Flow Technology for Telescoped Generation, Lithiation and Electrophilic (C3) Functionalization of Highly Strained 1-Azabicyclo[1.1.0]butanes

Article abstract of DOI:10.1002/anie.202014881

Strained compounds are privileged moieties in modern synthesis. In this context, 1-azabicyclo[1.1.0]butanes are appealing structural motifs that can be employed as click reagents or precursors to azetidines. We herein report the first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1-azabicyclo[1.1.0]butanes. The flow method allows for exquisite control of the reaction parameters, and the process operates at higher temperatures and safer conditions with respect to batch mode. The efficiency of this intramolecular cyclization/C3-lithiation/electrophilic quenching flow sequence is documented with more than 20 examples.

Full text of DOI:10.1002/anie.202014881

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Accepted Article
Title: Flow Technology for Telescoped Generation, Lithiation and
Electrophilic (C3) Functionalization of Highly Strained 1-
Azabicyclo[1.1.0]butanes
Authors: Pantaleo Musci, Timo von Keutz, Ferdinand Belaj, Leonardo
Degennaro, David Cantillo, Oliver C. Kappe, and Renzo Luisi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202014881
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10.1002/anie.202014881
Angewandte Chemie International Edition
COMMUNICATION
Flow Technology for Telescoped Generation, Lithiation and
Electrophilic (C3) Functionalization of Highly Strained 1-
Azabicyclo[1.1.0]butanes
Pantaleo Musci, Timo von Keutz, Ferdinand Belaj, Leonardo Degennaro, David Cantillo, C. Oliver
Kappe* and Renzo Luisi*
In memory of Prof. Hans Reich for his outstanding contribution to the chemistry of organolithiums
P. Musci, Prof. Dr. L. Degennaro, Prof. Dr. R. Luisi
Flow Chemistry and Microreactor Technology FLAME-Lab
Department of Pharmacy – Drug Sciences
University of Bari “A. Moro”
Via E. Orabona 4, Bari, 70125 (Italy)
E-mail: renzo.luisi@uniba.it
T. von Keutz, Prof. F. Belaj, Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Institute of Chemistry, University of Graz
Heinrichstrasse 28, 8010, Graz (Austria)
E-mail: oliver.kappe@uni-graz.at
Homepage: http://goflow.at
T. von Keutz, Dr. D. Cantillo, Prof. Dr. C. O. Kappe
Center for Continuous Flow Synthesis and Processing (CC FLOW)
Research Center Pharmaceutical Engineering GmbH (RCPE)
Inffeldgasse 13, 8010 Graz (Austria)
Supporting information for this article is given via a link at the end of the document.
Abstract: Strained compounds are privileged moieties in modern
synthesis. In this context, 1-azabicyclo[1.1.0]butanes are appealing
structural motifs that can be employed as click reagents or precursors
to azetidines. We herein report the first telescoped continuous flow
protocol for the generation, lithiation, and electrophilic trapping of 1-
azabicyclo[1.1.0]butanes. The flow method allows for exquisite
control of the reaction parameters, and the process operates at higher
temperatures and safer conditions with respect to batch mode. The
efficiency of this intramolecular cyclization/C3-lithiation/electrophilic
quenching flow sequence is documented with more than 20 examples.
is that it is the first-ever reported use of a C3-lithiated
azabicyclo[1.1.0]butane.6
Strained compounds are considered privileged scaffolds
amenable to a number of useful chemical transformations.1 In
recent work, Baran and coworkers highlighted the potential
offered by strained bonds in organic synthesis.2 In particular, the
use of “spring-loaded” hetero- and carbocycles as “click reagents”
for rapid and direct installation of small ring bioisosters onto
heteroatoms was emphasized, including applications of this
strategy in medicinal chemistry. Among such strained compounds,
azabicyclo[1.1.0]butanes (ABBs) are emerging as useful
reagents for the preparation of azetidines.3 In fact, 1,3-
functionalized azetidines can be obtained by strain-release of
azabicyclo[1.1.0]butanes (Figure 1a).4 In this context, Aggarwal
reported an interesting approach for the preparation of azetidine
boronic esters 1 (Figure 1b).5 More specifically, the strategy
involved the reaction of an alkyl (or aryl) boronate with lithiated 1-
azabicyclo[1.1.0]butane (ABB-Li). ABB-Li was generated by C3-
deprotonation of ABB, which in turn was prepared in situ from 2,3-
dibromopropylamine. A remarkable aspect of this synthetic route
Figure 1. (a) Synthesis and use of strained 1-azabicyclo[1.1.0]butanes, (b)
generation and use of lithiated derivatives (ref 5) and (c) proposed flow
approach.
