Facile azide formation via diazotransfer reaction in a copper tube flow reactor

Article abstract of DOI:10.1016/j.tetlet.2015.02.036

A copper tube flow reactor is used in the conversion of primary amines into organic azides using imidazole-1-sulfonyl azide hydrogen sulfate. The catalyst is generated in situ from the metallic copper. The reaction can be quenched in acidic environment or via a cycloaddition of the azides formed with an alkyne. The possibility to perform this azide-alkyne cycloaddition using the copper released from the reactor is demonstrated with the synthesis of both a 1,2,3-triazole derivative of benzylamine and of a more complex BODIPY-DOTA adduct.

Full text of DOI:10.1016/j.tetlet.2015.02.036

Accepted Manuscript
Facile Azide Formation via Diazotransfer Reaction in a Copper Tube Flow Re-
actor
Koen Nuyts, Matthias Ceulemans, Tatjana N. Parac-Vogt, Geert Bultynck, Wim
M. De Borggraeve
PII:
S0040-4039(15)00306-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.02.036
TETL 45904
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
21 January 2015
4 February 2015
10 February 2015
Please cite this article as: Nuyts, K., Ceulemans, M., Parac-Vogt, T.N., Bultynck, G., De Borggraeve, W.M., Facile
Azide Formation via Diazotransfer Reaction in a Copper Tube Flow Reactor, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.02.036
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Koen Nuyts, Matthias Ceulemans, Tatjana N. Parac-Vogt, Geert Bultynck, Wim M. De Borggraeve

1
Tetrahedron Letters
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Facile Azide Formation via Diazotransfer Reaction in a Copper Tube Flow Reactor
a
a
a
b
Koen Nuyts , Matthias Ceulemans , Tatjana N. Parac-Vogt , Geert Bultynck and Wim M . De
a
Borggraeve ∗
a
Molecular Design and Synthesis, KU Leuven – University of Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
b
Laboratory of Molecular and Cellular Signaling, KU Leuven – University of Leuven, O&N I Herestraat 49, 3000 Leuven, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A copper tube flow reactor is used in the conversion of primary amines into organic azides using
imidazole-1-sulfonyl azide hydrogen sulfate. The catalyst is generated in situ from the metallic
copper. The reaction can be quenched in acidic environment or via a cycloaddition of the azides
formed with an alkyne. The possibility to perform this azide-alkyne cycloaddition using the
copper released from the reactor is demonstrated with the synthesis of both a 1,2,3-triazole
derivative of benzylamine and of a more complex BODIPY-DOTA adduct.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
Diazotransfer reaction
Flow chemistry
Azides
Copper reactor
1
-4
Flow chemistry is a useful tool for the synthetic chemist.
continuous flow conditions, it was found that it was possible to
catalyze the reaction by using copper turnings. Oxidation of
metallic copper under the influence of a sulfonyl azide results in
The ease with which flow reactors can be constructed by utilizing
standard tubing, connector pieces and syringe pumps, the
possibility to tightly control reaction time and reaction
temperature, the small quantities of product required for
optimization are great advantages. Furthermore, safety issues
such as toxicity and explosive decomposition of reagents are
the formation of
a
catalytic active Cu(II)-sulfonylamide
21, 22
complex.
This prompted us to investigate the possibility to
perform this reaction under flow conditions using a copper tube
reactor. The use of metallic copper as a source of an ionic
catalyst system has previously been demonstrated, e.g. in the
1-5
mitigated by the closed system and small reaction volumes.
2
3, 24
The latter argument shows great potential for flow chemistry in
the synthesis of organic azide.
synthesis of 1,4-disubstituted 1,2,3-triazoles.
The use of
copper flow reactors has already been successfully applied in the
synthesis of 1,4-disubstituted 1,2,3-triazoles and several coupling
Organic azides are a class of compounds with potential highly
25-40
6
reactions.
To the best of our knowledge, the application of
toxic and explosive properties. Despite these attributes they are
7
copper tube flow reactors was not reported for the diazotransfer
reaction.
valuable and versatile intermediates in organic synthesis.
Organic azides can be synthesized from primary amines via a
8
, 9
diazotransfer reaction. Triflyl azide is most commonly used as
-
Figure 1 -
1
0
a diazotransfer reagent. Its short shelf life and highly explosive
1
1, 12
A general procedure was developed via the optimization of the
synthesis of γ-azidobutyric acid (2) starting from γ-aminobutyric
acid (1) and ISA·H SO (Scheme 1). A 500 µL internal volume
2 4
reactor was constructed using copper GC tubing (Figure 1). The
reactor was connected to two syringes via a T-mixing piece. A
nature in neat form render this product rather unattractive.
The introduction of imidazole-1-sulfonyl azide (ISA) and more
recently its hydrogen sulfate salt (ISA·H SO , Scheme 1) as a
stable, easy to prepare and manipulate reagent has given the
2
4
1
3-19
diazotransfer reaction a whole new set of applications.
1
0:3:3 mixture of methanol:dichloromethane:water was chosen
-
Scheme 1 -
as the solvent since this monophasic mixture is reported to result
in a minimal precipitation of salts from the diazotransfer reaction.
Recently, the possibility to perform the diazotransfer reaction
under continuous flow conditions has been demonstrated by
7, 41
This mixture also proved to have better solvating properties
2
0
for the reagents used. The amine and diazotransfer reagent were
dissolved in separate stock solutions that were brought in two
separate syringes. Stock solution A is 145 mM in reagent 1.
Stock solution B contains a solution with variable quantities of
ISA·H SO (according to the number of equivalents needed).
Delville et al. However, issues with solubility of some of our
compounds prompted us to use a different solvent system and a
different catalyst. While screening for appropriate catalysts in
preparation of performing the diazotransfer reaction under
—
——
2
4
∗
Corresponding author. Tel.: +32-16-327693; fax: +32-16-327990; e-mail: wim.deborggraeve@chem.kuleuven.be

