Scalable Synthesis of Benzotriazoles via [3+2] Cycloaddition of Azides and Arynes in Flow

Article abstract of DOI:10.1002/ejoc.202001543

A method for the metal-free synthesis of benzotriazoles in flow is reported. Using azides and in situ generated arynes, benzotriazoles are formed in a [3+2] cycloaddition within minutes. Employing different substitution patterns of the azide and aryne coupling partners, a modular access to benzotriazoles is provided. Thermal strain of hazardous azides and accumulation of reactive intermediates is minimized by short reaction times in flow, improving the safety profile of the process. The scalability of the reaction is demonstrated.

Full text of DOI:10.1002/ejoc.202001543

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Scalable Synthesis of Benzotriazoles via [3+2] Cycloaddition of
Azides and Arynes in Flow
Authors: Merlin Kleoff, Lisa Boeser, Linda Baranyi, and Philipp
Heretsch
This manuscript has been accepted after peer review and appears as an
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001543
Link to VoR: https://doi.org/10.1002/ejoc.202001543
01/2020

10.1002/ejoc.202001543
European Journal of Organic Chemistry
COMMUNICATION
Scalable Synthesis of Benzotriazoles via [3+2] Cycloaddition of
Azides and Arynes in Flow
Merlin Kleoff, Lisa Boeser, Linda Baranyi, and Philipp Heretsch*
M.Sc. Merlin Kleoff, B.Sc. Lisa Boeser, B.Sc. Linda Baranyi, Prof. Dr. Philipp Heretsch
Institut für Chemie und Biochemie
Freie Universität Berlin
Takustraße 3, 14195 Berlin, Germany
philipp.heretsch@fu-berlin.de
Homepage: https://www.chemie.fu-berlin.de/heretsch
Supporting information for this article is given via a link at the end of the document.
Abstract: A method for the metal-free synthesis of benzotriazoles in
flow is reported. Using azides and in situ generated arynes,
benzotriazoles are formed in a [3+2] cycloaddition within minutes.
Employing different substitution patterns of the azide and aryne
coupling partners, a modular access to benzotriazoles is provided.
Thermal strain of hazardous azides and accumulation of reactive
intermediates is minimized by short reaction times in flow, improving
the safety profile of the process. The scalability of the reaction is
demonstrated.
we here describe a scalable method for the efficient preparation
of benzotriazoles by [3+2] cycloaddition of arynes and azides in
flow (Scheme 1C).
The copper(I)-catalyzed [3+2] cycloaddition of azides and alkynes
(CuAAC) has affected chemistry, biology, and medicinal research
alike.[1] In biological systems, azides and alkynes serve as
bioorthogonal linkers allowing conjugation between two
molecules by formation of 1,2,3-triazoles.[1f,1h,2] Owing to the
toxicity of copper for living cells, copper-free [3+2] cycloadditions
are of great interest.[3] Thus, the metal-free reaction of azides with
arynes to substituted 1,2,3-benzotriazoles could allow further
applications.[4,5]
With the appearance of pathogens resistant to common azole-
based pharmaceuticals, benzotriazoles emerged as valuable
substitutes and since have been employed for antibacterial,
antifungal, and antiviral agents with remarkable potency.[4c-f,6]
Therefore, rapid and scalable access to a broad range of
functionalized benzotriazoles could further support medicinal
studies.
As described by Larock[7a] and others,[7b−f] reaction of ortho-
trimethylsilyl triflates with fluoride ions generates arynes which
undergo [3+2] cycloaddition with azides (Scheme 1A). The
resulting benzotriazoles were obtained after reaction times of up
to 24 hours. To accelerate the reaction, a microwave protocol was
developed for the synthesis of benzyl substituted benzotriazoles
but required a reaction temperature of 125 °C (Scheme 1B).[8]
As heating of organic azides and highly reactive aryne
intermediates poses the danger of an explosion, upscaling is
problematic.[9] In recent years, flow chemistry has evolved as an
alternative to overcome these limitations.[10] Given the superior
heat and mass transfer in microreactors, various reactions can be
significantly accelerated while offering an improved safety and
sustainability profile.[10–12]
Scheme 1. A) Synthesis of benzotriazoles via [3+2] cycloaddition of arynes and
azides in batch at room temperature. B) Microwave-assisted reaction of arynes
with in situ formed benzyl azides. C) Expedient and scalable synthesis of
benzotriazoles in flow. TBAT: tetrabutylammonium triphenyldifluorosilicate; Tf:
trifluoromethanesulfonyl; TMS: trimethylsilyl.
At the outset, we screened conditions for the reaction of benzyne-
precursor 1a with benzyl azide (2a) leading to benzotriazole 3a
(Table 1). To streamline the process and minimize thermal strain
of organic azides, we aimed for a short residence time in a heated
tube reactor.
Initially, tetrabutylammonium fluoride (TBAF) was used as a
fluoride source since limited solubility of cesium fluoride in
