Practical Continuous-Flow Trapping Metalations of Functionalized Arenes and Heteroarenes Using TMPLi in the Presence of Mg, Zn, Cu, or la Halides

Article abstract of DOI:10.1002/anie.201502393

The flow metalation of various arenes and heteroarenes involving an in situ trapping with metal salts (ZnCl₂. LiCl, MgCl₂, CuCN. LiCl, LaCl₃. LiCl) under very convenient conditions (0 ?C, 40 s) is reported. The resulting Mg, Zn, Cu, or La organic species are trapped with various electrophiles in high yields. In several cases, unusual kinetically controlled regioselectivities are obtained. All these flow metalations can be scaled up simply by extending the reaction time and without further optimization. The reaction scope of such flow metalations is considerably broader than that of the corresponding batch procedures.

Full text of DOI:10.1002/anie.201502393

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502393
German Edition: DOI: 10.1002/ange.201502393
Synthetic Methods
Practical Continuous-Flow Trapping Metalations of Functionalized
Arenes and Heteroarenes Using TMPLi in the Presence of Mg, Zn, Cu,
or La Halides**
Matthias R. Becker and Paul Knochel*
Dedicated to the Technion–Israel Institute of Technology, Haifa
Abstract: The flow metalation of various arenes and hetero-
arenes involving an in situ trapping with metal salts
(ZnCl2·2LiCl, MgCl2, CuCN·2LiCl, LaCl3·2LiCl) under
very convenient conditions (08C, 40 s) is reported. The
resulting Mg, Zn, Cu, or La organic species are trapped with
various electrophiles in high yields. In several cases, unusual
kinetically controlled regioselectivities are obtained. All these
flow metalations can be scaled up simply by extending the
reaction time and without further optimization. The reaction
scope of such flow metalations is considerably broader than
that of the corresponding batch procedures.
treated with TMPLi. It was found that the lithiation of Ar-H
(or Het-H) by TMPLi is faster than the transmetalation of
TMPLi with the metal salt (Scheme 1).
Although this method can be used to perform a range of
new regioselective lithiations, the synthetic scope of such
metalations is narrowed since cryogenic temperatures are
required. Furthermore, we noticed that the scale-up of these
in situ trapping reactions proved to be difficult, requiring
much optimization. Herein, we report that these problems
can be solved by using continuous-flow conditions[6] allowing
T
he ortho-lithiation of arenes and heteroarenes is a powerful
tool for the functionalization of unsaturated molecules.[1]
TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl) is an especially
efficient base for such lithiations;[2] however, the high ionic
character of the carbon–lithium bond in aryllithiums often
precludes the presence of sensitive functionalities like esters,
nitriles, and nitro groups. The use of highly sterically hindered
silylated esters has recently solved this problem.[3] Further-
more, conducting lithiations under continuous-flow condi-
tions has increased the functional-group tolerance as well.[4]
Recently, we have reported that in situ trapping trans-
metalations can be performed on various aromatic and
heterocyclic substrates (Ar-H, Het-H).[5] In this procedure,
the unsaturated substrate is mixed at À788C with a metal salt
(M-X) such as ZnCl2·2LiCl, MgCl2, or CuCN·2LiCl and
Scheme 2. Continuous-flow setup for in situ trapping metalations
using TMPLi in the presence of metal salts (ZnCl2·2LiCl, MgCl2,
CuCN·2LiCl, LaCl3·2LiCl) (top) and iodination of ethyl 4-bromoben-
zoate (1a) using flow and batch conditions for the in situ trapping
metalation (bottom).
Scheme 1. In situ trapping metalation of aromatic substrates.
the rapid mixing of the reaction components and avoiding the
formation of hot spots. Furthermore, the in situ transmeta-
lation with the metal salt present generates a more stable
organometallic species. Thus the in situ trapping metalations
can now be performed at 08C (instead of À788C). Moreover,
these new reaction conditions considerably increase the
reaction scope of this method and permit a straightforward
scale-up of such metalations. The use of a continuous-flow
setup as described in Scheme 2 makes it possible to “in situ
transmetalate” a broad range of unsaturated substrates at 08C
within 40 s (instead at À788C under batch conditions). Thus,
[*] M. R. Becker, 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
[**] We thank the DFG (SFB 749 and DIP) for support and financial
contributions to this project. We also thank Rockwood Lithium
GmbH (Frankfurt) and BASF AG (Ludwigshafen) for the generous
gift of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502393.