2
Tetrahedron
Base was added as a second component to solution A in a fixed
ratio to ISA·H SO (Supplementary Material). When the base is
premixed with ISA·H SO , premature decomposition of this
After each run the increase of the internal volume of the
2
4
copper tube reactor was checked by weighing the reactor. This
increase due to the previously mentioned oxidation of Cu(0)
amounted to less than 0,5% of the total internal volume and was
deemed insignificant.
2
4
reagent is observed in the syringe as formation of gas bubbles.
An ice bath was used to immerse the T-mixer to prevent
decomposition while combining the mixtures before bringing
them into the copper tube flow rector at room temperature. Upon
leaving the reactor the reaction mixture was directly quenched by
adding the reaction mixture to acetic anhydride. Reaction time
To verify the possibility of cascading the diazotransfer
reaction with the Cu AAC using the copper ions formed in the
reactor tube, the synthesis of compound 2b was repeated in one
continuous process. The azide of compound 2a was introduced to
a solution 1,5 equivalents of 5-chloro-1-pentyne and 1,5
equivalents of sodium ascorbate. The reaction mixture was left
stirring overnight and compound 2b was isolated in a 57%
overall yield. The same procedure was used in the synthesis of
compound 11 (Scheme 2). The azide of compound 9 could not be
isolated in batch diazotransfer reactions. Hence, azide 9b was
synthesized in situ by performing the herein developed flow
procedure in a 150 µL copper tube flow reactor. The reaction
mixture was introduced to a flask containing 1,5 equivalents of
sodium ascorbate and 1,5 equivalents of 10. The reaction was left
stirring overnight and was purified via HPLC. The previously
elusive BODIPY functionalized complex 11 was obtained in a
9% overall isolated yield starting from 9.
and equivalents of ISA·H
LC/MS (Figure 2 and Figure 3).
2 4
SO were optimized and monitored via
-
-
Figure 2 –
Figure 3-
2 4
Using less than three equivalents of ISA·H SO relative to the
amine results in incomplete conversion of the amine. At the same
time it was observed that a precipitate forms in the reactor. By
using three or more equivalents of ISA·H
alleviated. A comparable rate of amine conversion is observed
when three or four equivalents of ISA·H SO . However, overall
formation of azide is lower in the case where four equivalents are
used. Addition of five equivalents results in both lower
conversion of the amine and less formation of the azide. At
shorter retention times the amine does not completely convert to
the azide. Longer retention times result in lower yields of the
azide. This could be due to further reduction of the formed azides
2 4
SO this problem is
2
4
-
Scheme 2 –
In conclusion, a straightforward flow protocol is developed for
the synthesis of azides via a diazotransfer reaction using a copper
tube flow reactor. This procedure requires less diazotransfer
reagent, a lower retention time and no addition of catalyst to any
of the stock solutions compared to the procedure of Delville et
2
1, 42
in the presence of copper.
optimally when a retention time of the mixture in the reactor of
0-300 seconds is used. The scope and limitations were studied
at room temperature using 3 equivalents of ISA·H SO and a
Generally, the amine is converted
6
2
0
2
4
al. It was shown that the reaction proceeds with higher yields
using alkyl amines compared to aryl amines. Diazotransfer
reactions to aryl amines are more efficient if the amine is more
nucleophilic. The possibility to perform the Cu AAC using the
