Sodiation of Arenes and Heteroarenes in Continuous Flow

Article abstract of DOI:10.1002/anie.201803961

The first sodiations of (hetero)arenes in continuous flow using NaDA (sodium diisopropylamide) in Me₂EtN are reported. This flow procedure enables sodiation of functionalized arenes and heteroarenes that decompose under batch-sodiation conditions. The resulting sodiated (hetero)arenes react instantly with various electrophiles, such as ketones, aldehydes, isocyanates, alkyl bromides, and disulfides, affording polyfunctionalized (hetero)arenes in high yields. Scale-up is possible without further optimization.

Full text of DOI:10.1002/anie.201803961

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Title: Sodiation of Arenes and Heteroarenes in Continuous Flow
Authors: Niels Weidmann, Marthe Ketels, and Paul Knochel
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10.1002/anie.201803961
Angewandte Chemie International Edition
COMMUNICATION
Sodiation of Arenes and Heteroarenes in Continuous Flow
Niels Weidmann+, Marthe Ketels+, and Paul Knochel*
Dedicated to Professor Dieter Seebach
Abstract: We report the first sodiations of (hetero)arenes in
continuous flow using NaDA (sodium diisopropylamide) in Me2EtN.
This flow-procedure enables sodiation of functionalized arenes and
heteroarenes that decompose under batch-sodiation conditions. The
resulting sodiated (hetero)arenes react instantly with various
electrophiles, such as ketones, aldehydes, isocyanates, alkyl
bromides and disulfides affording polyfunctionalized (hetero)arenes in
high yields. A scale-up is possible without further optimization.
substrate. Using a flow rate of 10 mL/min, it was possible to
achieve full sodiation of 1a within 0.5 s at –20 °C, compared to
batch sodiation at –78 °C.[15a]
The functionalization of aromatics and heteroaromatics is an
important synthetic task especially for the elaboration of
pharmaceuticals and agrochemicals.[1] Lithium bases have been
extensively used for the metalation of (hetero)arenes.[2] In
addition, other milder magnesium and zinc bases have been
developed in order to achieve a higher functional group tolerance
allowing the preparation of polyfunctional aromatics.[3] In the
course of these studies, it was realized by Yoshida,[4] Ley,[5]
Buchwald,[6] Organ[7] and others[8] that a high compatibility with
sensitive functional groups can be achieved by performing these
reactions under flow conditions. Such flow set-ups have multiple
advantages, such as mild reaction conditions (ambient
temperature metalations), short reaction times and scale-ups
without the need of further optimization.[9] In contrast to lithium
bases, corresponding sodium bases have received little attention
due to the high reactivity of the ionic C-Na bond and poor solubility.
Since sodium is ca. 1500 times more abundant than lithium in the
earth crust and lithium demand and prices are increasing in recent
years,[10] the use of sodium compounds is certainly
underexploited in organic synthesis. Already, Schlosser,
Mordini,[11] Mulvey[12] and Mioskowski[13] have demonstrated the
high potential of sodium organometallic chemistry.[14] Recently,
Collum[15] reported sodiations of aromatic and heterocyclic
substrates using sodium diisopropylamide (NaDA) as a soluble
highly reactive base in dimethylethylamine (DMEA) at cryogenic
temperatures.
Scheme 1. General set-up for the sodiation of (hetero)arenes of type 1 with
NaDA in a microflow reactor and subsequent trapping with electrophiles in batch.
The resulting 2,6-dichlorophenylsodium (2a) was quenched in
batch with iodine at 0 °C providing aryl iodide (4a) in 84% isolated
yield (Table 1, entry 1). Similarly, 2a was quenched in batch with
benzaldehyde (3b), PPh2Cl (3c, followed by the addition of sulfur),
phenylisocyanate
(3d)
and
S-(4-fluorophenyl)benzene-
sulfonothioate (3e) affording the expected products 4b-e in 64-
95% yield (entries 2-5). Remarkably, no benzyne formation was
observed under these flow conditions.
