Continuous multistep synthesis of 2-(azidomethyl)oxazoles

Article abstract of DOI:10.3762/bjoc.14.36

An efficient three-step protocol was developed to produce 2-(azidomethyl)oxazoles from vinyl azides in a continuous-flow process. The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl brom

Full text of DOI:10.3762/bjoc.14.36

Continuous multistep synthesis of 2-(azidomethyl)oxazoles
Thaís A. Rossa1,2, Nícolas S. Suveges3, Marcus M. Sá2, David Cantillo*1,4
and C. Oliver Kappe*1,4
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 506–514.
1Institute of Chemistry, University of Graz, NAWI Graz,
Heinrichstrasse 28, 8010 Graz, Austria, 2Departamento de Quıímica,
Universidade Federal de Santa Catarina, Florianópolis 88040-900,
SC, Brazil, 3Chemistry Institute, Federal University of Rio de Janeiro,
Rio de Janeiro, RJ, Brazil 22941-909, and 4Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010
Graz, Austria
doi:10.3762/bjoc.14.36
Received: 22 November 2017
Accepted: 08 February 2018
Published: 23 February 2018
This article is part of the Thematic Series "Integrated multistep flow
synthesis".
Email:
David Cantillo* - david.cantillo@rcpe.at; C. Oliver Kappe* -
oliver.kappe@uni-graz.at
Guest Editor: V. Hessel
© 2018 Rossa et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
azirines; continuous flow; heterocycles; oxazoles; process integration;
vinyl azides
Abstract
An efficient three-step protocol was developed to produce 2-(azidomethyl)oxazoles from vinyl azides in a continuous-flow process.
The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl bromide to
provide 2-(bromomethyl)oxazoles. The latter compounds are versatile building blocks for nucleophilic displacement reactions as
demonstrated by their subsequent treatment with NaN3 in aqueous medium to give azido oxazoles in good selectivity. Process inte-
gration enabled the synthesis of this useful moiety in short overall residence times (7 to 9 min) and in good overall yields.
Introduction
Oxazoles are an important class of five-membered aromatic important non-narcotic, non-steroidal anti-inflammatory drug
heterocycles containing one oxygen and one nitrogen atom in [6,7]. Sulfamoxole is a broad-spectrum antibiotic for the treat-
their structures. The oxazole moiety is relatively stable and is ment of bacterial infections (Figure 1b) [8]. In addition,
found widely in nature [1-3]. Naturally occurring oxazoles ongoing studies show the potential of amino and amido-
include compounds with antibiotic or antimicrobial properties oxazoles to act as fluorescent dipeptidomimetics (Figure 1c)
such as pimprinine [4] or phenoxan [5] (Figure 1a). Also many [9]. Due to their diene character, oxazoles find also use as inter-
synthetic active pharmaceutical ingredients (API) contain the mediates in the synthesis of other organic scaffolds such as
oxazole as an active moiety [1-3]. Oxaprozin, for example, is an furans and pyridines, via cycloaddition/retro-cycloaddition
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Beilstein J. Org. Chem. 2018, 14, 506–514.
[28,29]. In the latter reaction amide 5 was formed as a side-
product and the aziridine intermediate 3 was stable and could be
isolated when the reaction was carried out in non-polar solvents.
Scheme 1: Synthesis of oxazoles 4 by addition of acyl chlorides to
azirines 2, as described by Hassner et al. [28,29].
In particular, 2-(halomethyl)oxazoles 6 are a class of com-
pounds rather underexplored, even though they are frequently
key intermediates in the total synthesis of natural products
[30-32]. Recently, Patil and Luzzio reported the preparation of a
wide range of 2-substituted derivatives 7 by a simple nucleo-
philic halide displacement from 2-chloromethyl-4,5-diaryloxa-
zoles, illustrating their usefulness (Scheme 2) [33]. In a related
work, Luzzio et al. described the synthesis of 1,4-disubstituted
triazoles 8 through click reaction between 2-azidomethyl-4,5-
diaryloxazoles and alkynes in the presence of a copper(I) cata-
lyst (Scheme 2). The authors were able to synthesize an array of
small-molecule peptidomimetics that inhibited Porphyromonas
gingivalis biofilm formation [34].
Figure 1: Examples of naturally occurring oxazoles (a); some drugs
containing oxazole as the active moiety (b); general structure of fluo-
rescent dipeptidomimetics derived from trisubstituted oxazoles (c);
reactivity of the oxazole system as an azadiene (d).
tandem processes (Figure 1d) [10-13]. A classical example is
the preparation of pyridoxine (a form of vitamin B6) using this
approach [14,15].
There are several methods for the preparation of oxazoles de-
scribed in the literature. These include ring-closure reactions of
diazocarbonyl compounds with amides or nitriles [16],
α-haloketones and amides [17-19], cyanohydrins and aldehydes
(Fischer synthesis) [20,21], or oxidative additions of α-methy-
lene ketones to nitriles [22,23]. An alternative approach consists
of the ring expansion of azirines, which can be prepared from
vinyl azides 1, by the reaction with carbonyl compounds.