acetonitrile precluded its use in our flow process. At 50 °C and
with a residence time of 8 minutes, different solvents (entries 1−3)
were screened. While tetrahydrofuran (THF) and benzotrifluoride
resulted in low yields, employing acetonitrile as solvent, 3a was
isolated with a moderate yield of 53%. When potassium fluoride
and 18-crown-6 were used, almost no product was obtained
We have recently developed a flow platform for the synthesis of
natural products and their analogs. Reagents are driven with
argon instead of solvent to reduce solvent and reagent waste from
drying- and equilibration procedures.[13,14] Using this flow platform,
(entry
4).
Switching
to
tetrabutylammonium
triphenyldifluorosilicate (TBAT) as a fluoride source gave smooth
1
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10.1002/ejoc.202001543
European Journal of Organic Chemistry
COMMUNICATION
conversion to benzotriazole 3a and an improved yield of 74%
(entry 5). Further investigation of parameters revealed
a
residence time of 8 min at 40 °C led to an incomplete reaction
(68% yield, entry 6). At higher temperatures, complete
consumption of starting material was observed, but lower yields
were obtained (entries 7 and 8).
Employing higher flow rates and a shorter residence time of
4 minutes at 50 °C, incomplete conversion of starting material
was observed along with a lower yield of 64% (entry 9). Eventually,
when 1.7 equivalents of benzyne precursor 1a and
1.8 equivalents of TBAT were used, the yield of benzotriazole 3a
could be increased to 87% (entry 10). In accordance with our
previous studies, the reaction could be performed without
exclusion of air and moisture.[13a]
Table 1. Optimization of the [3+2] cycloaddition of benzyne and benzyl azide in
a flow reactor.
Entry
Fluoride
source
Solvent
T [°C]
Yield [%]
1
TBAF
TBAF
TBAF
KF/18-c-6
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
THF
50
50
50
50
50
40
55
60
50
50
30
33
53
3
2
PhCF3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Scheme 2. Scope of benzotriazoles 3a–k for the reaction of benzyne with
organic azides 2. Yields of isolated product are given. Reaction conditions: 1a
(0.34 mmol, 0.17 M, 1.7 equiv), 2a–k (0.2 mmol, 0.1 M, 1.0 equiv), TBAT
(0.36 mmol, 0.18 M, 1.8 equiv), 50 °C, 8 min. For further details, see the
Supporting Information. [a] Employing 1a (0.34 mmol, 3.4 equiv, 0.17 M), 2e
(0.1 mmol, 1.0 equiv, 0.05 M), and TBAT (0.36 mmol, 3.6 equiv, 0.18 M).
3
4
5
74
68
72
66
64
87
6
7
1,1’-Diazidoferrocene 2e is a valuable building block for redox-
switchable catalysts and sensors.[15,16] Due to the explosiveness
of 2e at temperatures above 56 °C,[15] synthetic applications are
limited, especially on larger scale. However, in flow, azide 2e
could be used without safety concerns. When 1.7 equivalents of
benzyne precursor 1a were employed, mono-benzotriazole 3e
was isolated in a moderate yield of 37%. Using 3.4 equivalents of
benzyne precursor 1a and 3.6 equivalents of TBAT,
dibenzotriazole 3f was obtained in 38% yield. The alkynyl
substituted ferrocenyl benzotriazole 3g was isolated in 67% yield.
Although, alcohols can react as nucleophiles with arynes, the
[3+2] cycloaddition of alcohol substituted azide 2h gave
benzotriazole 3h with a good yield of 72%. The enantioenriched
benzotriazole 3i (51% yield) was derived from the corresponding
menthyl azide under retention of stereoconfiguration.
8
9[a]
10[b]
Yields of isolated product are given. Reaction conditions: 1a (0.3 mmol, 0.15 M,
1.5 equiv), 2a (0.2 mmol, 0.1 M, 1.0 equiv), TBAT (0.32 mmol, 0.16 M,
1.6 equiv); flow rate: 0.4 mL, 8 min. [a] Performed with a residence time of
4 min. [b] Performed with 1.7 equiv of 1a and 1.8 equiv of TBAT. 18-c-6:
1,4,7,10,13,16-hexaoxacyclooctadecane; THF: tetrahydrofuran.
With the optimized flow protocol in hand, the scope of the [3+2]
cycloaddition of benzyne with various azides was investigated
(Scheme 2). Despite the intriguing properties of ferrocenyl
benzotriazoles,[4d] they have not been prepared from arynes and
ferrocenyl azides, thus far.[12b] This may be attributed to the
potential explosiveness and thermal lability of ferrocenyl azides,
hampering their use in reactions at elevated temperature.[15]
Employing our flow protocol, reaction of azidoferrocene 2b
provided the corresponding ferrocenyl benzotriazole 3b in a good
yield of 81%. Also, the bromo- (3c, 80% yield) and the ester-
functionalized ferrocenyl benzotriazoles (3d, 68% yield) could be
obtained.
Eventually, heterocyclic azides were tested as substrates. The
5,6-dihydro-2-oxazine 2j was prepared by aza-Michael addition of
6H-1,2-oxazine with sodium azide in protic solvents (see the
Supporting Information).[17] Cycloaddition with benzyne gave the
corresponding benzotriazole 3j in a yield of 55%.
2
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10.1002/ejoc.202001543
European Journal of Organic Chemistry
COMMUNICATION