copper released from the system is demonstrated by the synthesis
of compound 2b and compound 11. Once constructed, the copper
tube flow reactor, the easily applicable procedure and the
possibility of cascading the diazotransfer reaction with the Cu
AAC puts a wide range of azides and 1,4-triazoles within easy
reach of a wide variety of scientists.
retention time of 300 seconds (Table 1). The reaction was
quenched by introducing the mixture to a solution of 10
equivalents of 5-chloro-1-pentyne and CuI or in a 3:1 solution of
methanol and acetic acid, resulting in the formation of the
triazole xb or azide xc respectively (Figure 4).
-
Figure 4 –
For ease of purification the ethyl ester of γ-aminobutyric acid
was used to determine the isolated yield and the acidic quench
was replaced with a quench using a mixture of 10 equivalents of
5
-chloro-1-pentyne and CuI yielding the corresponding 1,4-
Acknowledgments
triazole via a copper(I) catalyzed azide-alkyne cycloaddition (Cu
AAC). This quenches the reaction and yields a less volatile
compound. Product 1b was obtained in a 59% overall isolated
yield over the two reaction steps. Conversion of benzylamine and
Fmoc-Lys-OH proceeded with yields of 77% and 74%
respectively. The diazotransfer to compound 4a resulted in
selective transformation of the alkyl amine, leaving the hetaryl
amine intact. Product 4c was obtained in a 65% yield.
Conversion of aromatic amines proved to be more problematic
due to the instability of their corresponding azides. To prevent
this undesired degradation during purification, all the organic
azides were converted to their respective 1,4-triazoles by
introducing the reaction mixture to a 5-chloro-1-pentyne/CuI
solution. The isolated yield of these compounds decreases from
K.N. thanks the research council of KU Leuven and the
department of chemistry of KU Leuven for funding (project
OT/11/047, project OT/14/067).
Supplementary Material
Experimental procedures, characterization data.
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4
Tetrahedron
Scheme 1. Synthesis of γ-azidobutyric acid via a copper catalyzed diazotransfer reaction using imidazole-1-sulfonyl azide.
Scheme 2. Synthesis of the BODIPY functionalized complex 11 by performing a diazotransfer reaction on amine 9, followed by a
Cu AAC with alkyne 10.
Figure 1. Set up of the copper tube flow reactor.
Figure 2. Influence of the number of equivalents of ISA·H
2
SO
4
and the retention time in the reactor on the conversion of amine 1
relative to an internal standard.
2 4
Figure 3. Influence of the number of equivalents of ISA·H SO and the retention time in the reactor on the formation of azide 2
relative to an internal standard.
Figure 4. The diazotransfer reaction of xa is either quenched by introducing the mixture to a solution of 5-chloro-1-pentyne and CuI
forming triazole xb, or quenched by introducing the mixture to a 3:1 solution of methanol and acetic acid forming azide xc.
2 4
Table 1. Diazotransfer reaction at room temperature, 3 equivalents of ISA·H SO , 300 seconds retention time in a 500 µL copper
tube flow reactor. Yields are isolated yields.
Entry
Amine
Product Yield
(%)
1
2
3
4
1a ethyl 4-aminobutyrate·HCl
2a benzylamine
3a Fmoc-Lys-OH·HCl
4a
1b
2b
3c
59
77
74
65
a
4c
5
6
7
5a p-anisidine
5b
6b
7b
8b
44
26
7
6a p-toluidine
7a p-chloroaniline
8a 4-aminobenzonitrile
8
/
a
Synthesis in a 150 µL copper tube flow reactor, reaction was quenched by introducing the reaction mixture to a 3:1 solution of methanol:acetic acid.

Figure 1

Figure 2

Figure 3

Figure 4

Scheme 1

Scheme 2