1
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10.1002/anie.202014881
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An important drawback of the reaction described above for its
implementation on synthetically relevant scales is that it requires
cryogenic conditions (-78 °C) and > 3 h reaction time. We
hypothesized that a continuous flow protocol in which ABB-Li is
generated and directly consumed in situ with a suitable
electrophile in a telescoped process (Figure 1c) would result in a
more convenient and scalable procedure. Continuous flow
technology permits the design of modular, fit-for-purpose reactors
that can be engineered for each reaction step and then
assembled into a single machine for carrying out sequential
telescoped processes.7 Moreover, the utilization of microreactor
technology typically enables the use of higher temperatures for
this type of organometallic reactions,8 often avoiding the use of
cryogenic conditions.9 We report herein the successful
development of a convenient continuous flow protocol for the
generation, lithiation, and electrophilic trapping of 1-
azabicyclo[1.1.0]butanes, including unprecedented reactions of
the lithiated cyclic intermediate with ketones, aldehydes and
imines. The three reaction steps were combined in a flexible,
modular machine that permitted an easy exchange of the
electrophile without the need for re-optimization of the setup.
Our investigation was initiated with a series of batch experiments
aimed to assess some critical parameters associated with this
process. First, the substitution of the widely employed PhLi with
s-BuLi for the conversion of dibromoamine 2 into ABB was
evaluated. This would permit employing a single base for the two-
step generation of ABB-Li. Second, the thermal stability of ABB-
Li needed to be evaluated. Thus, dibromoamine 2 was reacted
with 2 equiv of s-BuLi in THF at -78 °C, and the time required for
complete conversion from 2 to ABB determined (Table 1). Due to
the inherent lability of the ABB intermediate, it was reacted with
HBr and quantitatively converted into bromo-derivative 3, a
compound that could be readily quantified by 1H NMR monitoring
(Table 1).
examined next (Table 2). The lithiation of ABB was examined with
respect to reaction time and effect of a ligand (Table 2).
Benzophenone was used as a model electrophile.. The sequential
lithiation/trapping reaction from ABB furnished 91% yield of
strained alcohol 4a after 75 min in the presence of TMEDA at -
78 °C (Table 2, entry 3). In contrast, poor yield (29%) was
observed in the absence of TMEDA (entry 4), stressing the
importance of the ligand in accelerating the C3-deprotonation.10
Slightly lower yields were obtained when shorter reaction times
were employed (entries 1 and 2). To support the proposed
structure of 4a, quantitative conversion into the strain-released
derivative 5 was carried out by reacting 4a with an excess of HBr.
Notably, the intramolecular strain release leading to spiro
compound 6 was not observed.
Table 2. Optimization of the sequential generation and lithiation of ABB (batch).
Entry
Time[a]
45 min
60 min
75 min
60 min
Ligand[b]
TMEDA
TMEDA
TMEDA
none
Yield 4a [%] [c]
1
2
3
4
53
86
91
29
[a] Time interval for the generation of ABB-Li. The electrophile was subsequently
added and the reaction stirred at rt for 5 min. [b]1.2 equiv of ligand used. [c]Yields
calculated by 1H NMR using mesitylene as internal standard.
Table 1. Influence of the reaction time on the generation of ABB from 2 (batch)
An additional set of experiments was performed to assess the
feasibility of a one pot procedure, consisting of a sequential
intramolecular cyclization/C3-lithiation/electrophilic quenching.