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Table 1: Continuous-flow trapping metalation of arenes 1 followed by
reaction with electrophiles leading to products 2.
the mixing of a 1:2 mixture of the well-soluble ZnCl2·2LiCl
and ethyl 4-bromobenzoate (1a) in THF with TMPLi
(1.5 equiv) in a flow apparatus[7] for 40 s at 08C produces
after “batch iodolysis” the aryl iodide (2a) in 95% yield.
In strong contrast, when this procedure was performed in
a standard Schlenk flask (batch conditions) at À788C the
desired iodide (2a) was produced only in 53% yield despite
numerous optimization attempts. It should be noted that
TMP2Zn·2LiCl,[8] which would be produced in the absence of
ethyl 4-bromobenzoate (1a), does not metalate the aryl
bromide (1a) under these reaction conditions, showing that
the metalating agent of 1a is TMPLi. After transmetalation
with ZnCl2·2LiCl the resulting arylzinc reagent is quenched
with a range of electrophiles. Thus, a Pd-catalyzed Negishi
cross-coupling[9] with aryl iodides having either electron-
donating or electron-withdrawing substituents produces the
biphenyls (2b,c) in 77 and 78% yield, respectively (Table 1,
entries 1 and 2).
Entry
Substrate
Electrophile
Product[a]
1
2
1a
1a
R=m-OMe
R=p-CO2Et
2b: 78%[b,d]
2c: 77%[b,d]
3
4
1b
1c
2d: 73%[b,d]
2e: 70%[b,e]
Remarkable regioselectivities are obtained in such in situ
transmetalations. The most acidic hydrogen of the 3-substi-
tuted ethyl benzoates (1b,c) is at position 2. This position is
therefore always deprotonated with standard bases such as
TMPMgCl·LiCl and (TMP)2Mn·2MgCl2·4LiCl.[10] However,
under the kinetically controlled reaction conditions described
herein, the strong TMPLi base is able to abstract the ring
hydrogen at position 6, leading after Negishi cross-coupling or
copper-mediated acylation to the trisubstituted arenes (2d,e)
in 70–73% yield (entries 3 and 4). Such kinetic metalations
resulting in unique metalation regioselectivities are not
limited to benzoate derivatives. 2,4-Dichlorobenzonitrile
(1d) is also in situ zincated at position 6, affording the
cyano-substituted biphenyl (2 f) in 83% yield after Negishi
cross-coupling (entry 5). Also 2-bromobenzonitrile (1e)
undergoes smooth flow metalation with TMPLi in the
presence of ZnCl2·2LiCl (08C, 40 s). Copper-mediated
quenching with 3-bromocyclohexene (0.8 equiv) or benzoyl
chloride (0.8 equiv) lead to the trisubstituted nitriles (2g,h) in
73–88% yield (entries 6 and 7). Most of the examples in
Table 1 were performed on a 1.7 mmol scale. However, these
metalations can be scaled up by simply extending the reaction
time. Thus, the preparation of the trisubstituted nitrile (2g) on
a 10 mmol scale in 87% yield is possible without further
optimization, demonstrating the striking advantages of con-
tinuously processed reactions. Furthermore, the ortho-lithia-
tion of haloarenes such as 1 f and 1g, which are notoriously
prone to decompose via benzyne formation,[11] undergo flow
metalation with TMPLi in the presence of MgCl2 (0.5 equiv)
under standard conditions (08C, 40 s). Subsequent reactions
with ethyl cyanoformate (1.5 equiv) or p-chlorobenzaldehyde
(1.5 equiv) lead to the o-functionalized haloarenes (2i–k) in
69–84% yield (entries 8–10).
