Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional N,N-Dimethylamides and Tetramethylurea in Toluene

Article abstract of DOI:10.1002/chem.202102805

The continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0 equiv) with sec-BuLi (1.1 equiv) provided at 25 °C within 40 sec the corresponding aryllithiums which were acylated with various functionalized N,N-

Full text of DOI:10.1002/chem.202102805

Accepted Article
Accepted Article
Title: Continuous Flow Acylation of (Hetero)aryllithiums with
Polyfunctional N,N-Dimethylamides and Tetramethylurea in
Toluene
Authors: Paul Knochel, Dimitrije Djukanovic, Benjamin Heinz,
Francesca Mandrelli, Serena Mostarda, Paolo Filipponi, and
Benjamin Martin
This manuscript has been accepted after peer review and appears as an
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using the Digital Object Identifier (DOI) given below. The VoR will be
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202102805
Link to VoR: https://doi.org/10.1002/chem.202102805
01/2020

10.1002/chem.202102805
Chemistry - A European Journal
COMMUNICATION
Continuous Flow Acylation of (Hetero)aryllithiums with
Polyfunctional N,N-Dimethylamides and Tetramethylurea in
Toluene
Dimitrije Djukanovic,+a Benjamin Heinz,+a Francesca Mandrelli,b Serena Mostarda,b Paolo Filipponi,b
Benjamin Martin,b Paul Knochel*a
[a]
Dimitrije Djukanovic,+ Benjamin Heinz,+ Prof. Dr. Paul Knochel*
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstraße 5-13, Haus F, 81377 Munich (Germany)
E-Mail: paul.knochel@cup.uni-muenchen.de
Dr. Benjamin Martin, Dr. Francesca Mandrelli, Dr. Serena Mostarda, Dr. Paolo Filipponi
Novartis Pharma AG, Chemical Development
Fabrikstraße, 4002 Basel (Switzerland)
[b]
E-Mail: benjamin.martin@novartis.com
[+]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract: The continuous flow reaction of various aryl or heteroaryl
bromides in toluene in the presence of THF (1.0 equiv) with sec-BuLi
(1.1 equiv) provided at 25 °C within 40 sec the corresponding
aryllithiums which were acylated with various functionalized
N,N-dimethylamides including easily enolizable amides at 20 °C
within 27 sec, producing highly functionalized ketones in 48-90% yield
(36 examples). This method was well suited for the preparation of
α-chiral ketones such as naproxene and ibuprofen derived ketones
with 99% ee. A one-pot stepwise bis-addition of two different lithium
organometallics to 1,1,3,3-tetramethyurea (TMU) provided
unsymmetrical ketones in 69-79% yield (9 examples).
flow mode has also allowed a convenient use of esters as
acylating agents.[15]
The acylation of organometallics with carbonyl derivatives
represents an excellent preparation of ketones which are of high
interest in medicinal, agrochemical and material chemistry.[1]
Although acid chlorides were often used as acylation reagents,[1]
alternative carboxyl derivatives such as 2-thiopyridyl esters,[2]
Weinreb amides,[3] 2-pyridylamides,[4] morpholino-amides,[5]
N-acylpyrroles[6] or N,N-dimethylamides[7] have been used
successfully in combination with appropriate organometallics[8] or
transition metal catalysts.[9]
The performance of organometallic reactions in continuous flow
has recently given a novel dimension to a range of these synthetic
methods.[10] The accurate control of residence times,
temperatures and concentrations greatly improved many
reactions involving organometallic intermediates.[11] Thus, Nagaki
and Yoshida have recently reported the synthesis of
functionalized ketones from acid chlorides and lithium reagents
by extremely fast micro-mixing.[12] Although functionalized
ketones were prepared, this method required the use of water
sensitive acid chlorides as well as extremely fast mixing not
accessible on commercial flow apparatus.[12] The use of
ecologically and industrially friendly halide free acylation reagents
would be highly desirable. Hattan and Jamison have described
double additions to carbon dioxide for the preparation of various
ketones (Scheme 1a).[13] Kappe has used mixed anhydrides for a
continuous flow synthesis of α-haloketones.[14] The continuous
Scheme 1. a) Previous work on acylations in continuous flow starting from acyl
chlorides and CO2. b) Acylations of aryl and heteroaryllithiums of type 2
prepared via Br/Li-exchange in continuous flow with N,N-dimethylamides of type
1 affording ketones of type 3 and selective stepwise double acylation with
1,1,3,3-tetramethylurea (4) leading to ketones of type 5.