Thus, the generation of ABB-Li from 2 was carried out using 3.2
equiv of s-BuLi/TMEDA. The reaction was performed at three
different temperatures (-78 °C, -50 °C and -20 °C). Yields of 4a
were determined after different lithiation times (Table S1). Notably,
higher temperatures had a positive effect by increasing the
reaction rate, albeit negatively affected yields, most likely by
promoting the decomposition of ABB-Li. Thus, when the reaction
was carried out at -78 °C, 4a could be obtained with 95% yield
after 3 h, while at -50 °C 4a was formed in 90% yield after 2 h. At
-20 °C, 4a was formed with only 70% yield after 1.5 h. Even longer
reaction times (>1.5 h) caused a significant drop of the yield at
this temperature.
Entry
Time[a]
3 Yield %[b]
1
2
3
4
5
6
15 min
30 min
60 min
90 min
105 min
120 min
66
72
73
90
79
77
[a]Time before the addition of HBr. [b]Yields calculated by 1H NMR using 1,3,5-
trimethybenzene as internal standard.
On the basis of the optimization study conducted under batch
conditions, the next step was to transfer the one pot process into
a flow reactor. A flow system (Figure 2), consisting of two T-
shaped micromixers (M1, M2), and two coil reactors (R1, R2),
kept at two different temperatures, was employed for optimization
purposes (see Supplementary Material for details). To our delight,
the reaction performed very well under continuous flow conditions.
Importantly, higher temperatures were compatible with the
process. Thus, 4a was obtained in 85% yield at -20 °C and
Gratifyingly, the reaction proceeded with reasonable yields using
s-BuLi (Table 1, entries 1-3), and ABB could be obtained in 90%
yield after 90 min (entry 4). Longer reaction times resulted in lower
yields (entries 5 and 6). Assuming 90 min as the optimal reaction
time for the generation of ABB from 2, the C3-lithiation was
2
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10.1002/anie.202014881
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COMMUNICATION
remarkably, a 92% yield was achieved at 0 °C. These results are
in contrast with their batch counterparts: when the same
transformation was carried out at 0 °C in a batch vessel, a modest
50% yield of 4a was obtained. It is worth pointing out that under
flow conditions the ligand TMEDA was not required.
Figure
2.
Continuous flow
synthesis
of C3-functionalized
1-
azabicyclo[1.1.0]butane.
Next, the scope and functional group tolerance of the continuous
flow process was investigated (Scheme 1). This substrate screen
was carried out on a small scale, using NMR monitoring of the
crude reaction mixtures to assess the reaction outcome.
Characterization of the reaction products was performed using
isolated samples from the batch reactions. Product isolation from
the reaction mixtures obtained under flow conditions was
performed on a larger scale under intensified conditions (vide
infra). Notably, several unprecedented C3-functionalized 1-
aza[1.1.0]bicyclobutanes 4a-u were obtained in good to excellent
yields. Di(hetero)aryl ketones provided the corresponding
carbinols 4a-c. The use of alkyl aryl ketones successfully afforded
adducts 4e-j with good chemoselectivity. The presence of
halogens (4g-j) was also well tolerated. In the case of non-
aromatic ketones, no enolization was observed, and compounds
4o-q were obtained in good NMR yields. Remarkably,
derivatization of (R)-carvone proceeded smoothly with high
chemo- and stereoselectivity (4q).11 Good results were also
obtained when aldehydes were used as substrates (4k-n). ,-
Unsaturated aldehydes and ketones were also suitable starting
materials under our reaction conditions, furnishing exclusively the
1,2-addition products 4r and 4s. Notably, the expected C3-
functionalized 1-azabicyclo[1.1.0]butane structure of 4s could be
confirmed by X-ray analysis (Scheme 1).12 An imine was also
evaluated as electrophile, furnishing strained amine 4t. With α-
chloroacetophenone as the substrate, electrophilic addition of
ABB-Li to the carbonyl group was followed by intramolecular
cyclization, providing epoxide 4u in moderate yield.
Scheme 1. Continuous flow synthesis of C3-functionalized strained 1-
azabicyclo[1.1.0]butanes. NMR yields using 1,3,5-trimethoxybenzene as
standard are shown.