5
1d
2 f: 83%[b,d]
6
7
1e
1e
2g: 88%[b,f] (87%)[g]
2h: 73%[b,e]
NC-CO2Et
8
1 f
1 f
1g
2i: 84%[c]
2j: 79%[c]
2k: 69%[c]
9
10
[a] Yield of isolated product. [b] ZnCl2·2LiCl (0.5 equiv) was used.
[c] MgCl2 (0.5 equiv) was used. [d] Obtained using 2 mol% [Pd(dba)2]
and 4 mol% P(2-furyl)3. [e] Obtained by a Cu-mediated acylation.
[f] Obtained by a Cu-catalyzed allylation. [g] Yield obtained on a 10 mmol
scale.
These organometallic intermediates undergo various quench-
ing reactions such as an addition to p-chlorobenzaldehyde,
a Pd-catalyzed Negishi cross-coupling, or a copper-catalyzed
allylation providing the corresponding 2,3-disubstituted pyr-
idines (4a–c) in 80–98% yield (entries 1–3).
Whereas the metalation of 2-fluoropyridine (3a) failed
using a standard batch “in situ” trapping protocol (TMPLi,
ZnCl2·2LiCl, À788C, 5 min),[5,12] the same metalation per-
formed in a flow mode produces the alcohol (4a) on
These in situ trapping flow metalations are readily
extended to a range of highly sensitive, electron-deficient
pyridines and benzothiazoles (3a–h), which are substituted
with various electron-withdrawing groups such as a chloride,
a fluoride, or a cyano, ester, or nitro group (Table 2). Thus, the
2-substituted pyridines (3a,b) react under flow conditions in
the presence of MgCl2 or ZnCl2·2LiCl with TMPLi leading to
the corresponding pyridyl-magnesium and -zinc species.
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Table 2: Continuous-flow trapping metalation of N-heterocycles 3 fol-
lowed by reaction with electrophiles leading to products 4.
conditions using TMPLi and ZnCl2·2LiCl or CuCN·2LiCl,
leading after Negishi cross-couplings or a copper-mediated
allylation to the 3,4-disubstituted pyridines (4d–f) in 79–90%
yield (entries 4–6). Furthermore, the preparation of the nitrile
(4 f) on a 8 mmol scale in flow mode can be realized, affording
the desired biaryl (4 f) in 83% yield. Under our standard
conditions, the 2,3-disubstituted pyridines (3e,f) are smoothly
flow-metalated in position 4. Quenching with 3-bromocyclo-
hexene (1.0 equiv) or 4-iodobenzotrifluoride (0.8 equiv)
affords the trisubstituted pyridines (4g,h) in 85–89% yield
(entries 7 and 8). Under our flow metalation conditions, 2-
chloro-6-methoxypyridine (3g) is zincated in position 5 and
Negishi cross-couplings with aryl iodides having either
electron-donating or electron-withdrawing substituents
afford the corresponding biaryls (4i,j) in 89–99% yield
(entries 9 and 10). Interestingly, the metalation of 2-chloro-
6-methoxypyridine (3g) with TMPLi and ZnCl2·2LiCl failed
at À788C in a batch reactor, but the flow metalation of 3g on
a 10 mmol scale affords the desired product (4j) in 85% yield.
Also, the in situ trapping metalation of the sensitive 6-
nitrobenzothiazole (3h) failed under batch conditions at
À788C due to side reactions caused by the nitro group.
However, the in situ zincation in a flow reactor at 08C within
40 s and subsequent Negishi cross-coupling with 4-iodoani-
sole (0.8 equiv) leads to the 2,6-disubstituted benzothiazole
(4k) in 63% yield (entry 11).