Table 1. Sodiation of 1,3-dichlorobenzene (1a) using a microflow reactor and
subsequent batch quench of the intermediate organosodium 2a with various
electrophiles of type 3 leading to functionalized dichlorobenzenes of type 4.
entry electrophile
I2
product[a]
entry
electrophile
product[a]
1
3a[b]
Ph-CHO
3b[c]
4a: 84%
5
3e[b]
4e: 75%
Herein, we wish to report the first sodiation of (hetero)arenes
of type 1 in a microflow reactor set-up producing a broad range of
(hetero)aryl-sodium intermediates of type 2. These organosodium
reagents react instantly in batch with various electrophiles (3, E-
X) forming functionalized arenes and heteroarenes of type 4
(Scheme 1). The scope of this sodiation in flow is significantly
broader compared to batch reactions. The sodium base NaDA
was prepared according to a slightly optimized procedure by
Collum using less equivalents of sodium in DMEA and diluted to
a 0.2 M solution.[15a,16] This concentration was ideal for sodiation
performed in flow avoiding any precipitation.[17] The reaction
conditions were optimized with 1,3-dichlorobenzene (1a) as a
2
3
4
4b: 95%
4c: 74%
4d: 64%
6
7
8
3f[e]
4f: 75%
4g: 53%
4h: 53%
PPh2Cl
+ S8
MeI
3c[d]
Ph-NCO
3d[b]
3g[f]
nBu-Br
3h[g]
[a] Yield of analytically pure isolated product. [b] 2.5 equiv E-X. [c] 1.5 equiv
E-X. [d] 2.5 equiv PPh2Cl, then 10.0 equiv S8, overnight. [e] 5 mol%
CuCN·2LiCl, 2.5 equiv E-X. [f] 5.0 equiv E-X. [g] 10.0 equiv E-X.
[*]
[+]
N. Weidmann+, M. Ketels+, 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
These authors contributed equally to this work.
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10.1002/anie.201803961
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COMMUNICATION
We have then examined substitution reactions (Wurtz-Fittig-
couplings).[18] Whereas the use of an allylic bromide such as
cyclohexenyl bromide (3f) required copper-catalysis,[19] methyl
iodide (3g) and nbutyl bromide (3h) reacted instantly at −40 °C in
the absence of any transition metal catalyst with the in flow
generated arylsodium 2a affording the cross-coupling products
4f-h in 53-75% yield (entries 6-8).
sodiated in flow and trapped with aldehyde 3n yielding the
secondary alcohol 4o in 68% yield (entry 7).
Table 2. Sodiation of (hetero)arenes of type 1 leading via intermediate
organosodiums of type 2 to polyfunctional (hetero)arenes of type 4.
Scheme 2. Sodiation of sensitive heteroarene 2-chloropyrazine (1g) in a
microflow reactor and under batch conditions and subsequent trapping with
iodine leading to functionalized heteroarene 4p or decomposition.
substrate (sodiation
entry
electrophile
product[a]
temperature)
1b (–40 °C)
1b (–40 °C)
This flow sodiation procedure extends considerably the
reaction scope of such metalations and applies to sensitive
1
2
3i[b]
Ph-COCl
3j[c]
4i: 88%
4j: 71%
substrates
that
decompose
under
batch
sodiation
conditions.[20,15a] Thus, for example, 2-chloropyrazine (1g) cannot
be sodiated in batch with NaDA at –78 °C, however under our
optimized conditions (–78 °C, 0.5 s using
a flow rate of
10 mL/min) a complete consumption of the starting material takes
place affording after iodolysis the pyrazine 4p in 65% yield
(Scheme 2).
3
4
1c (–40 °C)
1d (–40 °C)
3k[c]
4k: 62%
4l: 85%
Table 3. Sodiation of sensitive (hetero)arenes of type 1 leading via intermediate
organosodiums of type 2 to polyfunctional (hetero)arenes of type 4.
substrate (sodiation
3l[b]
entry
electrophile
product[a]
temperature)
1g (–78 °C)
1h (–60 °C)
1i (–78 °C)
I2
5
6
1e (–20 °C)
1e (–20 °C)
3a[c]
4m: R = I; 53%
1
2
3
3o[b]
3p[b]
3q[b]
3r[b]
4q: 79%
4r: 97%
4s: 65%
Bu2S2
3m[c]
4n: R = SBu; 89%
7
1f (–40 °C)
3n[b]
4o: 68%
[a] Yield of analytically pure isolated product. [b] 1.5 equiv E-X. [c] 2.5 equiv
E-X.
Furthermore, related arenes bearing chloro-, iodo-, fluoro- or
trifluoromethyl-substituents were subjected to the optimized flow
conditions. Thus, 1,3-difluorobenzene (1b) was sodiated at
−40 °C providing the corresponding arylsodium 2b which was
subsequently quenched in batch with aldehyde 3i providing
alcohol 4i in 88% yield (Table 2, entry 1). Alternatively,
arylsodium 2b was trapped with benzoyl chloride (3j) in the
absence of any transition metal catalyst leading to benzophenone
derivate 4j in 71% yield (entry 2). Flow-sodiation of 2-
fluoroiodobenzene (1c) and subsequent quench with aldrithiol
(3k) led to the corresponding thioether 4k in 62% yield (entry 3).
