Flow Microreactor Technology for Taming Highly Reactive Chloroiodomethyllithium Carbenoid: Direct and Chemoselective Synthesis of α-Chloroaldehydes

Article abstract of DOI:10.1021/acs.orglett.0c01085

A straightforward flow synthesis of α-chloro aldehydes has been developed. The strategy involves, for the first time, the thermal unstable chloroiodomethyllithium carbenoid and carbonyl compounds. A batch versus flow comparative study showcases the superb capability of flow technology in prolonging the lifetime of the lithiated carbenoid, even at -20 °C. Remarkably, the high chemoselectivity realized in flow allowed for preparing polyfunctionalized α-chloro aldehydes not easily accessible with traditional batch procedures.

Full text of DOI:10.1021/acs.orglett.0c01085

pubs.acs.org/OrgLett
Letter
Flow Microreactor Technology for Taming Highly Reactive
Chloroiodomethyllithium Carbenoid: Direct and Chemoselective
Synthesis of α‑Chloroaldehydes
Pantaleo Musci,∇ Marco Colella,∇ Alessandra Sivo, Giuseppe Romanazzi, Renzo Luisi,*
and Leonardo Degennaro
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ABSTRACT: A straightforward flow synthesis of α-chloro
aldehydes has been developed. The strategy involves, for the first
time, the thermal unstable chloroiodomethyllithium carbenoid and
carbonyl compounds. A batch versus flow comparative study
showcases the superb capability of flow technology in prolonging
the lifetime of the lithiated carbenoid, even at −20 °C.
Remarkably, the high chemoselectivity realized in flow allowed
for preparing polyfunctionalized α-chloro aldehydes not easily
accessible with traditional batch procedures.
toxicity, and corrosivity, particularly on a large scale.3,4 In
addition, such halogenations could result with low regiose-
lectivity and chemoselectivity, or multiple halogenations.5 A
different approach is based on the use of organometallic
reagents able to transfer the halogenated carbon to a suitable
carbonyl precursor. In fact, the acylation of lithium carbenoids
has been reported by Pace, Luisi, and co-workers as an effective
alternative to direct halogenation, tackling problems such as
polyhalogenation and site selectivity (Scheme 1b).6 Note that,
because of the high thermal instability of the involved lithium
carbenoids, this strategy requires the use of a large excess of
carbenoid, very low temperatures (i.e., less than or equal to
−78 °C) and the internal quenching procedure. However, the
use of microreactor technology allowed for developing more
sustainable flow protocols, for the preparation of α-chlorinated
carbonyls. In fact, Knochel reported an attractive flow
approach to α-chlorinated ketones based on the use of lithium
chloroacetate in a Claisen reaction (Scheme 1b).7
n organic synthesis and drug development, α-chlorinated
1
Icarbonyls are useful building blocks.
The most general
strategies for their preparation are based on α-chlorination of
carbonyls with suitable chlorinating agents.2 Numerous
different chlorinating reagents could be used (Scheme 1a).
Nevertheless, such halogenation reactions involve inorganic
compounds (i.e., molecular chlorine) or polychlorinated
organic molecules, which pose problems of waste streams,
Scheme 1. Strategies To Access α-Halo Carbonyls
Other approaches for the flow synthesis of α-haloketones
have been recently reported by Ley8 and Kappe.9 In contrast to
α-chloro ketones, the preparation of α-chloro aldehydes is less
straightforward. Interestingly, Studer10 reported the direct
conversion of primary and secondary alcohols into the
corresponding α-chloro aldehydes using trichloroisocyanuric
Received: March 25, 2020
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© XXXX American Chemical Society
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acid, while Renaud11 used trichloromethanesulfonyl chloride as
an α-chlorinating agent for aldehydes (Scheme 1c). Notwith-
standing the usefulness of these strategies, they are based on
toxic or reactive reagents, and starting materials not always
readily available. Moreover, with the exception of few cases
shown by Renaud, these approaches cannot be applied to a
direct synthesis of α-chloro aldehydes bearing quaternary
centers. A different approach, based on carbonyl homologation
followed by a Meinwald-type epoxide−aldehyde isomerization,
was reported in the 1970s by Kobrich (Scheme 1d).12
Nevertheless, the process required the internal quenching of
the unstable dichloromethyllithium at very low temperature
(−100 °C) and, as a second step, a thermally induced
isomerization. Inspired by Kobrich’s seminal work, and
counting on our experience in the use of flow chemistry as
sustainable technology for taming reactive intermediates,13 we
report herein a direct one-step synthesis of functionalized α-
chloro aldehydes bearing quaternary centers (Scheme 1e).
