Continuous flow magnesiation of functionalized heterocycles and acrylates with TMPMgCl·LiCl

Article abstract of DOI:10.1002/anie.201404221

A flow procedure for the metalation of functionalized heterocycles (pyridines, pyrimidines, thiophenes, and thiazoles) and various acrylates using the strong, non-nucleophilic base TMPMgCl·LiCl is reported. The flow conditions allow the magnesiations to be performed under more convenient conditions than the comparable batch reactions, which often require cryogenic temperatures and long reaction times. Moreover, the flow reactions are directly scalable without further optimization. Metalation under flow conditions also allows magnesiations that did not produce the desired products under batch conditions, such as the magnesiation of sensitive acrylic derivatives. The magnesiated species are subsequently quenched with various electrophiles, thereby introducing a broad range of functionalities. Go with the flow: Flow conditions allow a practical metalation of functionalized heterocycles and various acrylates in the presence of the base TMPMgCl·LiCl (TMP=2,2,6,6-tetramethylpiperidyl). More convenient temperatures and very fast reaction times can usually be achieved by applying the flow conditions. Sensitive acrylic derivatives can be magnesiated under flow conditions. Furthermore, the flow reactions are readily scalable without further optimization.

Full text of DOI:10.1002/anie.201404221

Angewandte
Chemie
DOI: 10.1002/anie.201404221
Flow Metalation
Continuous Flow Magnesiation of Functionalized Heterocycles and
Acrylates with TMPMgCl·LiCl**
Trine P. Petersen, Matthias R. Becker, and Paul Knochel*
Abstract: A flow procedure for the metalation of functional-
ized heterocycles (pyridines, pyrimidines, thiophenes, and
thiazoles) and various acrylates using the strong, non-nucle-
ophilic base TMPMgCl·LiCl is reported. The flow conditions
allow the magnesiations to be performed under more conven-
ient conditions than the comparable batch reactions, which
often require cryogenic temperatures and long reaction times.
Moreover, the flow reactions are directly scalable without
further optimization. Metalation under flow conditions also
allows magnesiations that did not produce the desired products
under batch conditions, such as the magnesiation of sensitive
acrylic derivatives. The magnesiated species are subsequently
quenched with various electrophiles, thereby introducing
a broad range of functionalities.
heterocycles such as pyridines containing electron-withdraw-
ing substituents can be accomplished successfully, although at
cryogenic temperatures (as low as À788C). The low temper-
atures are required to avoid dimerization through nucleo-
philic addition reactions to the pyridine ring. Herein, we
report that the base 1 enables magnesiation of a range of
sensitive N-heterocycles at unprecedentedly high reaction
temperatures and short reaction times. The flow technology
also allows the metalation of various acrylates that is
otherwise not possible.
We first focused our studies on the magnesiation of the
very electron-poor 2,3-dichloro-5-trifluoromethylpyridine
(2a). In batch, full conversion of 2a into the magnesiated
intermediate 3a was achieved in 2 h at À408C, thereby
furnishing, after iodolysis, the tetrasubstituted pyridine 4a in
56% yield (Scheme 1). The use of higher reaction temper-
atures led to extensive decomposition of the pyridylmagne-
sium reagent through oligomerization. However, by using
W
hereas most organometallic reactions, including directed
metalations,[1] are conducted under batch conditions in
academic laboratories, there has been great interest in the
performance of such reactions under
flow conditions.[2] More convenient
reaction conditions usually result from
flow conditions because of the improved
heat transfer and faster mixing of
reagents in flow reactors compared to
batch reactors; furthermore, this
approach may also improve selectivity
issues. It has also been shown that the
Scheme 1. Comparison of batch and flow conditions for the metalation of 2,3-dichloro-5-
(trifluoromethyl)pyridine (2a) in the presence of TMPMgCl·LiCl (1) and a subsequent iodolysis.