To further evaluate the applicability of this telescoped
process, we examined Aggarwal’s 1,2-metalate rearrangement5
under continuous flow conditions (Scheme 2).13 By simply
introducing a solution of phenylboronate (PhBPin) as the
electrophile feed, the entire sequence consisting of intramolecular
cycliczation, C3-lithiation, electrophilic trapping and strain release
via 1,2 B to C migration, was accomplished in an one-flow fashion
obtaining functionalized azetidine 7 in 64% yield.
3
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Scheme 2. Continuous flow synthesis of azetidine boronic esters via a
telescoped cyclization/lithiation/electrophilic trapping and strain release
sequence.
After assessing the functional group tolerance of this flow
synthesis of C3-functionalized 1-azabicyclo[1.1.0]butanes, we
decided to further develop the continuous flow process to
increase its efficiency and productivity (Scheme 3). To our delight,
in addition to s-BuLi, the less expensive and milder n-BuLi could
also be utilized as base (Methods A and B, Scheme 3). The
concentration of both reagents could be increased to 1.6 M and
1.3 M for n-BuLi and s-BuLi, respectively. Thus, the commercial
solutions of the reagents in hexanes were directly used without
dilution. The increased concentration had a significant positive
effect on the rate of formation of ABB-Li. Under these intensified
conditions, the flow rates of the reagent feeds could be increased,
resulting in a shortened residence time of only 2.5 min (Scheme
3). The total residence time, including the reaction with the
electrophile (1 min) was 3.5 min. Gratifyingly, the improved
conditions also increased the yields of products 4 in some cases.
Compound 4d, for example, with which an NMR yield of 49% has
been observed with the previous conditions, was isolated in 80%
yield after column chromatography. 1-Azabicyclo[1.1.0]butane 4a
was isolated in 94% and 81% yield using sec- and n-BuLi as the
base, respectively (Scheme 3). The yield was also significantly
higher for 4u (65%). Under the intensified conditions, amine 4v
could also be prepared, as well as the azetidine boronic ester 8.
Importantly, the continuous flow procedure proved to be
sufficiently robust: a long run experiment using benzaldehyde as
electrophile revealed that that the continuous flow reactor can
produce a constant yield of 70-75% of 4k over a 4 h period (see
Figure S2 in the Supporting Information), with a productivity of ca.
9 mmol/h for a 3.7 mL reactor.
Scheme 3. Continuous flow synthesis of C3-functionalized 1-
azabicyclo[1.1.0]butane under intensified conditions. Isolated yields after
column chromatography are shown.
In conclusion, in this work we have demonstrated that with the aid
of flow technology it is possible to develop a straightforward
protocol for the generation of strained 1-azabicyclo[1.1.0]butane,
its C3-lithiation and further electrophilic functionalization in a
single machine that executes the three-step telescoped sequence.
The process has proven to be robust, and a new class of strained
azacycles was made available for further use as click reagents for
bioconjugation chemistry,14 and as precursors of functionalized
azetidines.
Acknowledgements
This research was supported by the project MISE, Horizon 2020
(PON 2014/2020 FARMIDIAB “code 338”) and the University of
Bari (Fin. Ateneo Degennaro2019). The CC FLOW Project
(Austrian Research Promotion Agency FFG 862766) is funded
through the Austrian COMET Program by the Austrian Federal
Ministry of Transport, Innovation and Technology (BMVIT), the
Austrian Federal Ministry for Digital and Economic Affairs
(BMDW), and the State of Styria (Styrian Funding Agency SFG).
Keywords: Flow chemistry • Flash Chemistry • Organolithiums •
Strained azacycles • Azetidines
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Entry for the Table of Contents
Strained….in Flow! The first telescoped continuous flow protocol for the generation, lithiation, and electrophilic trapping of 1-
azabicyclo[1.1.0]butane is reported. Several structurally unique C3-functionalized 1-azabicyclo[1.1.0]butanes were prepared using
this strategy starting from readily available starting materials. ……
Institute and/or researcher Twitter usernames: @KappeLab, @luisi_lab
6
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