Even if the genesis of dichloromethylithium in continuous
flow conditions was recently reported,13d our investigation
considered a dihalocarbenoid generated from readily available
chloroiodomethane 1, for two reasons: (1) the installation of a
better leaving group (i.e., iodine) would favor the formation of
the α-chloroepoxide, precursor of the α-chloro aldehyde; and
(2) chloroiodomethane (with a boiling point (bp) of 108 °C)
could be an environmentally safer alternative to the low-boiling
dichloromethane (bp = 39.6). Moreover, since we were unable
to find previous reports on the use of chloroiodomethyllithium
1-Li in the direct preparation of α-chloro aldehydes, we
speculated that it would have been interesting to explore this
tactic. As reported in Scheme 2, first we tested 1-Li in the
Li.6c With the aim to get some insights on the lifetime of 1-Li
at −78 °C, a simple chemical method based on a lithiation/
deuteration sequence, and quantitative GC and MS analysis
was set up (Scheme 2c).14 The results of this study show that
quenching of 1-Li after 1 min produced 1-D in 22% yield, with
an entire recovery (1 + 1-D) of 32%. Thus, ∼70% of 1 is lost
upon lithiation, likely as a consequence of the chemical
instability of 1-Li. Prolonging the time up to 15 min, before
electrophilic quenching, resulted in a 17% recovery (1 + 1-D)
with >80% loss of 1. By using this simple approach, regardless
of the kinetic of the lithiation process, we could estimate the
lifetime of the lithium carbenoid 1-Li (i.e., <1 min) assessing
its unsuitability for an external quenching protocol. With the
aim to validate the flow microreactor technology, and the flash
chemistry approach,15 we conducted the same study on the
reactivity and lifetime of carbenoid 1-Li under continuous flow
conditions. A flow microreactor system consisting of two T-
shaped micromixers (M1 and M2) and two microtube reactors
(R1 and R2) was used for this purpose (see Scheme 3).
Scheme 3. Testing Reactivity and Lifetime of
Dihalocarbenoid 2 in Flow
Scheme 2. Testing Reactivity and Lifetime of
Dihalocarbenoid 1-Li in Batch
Reacting 1 with LDA in M1 generates intermediate 1-Li that
could be transferred in M2, where it is quenched (trapped)
with CD3OD. Several experiments were performed, varying the
temperature (T) and the residence time in R1 (tR1) and the
solution of each experiment directly analyzed by GC and MS
techniques, in order to assess mass recovery and deuterium
content. Analysis of the collected data allowed us to generate
the contour map reported in Scheme 3.
Under flow conditions (Scheme 3), the highest yields of 1-D
(94%) could be obtained at short residence times (tR1 = 330
ms) and at relatively high temperature (−20 °C). Note that
the yields reported in this contour map consider both the
recovery of 1 and 1-D and the deuterium content (see the
Supporting Information). Remarkably, a rather wide operative
reaction with benzophenone, in batch at −78 °C, and under
internal quenching conditions. With our delight, we observed
the direct formation of the α-chloro aldehyde 3a in 55% yield.
Next, the same reaction was run under external quenching
conditions, with trapping of 1-Li just after 1 min (Scheme 2b).
In this latter case, 3a formed in a low 18% yield jointly to a
30% yield of the side product 4, likely deriving from an
eliminative dimerization of the highly chemically unstable 1-
B
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window is observed under flow conditions (the red diagonal in
the contour map). In fact, lowering the reaction temperature
resulted in prolonging of the lifetime of 1-Li. For example, 1-D
could be obtained in 87% yield running the flow system at −78
°C with a residence time of 9.4 s. These results clearly
highlight the capability of flow microreactor technology to
control the lifetime of very reactive intermediates, such as a
dihalocarbenoid, under conditions (i.e., −20 °C, external
trapping) that seems to be unsuitable in batch.16 With the
optimized conditions in hand, the scope of this flow
methodology was examined (see Scheme 4).
Scheme 5. Flow Synthesis, Followed by Acidic Treatment to
α-Chloroaldehydes
Scheme 4. Optimized Flow Synthesis for Direct Access to α-
Chloro Aldehydes
yields by using this direct flow approach. The cyclopropyl ring
(in 3j), as well as the cyclic structure (in 3k), were compatible
with this flow protocol. Note that all these molecules would
require a multistep approach for their preparation and cannot
be obtained in satisfactory yields using this strategy under
traditional batch conditions.
To further prove the superb performance of this flow
approach, with respect to batch operation, we perform some
representative reactions on diarylketones (2b and 2c) under
internal quenching conditions at −20 °C (Scheme 4). The
reaction proceeded with low conversion furnishing α-
chloroaldehydes 3b and 3c in 27% and 19% yields,
respectively. Under the same batch conditions, the more
challenging ketones 2gbearing an o-bromophenyl moiety
gave complex reaction mixtures and product 3g was observed
in 14% yield. A slightly different behavior was observed when
diarylketones 2m−2o, arylalkylketones 2p−2x, and dialkyl
ketones 2y−2ab were employed under optimal flow conditions
(Scheme 5). In fact, in this case, a mixture of the desired α-
chloroaldehyde 3 and its precursor chloroepoxide 9 was
obtained.