Herein, we report the use of readily available and convenient
N,N-dimethylamides of type 1[16,17] as convenient and effective
reagents for the acylation of various (hetero)aryllithiums of type
2[17] in toluene using a continuous flow set-up leading to various
functionalized ketones of type 3 including halogenomethyl
ketones and α-chiral ketones (Scheme 1b).
1
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10.1002/chem.202102805
Chemistry - A European Journal
COMMUNICATION
We have shown that TMU (1,1,3,3-tetramethylurea, 4) allows an
efficient and selective synthesis of new unsymmetrical ketones of
type 5 via in situ generated arylated N,N-dimethylamides 6 and
batch-prepared R2-Li species of type 7 (Scheme 1b).
Table 2. Optimization of the acylation temperature continuous flow.
Thus, in preliminary experiments, we have optimized the
preparation of aryllithiums of type 2. In order to achieve a fast
exchange with a stable aryllithium intermediate of type 2, we have
explored the metal-exchange and electrophilic quench of 1-
bromo-4-methylthiobenzene (8a)[17] in both THF and toluene at
ambient temperatures. Therefore, we treated 8a with sec-BuLi
(1.1 equiv) in THF or toluene. We found that the Br/Li-exchange
was fast in THF leading to the aryllithium 2a, but that this lithium
organometallic was not stable at 25 °C as shown by quenching
experiments with 4-fluorobenzaldehyde (9), leading to the
entry
T
[°C]
conversion
of 8a
[GC-%]
product
formation
3aa
[GC-%]
50
1
2
3
4
25
0
20
40
>99
>99
>99
>99
67
82
84
By optimizing the concentration of 8a and sec-BuLi, the residence
times for the Br/Li-exchange as well as the acylation temperature,
a high GC-yield of the ketone 3aa was achieved. Thus, performing
the acylation reaction in continuous flow at either 25 °C or 0 °C
led only to 50-67% of the ketone 3aa (Table 2, entries 1 and 2).
However, lowering the reaction temperature to 20 °C or 40 °C
gave satisfactory yields (82-84%; entries 3 and 4).
expected alcohol 10 in only 24-27% yield; (Table 1, entries 1-2).
[18,19,20]
Switching to the common solvent toluene
afforded the
aryllithium species 2a in better yields, but the Br/Li-exchange
reaction was too sluggish and required up to 2 h reaction time for
completion (Table 1, entries 3-5). In balance, we found that simply
adding 1.0 equiv of THF to the toluene solution of 8a led to a fast
Br/Li-exchange within 1 min at 25 °C and produced, after
quenching with 9, the alcohol 10 in 95% calibrated GC-yield
(Table 1, entry 6).
Table 1. Optimization of the aryllithium generation in batch and flow.
entry
set-
up
solvent
time
[min]
conversion
of 8a
[GC-%]
90
Formation
of 10
[GC-%]
24
27
8
49
57
95
85
1
2
3
4
5
6
7
8
9
batch
batch
batch
batch
batch
batch
batch
batch
flow
THF
THF
1
30
1
30
120
1
10
30
1
93
18
75
94
96
98
>99
>99
toluene
toluene
toluene
toluene[a]
toluene[a]
toluene[a]
toluene[a]
60
99
[a] 1.0 equiv of THF was added which corresponded to a ca. 50:1 toluene:THF mixture.
In contrast, using n-BuLi led to a slower Br/Li exchange of 8a
incompatible with the stability of the generated metal species.
