindered position, namely position 6, which is
is favored for thermodynamic reasons, since H5 is the most
acidic hydrogen atom in the molecule. This high tendency to
metalate position 5 can be overcome by an in situ quench with
ZnCl2 and TMPLi. The metalation of 1c is complete within
5 min at À788C, thereby producing the C3-zincated thio-
phene as the major regioisomer (C3/C5 = 75:25). Interest-
ingly, the complexation of ZnCl2 with additional LiCl lowers
this regioselectivity. After iodolysis, the thienyl iodide 4i is
2
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Table 1: Synthesis of products 7 by metalation with TMPLi in the
Table 1: (Continued)
Product[a]
presence of MgCl2, ZnCl2, or CuCN and quenching with electrophiles.
Entry
Substrate
Electrophile
Entry
Substrate
Electrophile
Product[a]
14
6 f
7n: 80%[b,f]
1
2
6a
6a
R=CO2Me
R=CF3
7a: 90%[b,f]
7b: 77%[b,f]
[a] Yield of analytically pure product. [b] ZnCl2·2LiCl was added.
[c] MgCl2·2LiCl was added. [d] MgCl2 was added. [e] CuCN·2LiCl was
added. [f] Obtained by a palladium-catalyzed cross-coupling with 2%
[Pd(dba)2] and 4% P(2-furyl)3.
3
6a
TMSCl
7c: 96%[c]
obtained in 64% yield. The addition of ZnCl2 allows Negishi
cross-coupling reactions with electron-poor iodides, such as 4-
iodobenzonitrile, as well as electron-rich iodides, such as 4-
iodoanisole, to give, after chromatographic separation, 2,3-
disubstituted thiophenes 4j and 4k in yields of 76 and 73%,
respectively. Performing the in situ trapping with CuCN·2
LiCl allows an allylation with 3-bromocyclohexene
(0.7 equiv) to furnish 4l in 70% yield.
In contrast, the corresponding furan derivative 1d is
always metalated predominantly at position 3. The use of the
in situ quench procedure furnishes the 3-metalated furan with
superior regioselectivity and higher conversion, and gives the
3-substituted furans 4m and 4n in yields of 70 and 81%,
respectively, after allylation or cross-coupling (Scheme 4).
This in situ quench method also allows the smooth
metalation of sensitive heterocycles. The direct magnesiation
or lithiation of 2-chloro-3-cyanopyridine (6a) is difficult.
Attempts to use TMPLi, TMP2Mg·2LiCl, or TMPMgCl·LiCl
4
6a
7d: 96%[e]
5
6
6b
6c
7e: 84%[b,f]
7 f: 79%[b,f]
7
8
6d
6d
7g: 94%[d]
for
deprotonation
led
to
decomposition.
Only
TMP2Zn·2MgCl2·2LiCl allows the zincation of 6a in 48 h at
258C in good yield. In contrast, metalation with TMPLi in the
presence of ZnCl2·2LiCl allows the same zinc species to be
prepared within 5 min at À788C.[16] Negishi cross-coupling
with methyl 4-iodobenzoate or 1-iodo-4-(trifluoromethyl)-
benzene led to the 4-arylated pyridines 7a and 7b in 90% and
77% yield, respectively (Table 1, entries 1 and 2). The use of
TMPLi in the presence of MgCl2·2LiCl allows a smooth
silylation of 6a with TMSCl to provide pyridine 7c in 96%
yield (entry 3). An in situ quench using CuCN·2 LiCl fur-
nishes, after allylation, pyridine 7d in 96% yield (entry 4). In
the case of other cyano-, ester-, nitro-, or thioether-substituted
pyridines such as 6b,[17] and 6c–6 f, the lithiated derivatives of
which are prone to decomposition and have to be handled at
low temperature, the in situ quench with MgCl2·2LiCl,
ZnCl2·2LiCl, or CuCN·2LiCl and TMPLi offers a simple
preparative alternative and furnishes directly within 5 min the
corresponding organometallic intermediates, which undergo
additions to aldehydes, Negishi cross-coupling reactions,
allylations, or acylations in 70–94% yield (entries 5–14).
In summary, the faster deprotonation of arenes and
heteroarenes with TMPLi compared to the transmetalation
of TMPLi with Mg, Zn, or Cu halides has allowed us to
develop an in situ quench method, in which functionalized
aromatic or heteroaromatic substrates mixed with Mg, Zn, or
Cu halides have been metalated within 5 min by TMPLi at
7h: 86%[b,f]
9
6d
6d
7i: 86%[e]
10
7j: 94%[e]
11
12
6e
6e
R=CF3
R=CN
7k: 80%[b,f]
7l: 70%[b,f]
13
I2
6 f
7m: 87%[c]
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À788C, and lead after transmetalation to various functional-
ized Mg, Zn, or Cu derivatives. The method allows a range of
functionalized pyridines and related heterocycles to be
metalated smoothly, more efficiently, and in higher yields
than conventional metalations. In several cases, a different
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metalation procedures, thereby providing previously unac-
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currently being investigated as well as other extensions of the
method.
Received: March 25, 2014
Published online: && &&, &&&&
Keywords: amide bases · cross-coupling · metalation ·
.
nitrogen heterocycles · organometallic compounds
À
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Supporting Information.
4
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Angewandte
Communications
Communications
Regioselective Metalations
A. Frischmuth, M. Fernꢁndez, N. M. Barl,
F. Achrainer, H. Zipse, G. Berionni,
H. Mayr, K. Karaghiosoff,
P. Knochel*
&&&& — &&&&
New In Situ Trapping Metalations of
Functionalized Arenes and Heteroarenes
with TMPLi in the Presence of ZnCl2 and
Other Metal Salts
Fast, faster, the fastest: Aromatic and
heterocyclic substrates, when treated
with TMPLi (TMP=2,2,6,6-tetramethyl-
piperidyl), undergo a kinetic lithiation and
then a transmetalation with a metal salt
such as MgCl2, ZnCl2, or CuCN. This
allows an expedited metalation of sensi-
tive pyridines bearing a nitro, ester, or
cyano group and allows the preparation
of kinetic regioisomers of functionalized
aromatic compounds or heterocycles.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!