use of continuous flow reactors allows
the safe handling of hazardous or explo-
sive reagents.[3] Pioneering studies by
the research groups of Yoshida,[4] Ley,[5] Haswell,[6] and
Organ[7] have already demonstrated that flow conditions
may considerably improve the substrate scope of important
organometallic reactions such as halogen–lithium exchange[8]
as well as Suzuki[9] and Murahashi coupling reactions.[10]
Recently, we reported the use of a highly THF-soluble
base TMPMgCl·LiCl (1, TMP = 2,2,6,6-tetramethylpiper-
idyl), which is able to magnesiate a wide range of unsaturated
polyfunctional substrates.[11] The metalation of sensitive N-
continuous flow equipment[12] consisting of three pumps,
a glass chip reactor, and a coiled reactor we were able, after
some optimization, to prepare the Grignard reagent 3a at
258C and with a residence time of 30 s in a glass chip reactor
in a yield > 75%. Further quenching with iodine in the chip
reactor followed by a coiled reactor (at 258C with a residence
time of 1 min) provided the desired pyridine 4a in 73%
yield.[13] The magnesiated pyridine also reacted well with
benzaldehyde, thereby leading to the functionalized pyridine
4b in 80% yield (Table 1, entry 1). Interestingly, using
acetone, a substrate prone to enolization instead of addition
reactions, provided the tertiary alcohol 4c in 63% yield
(Table 1, entry 2). The more-convenient temperature range
when using flow techniques is a key advantage.
[*] Dr. T. P. Petersen, M. R. Becker, Prof. Dr. P. Knochel
Ludwig-Maximilians-Universitꢀt Mꢁnchen
Department Chemie Butenandtstrasse 5–13, Haus F
81377 Mꢁnchen (Germany)
The metalation of 3-chloropyridine (2b) with
TMPMgCl·LiCl (1) under flow conditions was completed in
1 min at 258C (versus 30 min at 08C in batch). Quenching the
reaction with various electrophiles (DMF, allyl bromide, and
iodine) provided the expected pyridines 4d–f in 66–78% yield
(Table 1, entries 3–5). The intermediate 3-chloro-2-pyridyl-
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank Villum Fonden (T.P.P.) and the SFB 749 (DFG) for support
and financial contributions to this project. TMP=2,2,6,6-tetrame-
thylpiperidyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201404221.
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Table 1: Continuous flow metalation of functionalized pyridines and
Table 1: (Continued)
pyrimidines followed by reaction with electrophiles.
Entry
N-Hetero-
cycle
Electrophile
[quenching conditions]
Product,
yield[c] [%]
[metalation
conditions]
I2
10
2c
[1.2 equiv, 258C, 2 min]
4k 71
Entry
N-Hetero-
cycle
Electrophile
[quenching conditions]
Product,
yield[c] [%]
4-chlorobenzaldehyde
[1.7 equiv, 258C, 6 s]
11
12
13
[metalation
conditions]
2d
4l: 62
[258C, 1 min]
benzaldehyde
[2.9 equiv, 258C,
1.5 min]
DMF
1
[6.1 equiv, 258C, 10 s]
2e
4m: 73
2a
4b: 80
[08C, 1 min]
[258C, 30 s]
4-chlorobenzaldehyde
[1.7 equiv, 258C, 11 s]
acetone
[10 equiv, 258C, 2.4 min]
2
3
2a
2 f
4n: 66
4o: 78
[258C, 2 min]
4c: 63
4d: 78
DMF
14
DMF
[6.0 equiv, 258C, 30 s]
2g
[6 equiv, 258C, 5 min]
2b
[08C, 20 min]
[258C, 1 min]
allyl bromide[a]
[1.2 equiv, 258C, 8 s]
benzaldehyde
[2.0 equiv, 258C,
2.7 min]
4
5
2b
2b
15
2g
4e: 74
4 f: 66
4p: 87
[a] CuCN·2LiCl (0.03 equiv) was added to the electrophile solution.
[b] [Pd(dba)2] (0.01 equiv), P(o-furyl)3 (0.02 equiv), and ZnCl2 (1.1 equiv)
were added to the electrophile solution. [c] Yield of isolated product.
I2
[1.2 equiv, 258C, 2 min]
magnesium chloride (3b) could also be mixed with a stream of
THF containing an aryl iodide (1.5 equiv),[14] ZnCl2
(1.1 equiv), [Pd(dba)2] (0.01 equiv), and P(o-furyl)3
(0.02 equiv)[15] to allow the Negishi cross-coupling, when
being pumped through a heated coiled reactor (508C,
27 min). The use of 4-iodotoluene or 4-iodoanisole as electro-
philes under these conditions resulted in the 2-arylated
pyridines 4g and 4h being isolated in yields of 76 and 95%,
respectively (Table 1, entries 6 and 7). Alcꢀzar and co-work-
ers recently provided the first example of Negishi cross-
coupling reactions under flow conditions using commercially
available organozinc reagents.[16] Complementary to this
study, we demonstrate the first in situ formation of zinc
species by a multistep sequence involving deprotonation,
magnesiation, and transmetalation to zinc followed by
a Negishi cross-coupling, all in one continuous flow.