Longer storage time of 2a at 25 °C (10-30 min) afforded lower
yields of 10 showing the instability of 2a over time (Table 1, entries
7 and 8). In counterpoint, performing this reaction at this
temperature in flow led to a quantitative formation of 10, showing
that a flow set-up using toluene in the presence of 1.0 equiv of
THF was most advantageous (entry 9). The low stability of
aryllithiums at ambient temeratures justified this “on-demand”
preparation in continuous flow and enabled potential scale-ups. In
preliminary reactions, we observed that proton-quenching via
amide enolization in THF led to proto-desbrominated products
(thioanisole). The present solvent system (toluene containing
1.0 equiv of THF) also reduced this enolization side-reactions on
amides bearing acidic protons.[21,22]
Scheme 2. A continuous flow acylation of various amides 1 with in situ
generated lithium organometallics 2 leading to polyfunctional ketones 3. [a] The
indicated yields refer to yields of the isolated products.
2
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10.1002/chem.202102805
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With these conditions in hand, using the aryl bromide 8a (0.25 M
in toluene containing 1.0 equiv of THF) with a flow rate of 5.0
mL/min and sec-BuLi (1.1 equiv, 1.35 M in n-hexane) with a flow
rate of 1.1 mL/min, we have quantitatively generated the
corresponding aryllithium 2a at 25 °C (t1 = 40 sec). After
precooling the lithium species for 10 sec, the acylation step was
performed at 20 °C (t2 = 27 sec) affording, via the formation of
the tetrahedral intermediate 11 and subsequent quenching with
sat. aq. NH4Cl, the desired ketone 3aa in 82% isolated yield. A
scale-up of this reaction in continuous flow was easily achieved
by simply prolonging the collecting time (from 0.5 min to 6.5 min)
and led to a comparable yield (78%, Scheme 2).
Various aryllithiums (2b-2e) bearing MeO, Br or Cl as
substituents were quantitatively prepared by Br/Li-exchange from
the corresponding aryl bromides and their acylation with 1a
afforded the expected ketones 3ab-ae in 75-85% isolated yield.
Also, heterocyclic lithium species were generated in this way and
the acylation with 1a produced the heterocyclic ketones 3af and
3ag in 82-89% yield. A related functionalized amide such as 2,2-
diethoxy-N,N-dimethylacetamide (1b) behaved in the same way
providing, after the reaction with fluoro-substituted aryllithiums,
the ketones 3bh-3bj in 74-78% yield. Also, various α-
monofluoro-, difluoro- or monochloro-substituted amides 1c, 1d
and 1e gave the expected ketones despite the presence of readily
enolizable protons at the α-position to the amide group. The use
of the non-polar solvent toluene significantly reduced such
enolization side-reactions as mentioned above.[21] Thus, the
α-halogenated ketones 3cg-cj, 3da-dl and 3ef were obtained in
48-78% yield. N,N-Dimethylamides such as 1f, 1g and 1h,
bearing remote oxygen- or nitrogen-containing functional groups,
provided aromatic and heterocyclic ketones 3ff-fn, 3gk and 3ho
in 63-81% isolated yield. As a limitation, we have found that
N,N-dimethyl-phenylacetamide (1i) gave in this procedure only
average yields of the desired aryl benzyl ketones 3ia and 3ik due
to competitive enolization and consequent proto-debromination of
the starting material (ca. 25% of enolization was noticed in the
present solvent system, whereas over 70% enolization was found
in pure THF). [1,1,1]-bicyclopentane carboxamide 1j was also a
suitable substrate and the reaction with various lithiums of type 2
furnished the bicyclopent-1-yl ketones 3jp and 3jr in 59-70%
isolated yield.[23] Finally, the dialkyl ketone 3hs was prepared by
directly using n-BuLi as organolithium species via a 2-pump
system (Scheme 2).
Scheme 3. Preparation of functionalized benzophenones and heterocyclic
ketones in continuous flow by acylation of (hetero)aryllithiums of type 2 with
ArCONMe2 6. [a] The indicated yields refer to yields isolated products.
The preparation of racemizable α-chiral ketones was readily
achieved with this new acylation procedure (Scheme 4). This is
demonstrated in the case of naproxen and ibuprofen derived
α-chiral ketones. Those analogues of non-steroidal anti-
inflammatory drugs (NSAIDs) were of interest in the pursuit of
antivirals[24] and to tackle gastrointestinal side-effects such as
ulceration.[25] Thus, the readily available chiral N,N-dimethylamide
of naproxen 13a (99% ee) was treated under standard continuous
flow conditions with various functionalized aryllithiums of type 2
leading to the desired chiral ketones 14ac-an in 65-88% yield with
complete retention of chirality (99% ee).[26] Also, the chiral
N,N-dimethylamide of ibuprofen 13b (99% ee) was acylated with
(hetero)aryllithiums to give the chiral ketones 14bh-bs in 75-89%
isolated yield (98-99% ee).