As benzotriazole substituted piperidone 3k shows promising
antibacterial and antifungal activity,[6] we aimed for its rapid and
scalable synthesis. Employing our method, we prepared 3k in a
yield of 66%. To demonstrate the scalability of our flow protocol,
we synthesized 3k also on gram scale corresponding to a
theoretical productivity of 0.33 g/h in a similar yield of 69% with
the same reactor setup.
for preparative support. We acknowledge the assistance of the
Core Facility BioSupraMol supported by the DFG.
Keywords: arynes • click chemistry • cycloaddition • flow
chemistry • nitrogen heterocycles
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Scheme 3. Scope of benzotriazoles 4a–f for the reaction of various arynes 1b‒
g with benzyl azide 2a. Yields of isolated product are given. Reaction conditions:
1b‒g (0.34 mmol, 1.7 equiv, 0.17 M), 2a (0.2 mmol, 0.1 M), TBAT (0.36 mmol,
1.8 equiv, 0.18 M), 50 °C, residence time: 8 min.
[5]
Finally, we investigated the scope of arynes by using
functionalized aryne precursors 1b‒g (Scheme 3). When electron
deficient aryne precursor 1b was employed, difluorinated
benzotriazole 4a was isolated in 56% yield. The sesamol-derived
aryne precursor 1c reacted smoothly to benzotriazole 4b in a
good yield of 75%. Using fluorinated aryne precursor 1d, an
inseparable mixture of the 5- and 6-fluoro isomers of
benzotriazole 4c (61% yield) was obtained in a 3:1 ratio. In
contrast, reaction with ortho-substituted precursors 1e‒g
selectively gave the 4-functionalized benzotriazoles 4d‒f (60‒
71% yield), as assigned by nOe spectroscopic analysis.
In conclusion, we have developed a flow protocol for the metal-
free synthesis of benzotriazoles by [3+2] cycloaddition of azides
and in situ generated arynes. Due to the short residence time of
8 minutes, thermal strain is minimized enhancing the safety and
efficiency of this protocol. A variety of functionalized azides and
arynes have been employed to provide the corresponding
benzotriazoles, including the gram-scale preparation of an
antibacterial benzotriazole.
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Financial support for this work was provided by the Boehringer
Ingelheim Stiftung. We are grateful to Dr. Johannes Schwan, Dr.
Reinhold Zimmer, and Nicole Fouquet (all Freie Universität Berlin)
3
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10.1002/ejoc.202001543
European Journal of Organic Chemistry
COMMUNICATION
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Linda Baranyi was born in 1993 in Furth im
Wald, Germany. She studied chemistry at
the Humboldt-Universität zu Berlin where
she received her B.Sc. in 2018. Currently,
she is conducting her master studies in
chemistry at Freie Universität Berlin.
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Philipp Heretsch was born in Lippstadt,
Germany, in 1982. He obtained his PhD
degree from Universität Leipzig (supervisor:
Prof. Dr. A. Giannis) in 2009. After a
[14] M. Kleoff, J. Schwan, M. Christmann, P. Heretsch, ChemRxiv 2020, DOI:
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postdoctoral stay with K.C. Nicolaou at The
Scripps Research Institute, La Jolla,
[15] A. Shafir, M. P. Power, G. D. Whitener, J. Arnold, Organometallics 2000,
19, 3978‒3982.
California, and at Rice University, Houston,
Texas, he was appointed assistant professor
at Freie Universität Berlin in 2015. His group
is interested in framework manipulation
strategies in the context of abeo-steroid and
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alkaloid synthesis as well as application of flow chemistry in natural
product synthesis.
Merlin Kleoff was born in Berlin, Germany, in
1994 and studied chemistry at Freie
Universität Berlin where he received his
B.Sc. in 2015. During his Master studies, he
worked with Prof. Dr. H.-U. Reißig on the
preparation of super Lewis basic terpyridine
ligands. In 2018, he completed his M.Sc.
with a thesis on the synthesis of new
ferrocene building blocks in the group of
Prof. Dr. B. Sarkar. He then joined the group
of Prof. Dr. P. Heretsch for his PhD where
he is currently working on synthetic applications of flow chemistry.
Lisa Boeser was born in Berlin, Germany, in
1998 and studied chemistry at Freie
Universität Berlin. She completed her B. Sc.
with a thesis on the scalable synthesis of
ferrocenyl azides in flow in the group of Prof.
Dr. P. Heretsch in 2019. Currently, she is
conducting her master studies at Freie
Universität Berlin.
4
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10.1002/ejoc.202001543
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Substituted benzotriazoles are prepared from arynes and azides in a metal-free [3+2] cycloaddition within minutes. Using a flow
reactor, thermal strain of hazardous azides is minimized for a readily scalable and safe process.
Twitter username: @HeretschPhilipp
5
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