4-iodotoluene[b]
[1.5 equiv, 508C, 27 min]
6
7
2b
2b
4g: 76
4-iodoanisole[b]
[1.5 equiv, 508C, 27 min]
4h: 95
4i: 84
DMF
8
9
[6 equiv, 258C, 2 min]
2c
[258C, 1 min]
allyl bromide[a]
[1.2 equiv, 258C, 8 s]
Similarly, the magnesiation of the 3-bromopyridine (2c)
was performed under the same flow conditions (1 min, 258C).
Subsequent quenching with neat DMF furnished the formy-
lated pyridine 4i in 84% yield (Table 1, entry 8). This yield
2c
4j: 78
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Table 2: Continuous flow metalation of functionalized five-membered
heterocycles followed by reaction with electrophiles.
was obtained on a 1.7 mmol scale; however, it did not require
any further optimization to scale-up the reaction to 45 mmol,
which provided 4i in 79% yield. Under batch conditions, the
scale-up of this metalation (> 10 mmol) proved to be
complicated, with oligomerization reactions occurring even
for this relatively stable pyridine.
Mixing the magnesiated intermediate 3-bromo-2-pyridyl-
magnesium chloride (3c) with a stream of a solution of allyl
bromide (1.2 equiv) in THF in the presence of CuCN·2LiCl
(0.03 equiv) instead of DMF furnished the allylated pyridine
4j in 78% yield (Table 1, entry 9). Similarly, the iodolysis of
3c provided the sensitive 2-iodo-3-bromopyridine 4k in 71%
yield (Table 1, entry 10).
Various dihalopyridines such as 2d–f, which have pre-
viously been metalated by TMPMgCl·LiCl (1) in batch at
À258C or À408C, were regioselectively magnesiated under
flow conditions within 1 or 2 min at 0 or 258C to afford the 6-
magnesiated pyridines, which were subsequently treated with
DMF or 4-chlorobenzaldehyde to provide the trisubstituted
pyridines 4l–n in 62–73% yield (Table 1, entries 11–13). 2,4-
Dimethoxypyrimidine (2g) was regioselectively metalated in
position 6 under flow conditions at 08C in 20 min to furnish
the intermediate magnesium reagent, which was quenched
with either DMF or benzaldehyde to provide the formylated
product 4o or the alcohol 4p in yields of 78 and 87%,
respectively (Table 1, entries 14 and 15).
Entry
Heterocycle
[metalation con- [quenching condi-
Electrophile
Product, yield[c] [%]
ditions]
tions]
DMF
[6.1 equiv, 258C,
10 s]
1
2
5a
6a: 79
[258C, 1 min]
4-iodoanisole[a]
[1.5 equiv, 508C,
27 min]
5a
6b: 87
6c: 72
DMF
[6 equiv, 258C, 13 s]
3
5b
[258C, 3 min]
The extension of our procedure to five-membered hetero-
cycles was readily achieved. Thus, the magnesiation of 2-
chlorothiophene (5a), which in batch required a reaction time
of 1.5 h at 08C, was complete under flow conditions in 1 min
at 258C and proceeded, as expected, at position 5. Quenching
the reaction with DMF (258C, 10 s) afforded the 2,5-
disubstituted thiophene 6a in 79% yield (Table 2, entry 1).
Treating the magnesiated intermediate with a solution of 4-
iodoanisole (1.5 equiv), ZnCl2 (1.1 equiv), [Pd(dba)2]
(0.01 equiv), and P(o-furyl)3 (0.02 equiv) under flow condi-
tions (508C, 27 min) afforded the 5-arylated product 6b in
87% yield (Table 2, entry 2).
4-chlorobenzalde-
hyde
[1.7 equiv, 258C,
6 s]
4
5
5b
6d: 88
6e: 90
allyl bromide[b]
[1.0 equiv, 258C,
8 s]
5c
[258C, 1 min]
[a] [Pd(dba)2] (0.01 equiv), P(o-furyl)3 (0.02 equiv), and ZnCl2 (1.1 equiv)
were added to the electrophile solution. [b] CuCN·2 LiCl (0.03 equiv) was
added to the electrophile solution. [c] Yield of isolated product.
The magnesiation of 2,5-dichlorothiophene 5b was com-
plete after 30 min at 258C in batch, but was achieved under
flow conditions at 258C in 3 min. Quenching the intermediate
with either DMF or 4-chlorobenzaldehyde afforded the
products 6c or 6d in yields of 72 and 88%, respectively
(Table 2, entries 3 and 4). 2-Bromothiazole (5c) was meta-
lated in the 5-position at 258C in 1 min under flow conditions
(versus 30 min at À408C under batch conditions). Quenching
with allyl bromide in the presence of a catalytic amount of
CuCN·2LiCl led to 6e in 90% yield (Table 2, entry 5).