In addition, trifluoromethyl-substituted arene 1d was sodiated at
−40 °C and quenched with aldehyde 3l leading to alcohol 4l in
85% yield (entry 4). Furthermore, the optimized flow conditions
were applied to the sodiation of heteroarenes. Thus, 2-
chloropyridine (1e) was sodiated in flow at convenient conditions
(–20 °C, 0.5 s at a flow rate of 10 mL/min; compared to –78 °C in
batch[15a]) and the intermediate 2-chloro-3-pyridyl sodium (2e)
was subsequently trapped with iodine (3a) and dibutyl disulfide
(3m) leading to the functionalized pyridines 4m and 4n in 53-89%
yield (entries 5-6). Trifluoromethyl-substituted pyridine 1f was
4
5
1j (–78 °C)
1k (–78 °C)
4t: 77%
4u: 76%
3f[c]
Me2S2
3s[d]
6
1l (–60 °C)
4v: 70%
7
8
1l (–60 °C)
1l (–60 °C)
3t: R = OMe[b]
3b: R = H [b]
4w: R = OMe; 80%
4x: R = H; 81%
[a] Yield of analytically pure isolated product. [b] 1.5 equiv E-X. [c] 5 mol%
CuCN·2LiCl, 2.5 equiv E-X. [d] 2.5 equiv E-X.
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10.1002/anie.201803961
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In addition to 2-chloropyrazine (1g), 2-fluoropyrazine (1h) and
substituted pyridines 1i and 1j that decompose upon batch-
sodiation were successfully sodiated under flow conditions and
trapped with aldehydes yielding functionalized heteroarenes 4q-t
in 65-97% yield (Table 3, entries 1-4). Copper-catalyzed[19] batch
allylation under flow-conditions of sodiated 2-iodothiophene (1k)
led to functionalized thiophene 4u in 76% yield (entry 5). At
−60 °C it was possible to sodiate 2-bromofluorbenzene (1l)
without aryne-formation. Instant reaction of the sodiated
intermediate 2l with dimethyl disulfide (3s) or benzaldehydes 3t
and 3b furnished functionalized arenes 4v-x in 70-81% yield
(entries 6-8).
Noteworthy, sodiation of 4-fluorobenzonitrile at –78 °C led to
the desired sodium arene 8 without the attack at the nitrile
functionality.[23] Batch quench of sodiated intermediate 8 with
benzaldehyde (3b), ketone 5n and disulfide 3k led instantly to
functionalized benzonitriles 9a-c in 75-81% yield (Scheme 4).
Additionally, a scale-up[24] was possible without any further
optimization by simply extending the running time. Thus, a scale-
up by factor 30 was conducted and functionalized benzonitrile 9a
was obtained in 76% yield on a gram scale (Scheme 4).
In summary, we have reported the first sodiation of
(hetero)arenes containing sensitive functional groups using a flow
set-up. The procedure could be scaled up without any further
optimization. Further investigations of flow-sodiations are
currently under way in our laboratories.
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (SFB 749) for
financial support. M. K. thanks the Foundation of German
Business for a fellowship.
Keywords: flow chemistry • sodium • metalation • NaDA •
pyrazine
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Scheme 3. Sodiation of (hetero)arenes of type 1 and subsequent batch quench
with ketones of type 5 leading to tertiary alcohols of type 6.
Addition of organometallics to ketones is always subject to
side reactions.[21] In particular, sterically hindered ketones are
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alkyllithium or-magnesium species.[22] Remarkably, the in flow
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ketones of type 5, leading to tertiary alcohols of type 6. Thus,
polyfunctional arenes and heteroarenes 6a-l were obtained in up
to 91% yield (Scheme 3).
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Scheme 4. Sodiation of highly sensitive 4-fluorobenzonitrile (7) and subsequent
batch quench with electrophiles yielding functionalized benzonitriles 9a-c.
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COMMUNICATION
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
Niels Weidmann+, Marthe Ketels+, Paul
Knochel*
Page No. – Page No.
Sodiation of Arenes and
Heteroarenes in Continuous Flow
Taming Sodium: Sodium is an abundant, non-toxic metal, however the high ionic
character of the C-Na-bond precludes many applications in synthesis. Using flow
chemistry, we report the first sodiation of arenes and heteroarenes under flow
conditions using the soluble base NaDA (sodium diisopropylamide) allowing
sodiation of (hetero)arenes containing sensitive functional groups that decompose
under batch-sodiation conditions. The resulting sodiated (hetero)arenes react
instantly with various electrophiles yielding polyfunctionalized (hetero)arenes in high
yields.
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