Substituted 2-acylazirines rearrange to oxazoles in the presence
of bases [24-26]. In addition the light-mediated synthesis of
oxazoles from azirines and aldehydes also has been described
by Lu and Xiao [27]. Hassner and Fowler described the reac-
Scheme 2: Preparation of 2-functionalized oxazoles 7 from 2-(chloro-
methyl)oxazoles 6 and their application to the synthesis of peptido-
mimetics 8.
tion of azirines 2 with acyl chlorides with formation of interme- Important drawbacks observed in the generation of compounds
diate adduct 3 to give oxazoles 4 in polar solvents (Scheme 1) of type 7 include the instability of the halide intermediate 6,
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Beilstein J. Org. Chem. 2018, 14, 506–514.
which might be difficult to isolate due decomposition reactions, vent. The experiments were carried out placing 0.5 mL of the
as well as selectivity issues during the generation of the oxazole solution in the vial, which was sealed with a crimp-cap. The
ring. It has been shown that problems associated with unstable reactions were performed at three different temperatures
intermediates or reagents can be overcome with the use of con- (130–150 °C, Table 1). Notably, at 150 °C a very fast (1 min)
tinuous-flow chemistry. Continuous-flow processing has and clean reaction (>99% purity by HPLC–UV analysis) was
demonstrated to be an ideal tool for the development of uninter- achieved.
rupted multistep reactions [35-37]. The integration of several
sequential steps can be readily achieved through a continuous
Table 1: Batch optimization of the thermolysis of vinyl azide 1a.a
addition of reagent streams, quenching, liquid–liquid extraction,
or even filtration stages, thus avoiding the handling of unstable
intermediates [35-37].
In this article we present an integrated continuous-flow proce-
dure for the preparation of 2-(azidomethyl)oxazoles 7 starting
from vinyl azides through an azirine intermediate (Scheme 3).
The process starts with the generation of the azirine from the
vinyl azide by thermolysis. Formation of azirines from vinyl
azides by photolysis and thermolysis in continuous flow has
been previously described [38,39]. The azirine intermediate is
then reacted with a 2-haloacyl halide at room temperature, to
form the 2-(halomethyl)oxazole moiety. Subsequent reaction
with an aqueous stream containing NaN3 then leads to the for-
entry
temp. (°C)
conv. (%)b
purity (%)b
1
2
3
130
140
150
88
97
>99
>99
>99
>99
aConditions: 1a in acetone (0.5 M), 0.5 mL solution in a 1.5 mL vial.
bDetermined by HPLC peak area integration at 254 nm.
mation of the desired 2-(azidomethyl)oxazole. The optimiza- Next, the formation of 2-(bromomethyl)oxazole 6a from azirine
tion of each reaction step and the integration to a fully continu- 2a was also optimized under batch conditions. All reactions
ous process are described in detail.
were carried out under an argon atmosphere using a 0.5 M solu-
tion of the substrate 2a in acetone. In general, the addition of
the reagents was performed at 0 °C in an ice-bath followed by
stirring the reaction mixture at room temperature. When tri-
ethylamine (TEA) or N,N-diisopropylethylamine (DIPEA) were
used as the base a solid formed after a few minutes in the reac-
tion mixture (Table 2, entries 1–4), probably their correspond-
ing ammonium bromide salts. Yet, good purities were achieved
employing both bases and the incomplete conversions were
ascribed to the presence of water in the reaction mixture.
For this reason, further transformations were carried out
in acetone dried over molecular sieves (3 Å). Using 1,5-diazabi-
Results and Discussion
Thermolysis of the vinyl azide and oxazole
formation. Batch optimization
The reaction conditions for the thermolysis of the vinyl azide
and the subsequent ring expansion of the intermediate azirine to
form the oxazole ring were initially optimized in batch. For
these experiments, vinyl azide 1a was used as a model sub-
strate. The small-scale batch thermolyses were carried out using
sealed 1.5 mL vials heated in an aluminum platform. A 0.5 M
solution of substrate 1a was prepared using acetone as the sol-
Scheme 3: Integrated continuous-flow synthesis of 2-(azidomethyl)oxazoles 7.
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Beilstein J. Org. Chem. 2018, 14, 506–514.
Table 2: Optimization of the reaction conditions for the generation of oxazole 6a from azirine 2a.a
entry
halide equiv
X
base (equiv)
time (min)
temp.
conv. (%)b
purity (%)b
1c
2c
3c
4c
5
1.1
1.1
1.2
1.2
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.3
Br
Br
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Br
TEA (1.1)
TEA (1.1)
DIPEA (1.1)
DIPEA (1.1)
DBN (1.1)
DBN (1.1)
DBN (1.1)
DBN (1.1)
DBN (1.1)
DBN (1.1)
–
3
30
3
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
−10 °C
rt
90
94
82
77
76
77
74
70
79
75
73
81
77
79
80
66
30
3
76
>99
>99
92
6
30
10
5
7
8d
9d
10e
11
12
13
>99
>99
>99
>99
>99
>99
5
4
1
rt
–
1
rt
–
1
rt
aConditions: 0.50 mL solution of 2a in acetone (0.5 M) was mixed with 0.50–0.65 mL of a solution of the acyl halide in acetone (0.5 M), followed by
addition of the base (0.275 mmol). bDetermined by HPLC (254 nm) peak area integration. cFormation of insoluble solid during the reaction. dBase
added after 3 min of reaction. eSubstrate added after 1 min of reaction.