Next, we turned our attention to the preparation of highly
functionalized benzophenone derivatives and heterocyclic
ketones (Scheme 3). Thus, the cyano group in N,N-dimethyl-4-
cyanobenzamide (6a)[17] was well tolerated leading to the cyano-
substituted benzophenones 12ae-an in 61-79% isolated yield.
Remarkably, by using N,N-dimethyl-4-iodobenzamide (6b), no
competitive I/Li-exchange was observed and the desired iodo-
substituted benzophenones 12bq and 12br were obtained in 63-
79% yield. Also, commercially available N,N-diethylnicotinamide
(6c) provided the heterocyclic ketone 12cr in 58% yield after the
usual sequence in continuous flow.
Scheme 4. Preparation of chiral naproxene or ibuprofen ketone derivatives of
type 14 by the reaction of aryllithiums 2 with naproxene or ibuprofen derived
N,N-dimethylamides 13 in continuous flow. [a] The indicated yields refer to
yields of isolated products.
3
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10.1002/chem.202102805
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Finally, we have extended this acylation in continuous flow to a
semi-batch telescoped procedure for the preparation of
unsymmetrical ketones of type 5 using TMU (4) as a C1-building
block (Scheme 5).[8a, 27] Thus, the treatment of a mixture of ArBr
(8) and TMU (4) in toluene with sec-BuLi at 20 °C for 50 sec in
continuous flow provided the tetrahedral intermediate 15 which
was poured into a toluene solution of various organolithiums R-Li
(7, R2 = Bu, (Het)Ar or Bn). These aryllithiums were conveniently
prepared via direct metalation, using sec-BuLi and TMEDA (1.0
equiv) in toluene at 20 °C (10-30 min) in batch. Presumably, due
to a high stability of the intermediate 15, the second addition was
quite slow and took up to 12 h at 25 °C. After aqueous workup,
the corresponding ketones 5a-5f were obtained in 69-79% yield.
Remarkably, no additional equivalent of THF was needed to
ensure a fast Br/Li-exchange, showing that TMU played a similar
activator role as THF for the fast formation of the lithium
species.[28]
Acknowledgements
B. Heinz thanks the Novartis Pharma AG for the fellowship. We
thank Albermarle (Hoechst, Germany) and BASF for the
generous gift of chemicals and Vapourtec for technical support.
Keywords: continuous flow • amide • acylation • lithium • toluene
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In summary, we have reported a new convenient acylation of
organolithiums 2 with various enolizable and functionalized
N,N-dimethylamides 1 in continuous flow at 20 °C. The required
aryllithiums (2) were also prepared in continuous flow at 25 °C
using a Br/Li-exchange mediated by sec-BuLi with toluene as
solvent in the presence of 1.0 equiv of THF. This acylation was
scalable without further optimization and was found to be suitable
for the preparation for a broad range of polyfunctional ketones,
including α-chiral ketones of type 14 with excellent
enantioselectivities. Furthermore, this method was extended to a
semi-batch telescoped preparation of unsymmetrical ketones
using TMU (4) as C1-building block. Compared to previous
acylation procedures, readily prepared and stable N,N-
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functionalities, were used. The solvent toluene in the presence of
2 vol% THF minimized enolization side reactions and allowed
ambient reaction temperatures. Further applications are
underway.
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10.1002/chem.202102805
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N,N-Dimethylamides for continuous flow acylations: A new acylation of (hetero)aryllithiums with polyfunctional and enolizable N,N-
dimethylamides in toluene in continuous flow was reported. The required lithium species was prepared at 25 °C from (hetero)aryl
bromides and sec-BuLi in toluene. Additionally, a new telescoped procedure, using tetramethylurea as C1-building block, was described
providing highly functionalized unsymmetrical ketones.
Institute and/or researcher Twitter usernames: @KnochelLab
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