However, stirring the crude mixture of 3 and 9 under mild
acidic conditions in the presence of Amberlist-15 cleanly
provided the chloroaldehyde 3. In this way, aldehydes 3m−3z
and 3aa−3ab were obtained in good yields and chemo-
selectivity. Remarkably, the excellent group tolerance, realized
under flow conditions, allowed using enolizable ketones, or
ketones bearing electrophilic moiety such as 2-chloro-1-
phenylethan-1-one (2w) and 5-chloro-1-phenylbutan-1-one
(2x) that furnished 3w and 3x in 46% and 75% yield,
Under optimized conditions (−20 °C, tR1 = 330 ms), and
using benzophenone as a carbonyl acceptor, the α-chloro
aldehyde 3a was directly recovered in 84% yield. It is likely that
the formation of 3a is a consequence of a fast Meinwald-type
rearrangement of α-chloroepoxide 9 via carbonyl α-cation
(vide infra). When the same reaction was conducted under
batch conditions at −20 °C, and using the internal quenching
protocol (Scheme 2), 3a was recovered only in a low 17%
yield. The use of symmetrical and nonsymmetrical substituted
ketones gave access to the corresponding α-chloro aldehydes
3b−3l with good yields and high level of chemoselectivity. In
fact, the presence of sensitive functionalities such as halogens
(F, Cl, Br) on the phenyl ring, potentially incompatible with
the lithiation conditions, was completely tolerated, returning
very clean reaction mixtures. Additional functional groups,
such as a heterocyclic ring as in 3m (Scheme 5), or the triple
bond as in 3i (Scheme 4) could be easily installed in the α-
chloro aldehyde backbone. The method was not only limited
to di(hetero)arylketones but could be applied to some
alkylarylketones. In fact, α-chloro- and α-aryl-substituted
aldehydes 3j−3l were easily prepared in good to excellent
C
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respectively. Interestingly, 3w was impossible to obtain under
batch conditions, even at −78 °C and using the internal
quenching protocol. Other interesting examples are chlor-
oaldeyde 3y, bearing a heterocyclic core, and macrocyclic
aldehyde 3aa, and aliphatic aldehyde 3ab difficult to prepare
using a direct approach from simple feedstocks. However,
some limitations were observed with the use of fluorenone and
trifluoromethylphenylketone, converted to the corresponding
dihalohydrins 5 and 6, respectively (Scheme 5, bottom).17 It is
likely that intramolecular cyclization does not occur under
these reaction conditions. In addition, the use of di(2-
pyridyl)ketone resulted in a mixture of dihalohydrin 7 and
chloroepoxide 8. Attempts to induce the rearrangement of 8
resulted in the recovery of unreacted starting material or
decomposition under harsh conditions. The reluctance of 8 to
undergoing this Meinwald-type rearrangement could be
explained according to McDonald’s study,18,19 with the
involvement of a carbonyl α-cation that would be destabilized
by electron-withdrawing substituents such as the 2-pyridyl ring
(see Scheme 5). Such electronic effects could justify the results
obtained using ketones 2n and 2o (see Scheme 5), where an
incomplete rearrangement occurred.
In conclusion, in this work, we demonstrated that highly
unstable lithium dihalocarbenoid can be tamed by taking
advantage of the flash chemistry approach and using
microreactor technology. Under continuous flow conditions,
the direct synthesis of α-chloroaldehydes bearing a quaternary
center was feasible; the reaction showed a high level of
chemoselectivity and could be realized at −20 °C under
external quenching conditions. In contrast, the same approach
cannot be employed using batch operations. Remarkably, we
introduced an effective method for estimating the lifetime of
fleeting species either under batch or under flow conditions.
Further results exploiting this approach are available in our
laboratory and will be reported in due course.
Giuseppe Romanazzi − DICATECh, Politecnico di Bari, Bari
70125, Italy; orcid.org/0000-0001-5053-7883
Leonardo Degennaro − Flow Chemistry and Microreactor
Technology FLAME-Lab, Department of Pharmacy − Drug
Sciences, University of Bari “A. Moro”, Bari 70125, Italy;
orcid.org/0000-0002-2187-9419
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01085
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Author Contributions
∇These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Bari (Ateneo 2019) and Dompe
spa for financial support.
■
̀
DEDICATION
■
This work is dedicated to the memory of Prof. Jun-ichi Yoshida
(Kyoto University).
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
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Marco Colella − Flow Chemistry and Microreactor Technology
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