Entry
Substrate
Electrophile
Product[a]
1
3a
4a: 96%[c] (84%)[h]
2
3
3a
3b
4b: 98%[b,e]
4c: 80%[b,f]
4
5
3c
3c
4d: 90%[b,e]
4e: 79%[d]
4 f: 88%[b,e] (83%)[h]
The metalation of ethyl 2-furoate (5) with TMPMgCl·LiCl
proceeds at positions 3 and 5 in a 4:1 mixture,[14] but the use of
ate bases[15] or in situ trapping[5] in batch provides the 3-
metalated furan. The flow conditions lead to a practical
metalation (08C, 40 s) of 5 in position 3, resulting in the
formation of the furylzinc reagent 6 (Scheme 3). Negishi
cross-coupling with 4-iodoanisole furnishes the 2,3-disubsti-
tuted furan 7 in 72% yield. Similarly, the metalation of ethyl
5-bromo-2-furoate (8) is completed under flow conditions in
6
7
3d
3e
4g: 89%[d]
8
3 f
4h: 85%[b,e]
9
10
3g
3g
R=OMe
R=CN
4i: 99%[b,e]
4j: 89%[b,e] (85%)[h]
11
3h
4k: 63%[b,g]
[a] Yield of isolated product. [b] ZnCl2·2LiCl (0.5–1.1 equiv) was used.
[c] MgCl2 (0.5 equiv) was used. [d] CuCN·2LiCl (1.1 equiv) was used.
[e] Obtained using 2 mol% [Pd(dba)2] and 4 mol% P(2-furyl)3.
[f] Obtained by a Cu-catalyzed allylation. [g] Obtained using 5 mol%
[Pd(PPh3)4]. [h] Yield obtained on a 8–12 mmol scale.
a
12 mmol scale in 84% yield. Previously known
TMPMgCl·LiCl magnesiations of 4-functionalized pyridines
such as 3c,d in the presence of BF3·OEt2 lead to a selective
metalation at position 3.[13] However, they require low
temperatures as well as stoichiometric amounts of the Lewis
acid. In contrast, these 4-functionalized pyridines (3c,d) are
smoothly metalated at position 3 under continuous-flow
Scheme 3. In situ trapping zincation or lanthanation of functionalized
furans or thiophenes using TMPLi and ZnCl2·2LiCl or LaCl3·2LiCl in
flow mode.
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2013, 125, 8323; c) S. Oda, H. Yamamoto, Org. Lett. 2013, 15,
6030.
40 s at 08C leading to the zinc species 9. Previously, such
a metalation required 30 min at À508C.[14] Pd-catalyzed cross-
coupling of the zincated furan 9 with 1-iodo-3-nitrobenzene
furnishes the trisubstituted furan 10 in 86% yield (Scheme 3).
Although all the previous flow metalations were per-
formed by treating a mixture of the metalating substrate and
MgCl2, ZnCl2·2LiCl, or CuCN·2LiCl with TMPLi, other
valuable salts may be used instead of the above-mentioned
Mg, Zn, and Cu halides. Of special interest are lanthanum
halides such as LaCl3·2LiCl[16] since organolanthanums dis-
play a higher reactivity towards carbonyl addition compared
to Grignard reagents. Thus, we mixed 2,3-dibromothiophene
(11) with LaCl3·2LiCl (0.5 equiv) and submitted it to the flow
metalation with TMPLi (08C, 40 s). The intermediate lantha-
num derivative 12 was obtained in high conversion and
reacted with diethyl ketone (1.5 equiv) providing the tertiary
alcohol (13) in 64% yield (Scheme 3).
In summary, we have reported that the flow metalation of
arenes and heteroarenes involving an in situ trapping with
various metal salts (ZnCl2·2LiCl, MgCl2, CuCN·2LiCl,
LaCl3·2LiCl) proceeds under very convenient conditions
(08C, 40 s). The resulting Mg, Zn, Cu, or La organic species
are trapped with various electrophiles in high yields. In
several cases, unusual kinetically controlled regioselectivities
are obtained. All these flow metalations are scaled-up simply
by extending the reaction time and no special optimization is
required. The reaction scope of these flow in situ trapping
metalations is considerably broader than that of the batch
procedures. Further applications to more complex N-hetero-
cycles and other unsaturated substrates are currently under-
way.
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Keywords: flow chemistry · lithiation · magnesiation ·
metalation · zincation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12501–12505
Angew. Chem. 2015, 127, 12681–12685
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Received: March 14, 2015
Published online: May 14, 2015
Angew. Chem. Int. Ed. 2015, 54, 12501 –12505
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