Magnesiating thiophene-2-carboxylic acid ethyl ester (7a)
under flow conditions at 258C for 1 min gave a mixture of two
regioisomeric intermediates 8a,b in a ratio of 3.5:1, with the
most acidic C-5 position next to the electron-withdrawing
sulfur atom being predominantly deprotonated and favoring
the thermodynamically more stable intermediate 8a
(Scheme 2).[17] Decreasing the temperature to 08C improved
this ratio to 8.1:1, and further cooling to À208C combined
with an extension of the reaction time to 2 min to maintain
high conversion led to a significantly improved ratio of 33:1.
Quenching with DMF gave the formylated product 9a in 60%
Scheme 2. Temperature-controlled improvement of regioselectivity
under flow conditions with TMPMgCl·LiCl (1).
yield. This example demonstrates that the fine-tuning of the
metalation with TMPMgCl·LiCl (1) can dramatically improve
the regioselectivity of the magnesiation.
We then turned our attention to the flow metalation of
functionalized acrylates, which are notoriously difficult to
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Table 3: Continuous flow metalation of functionalized olefins followed
by reaction with electrophiles.
Entry
Olefin
[metalation condi-
tions]
Electrophile
[quenching condi-
tions]
Product,
yield[b] [%]
benzaldehyde
[2.0 equiv, 258C,
4.7 min]
1
10a
11a: 67
[258C, 10 min]
allyl bromide[a]
[1.2 equiv, 258C,
2.7 min]
2
3
10b
[408C, 1 min]
11b: 91
11c: 93
allyl bromide[a]
[1.2 equiv, À608C,
1.3 min]
Scheme 3. Magnesiation of diethyl fumarate (10c) and diethyl maleate
(10d) and subsequent quenching with aromatic aldehydes using
TMPMgCl·LiCl (1).
10c
[À608C, 1 min]
[a] CuCN·2LiCl (0.03 equiv) was added to the electrophile solution.
[b] Yield of isolated product.
readily performed using the commercially available base
TMPMgCl·LiCl (1). The reactions were performed under
more convenient conditions (higher temperatures and shorter
reaction times) than comparable batch processes. Very
sensitive acrylic derivatives could be stereoselectively meta-
lated and quenched with an aldehyde or an allylic bromide.
Furthermore, the flow synthesis was demonstrated to be
readily scalable up to 45 mmol without further optimization,
with very similar yields obtained. Extensions of this method
to more complex systems are currently underway.
metalate because of anionic polymerization. Thus, ethyl (E)-
3-(pyrrolidin-1-yl)acrylate (10a) was magnesiated by
TMPMgCl·LiCl (1; 1.1 equiv) at the 3-position in 10 min at
258C, which led to lactone 11a in 67% yield after quenching
with benzaldehyde and spontaneous cyclization (Table 3,
entry 1). In the case of methyl (E)-3-methoxyacrylate (10b),
the temperature of the metalation could be increased to 408C,
thereby shortening the reaction time to 1 min. Subsequent
allylation furnished the product 11b in 91% yield (Table 3,
entry 2). Remarkably, no polymerization or oligomerization
was detected under these drastic conditions. The magnesia-
tion of diethyl fumarate (10c) and diethyl maleate (10d) was
performed at low temperatures to avoid decomposition of the
unstable magnesium intermediate. By cooling a chip reactor
to À608C, full metalation of 10c was observed after a resi-
dence time of 1 min. The magnesiation of the fumarate 10c
and subsequent allylation led to a selective isomerization that
produced the 1,3-dienic diester 11c as a single stereoisomer
(Z/E > 99:1) in 93% yield (Table 3, entry 3).
Interestingly, the metalation of 10c,d proceeded under
our flow conditions with complete retention of configuration,
thereby producing, after addition to aromatic aldehydes, the
allylic alcohols 11d and 11e as single E and Z isomers in
yields of 75 and 92%, respectively (Scheme 3). Notably, no
lactone formation was observed for 11d because of the low
temperature used. Metalation of 10c,d was also attempted
under batch conditions (À608C, 1 min), however only poly-
merization was observed.
Received: April 11, 2014
Published online: June 24, 2014
Keywords: acrylates · flow chemistry · heterocycles ·
.
magnesium · metalation
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