cyclo[4.3.0]non-5-ene (DBN) as the base (Table 2, entry 5) full bromide. Finally, the variation of the amount of bromoacetyl
conversion of the azirine 2a was observed after 3 min reaction bromide had no significant effect on the outcome of the reac-
time. In this case the oxazole 6a was formed with 74% purity tion (Table 2, entries 12 and 13).
and no formation of solids was observed. At longer reaction
time (30 min) a slight decrease in purity could be detected, To identify the reaction byproducts formed during the coupling
probably due to slow decomposition of 6a (Table 2, entry 6). of azirine 2a and bromoacetyl bromide, the reaction was per-
The reaction with chloroacetyl chloride instead of the bromo formed on a 3 mmol scale. The reaction mixture was quenched
derivative delivered the corresponding (chloromethyl)oxazole with NaHCO3 solution, extracted with ethyl acetate and concen-
with similar selectivity, the reaction was slower though, with trated under reduced pressure. The 1H NMR analysis of the
92% conversion being achieved after 10 min (Table 2, entry 7). crude product mixture revealed three major side products.
The adjustment of other parameters such as the order of added Purification by column chromatography permitted the separa-
reactants or variation in temperature showed little influence on tion and isolation of each component (Scheme 4), which were
the outcome of the reaction (Table 2, entries 8–10). Notably, characterized by 1H NMR, 13C NMR and low-resolution mass
oxazole 6a was also formed in the absence of base (Table 2, spectroscopy. In agreement with the observations by Hassner et
entries 11–13). This was probably due to the weak basic char- al. [28,29], dibromoamide 5a and its hydrolysis product 9a were
acter of the oxazole moiety itself, producing the oxazole hydro- obtained in addition to ketoester 10a. The distribution profile
Scheme 4: Side products generated during the reaction of azirine 2a with bromoacyl bromide at room temperature.
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Beilstein J. Org. Chem. 2018, 14, 506–514.
calculated by 1H NMR peak integration revealed a composition of NaN3 in order to avoid the generation of hydrazoic acid.
of 76% product 6a, and side products in 7% (5a), 10% (9a) and Taking this into account, we decided to replace DBN by less
7% (10a), respectively. The oxazole 6a was isolated as yellow expensive DIPEA for the subsequent reactions. Using both sub-
solid (mp 76.3–78.1 °C) in 57% yield.
strates 2a and 2b, it was observed that after 5 min of reaction at
rt, the conversion of bromo oxazoles 6 into azido oxazoles 7
The optimization of the reaction conditions for the nucleophilic was up to 92% (Table 3, entries 1 and 4). When the reaction
halide displacement with sodium azide were also evaluated in temperature was increased from rt to 50 °C, good conversions
batch. A one-pot procedure starting from the azirine (without were achieved after 5 min reaction for both for the model sub-
isolation of the 2-(bromomethyl)oxazole) was utilized to simu- strate 2a and the azirine 2b (Table 3, entries 2 and 5). NaN3 was
late the conditions of an integrated process. Thus, azirine 2a not fully soluble in the reaction mixture (after mixing with the
was reacted with bromoacetyl bromide in a 1.5 mL vial using acetone medium), which would be problematic for the later
the conditions stated in Figure 2 (1.1 equiv bromide added at translation to flow conditions. Diluting the NaN3 solution from
0 °C, cf. Table 2, entry 5) in dry acetone for 3 min. Then, DBN 2.5 M to 1.5 M (and therefore adding a larger volume of the
was added to neutralize the acidic medium, followed by a 2.5 M solution to obtain the same excess of the reagent) resulted in
aqueous solution of NaN3 (1.1 equiv) and the resulting mixture fully homogeneous conditions suitable for flow processing
was stirred at room temperature. A conversion of 89% to 7a (Table 3, entry 3).
from bromo oxazole 6a with a selectivity of 74% was achieved
after 30 min (Figure 2).
Continuous-flow experiments
Azirine formation. With the optimal conditions for the three
Subsequently, the amount of NaN3 was increased to 1.3 equiv reaction steps in hand, we translated the process to continuous-
to enhance the reaction rate. During the formation of the flow conditions. For that purpose, individual continuous-flow
2-(bromomethyl)oxazoles 6 addition of a base is not required reactors for each step were setup, the reaction conditions
(see Table 2, entries 11–13). However, neutralization of the re- re-optimized when necessary, and finally all the steps inte-
sulting oxazole hydrobromide is required prior to the addition grated in a single continuous stream.
Figure 2: HPLC monitoring of the formation of 2-(azidomethyl)oxazole 7a.
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Beilstein J. Org. Chem. 2018, 14, 506–514.
Table 3: Batch optimization of the generation of 2-(azidomethyl)oxazoles 7a and 7b.a
entry
R
NaN3 conc. (M)
temp. (°C)b
conv. (%)c,d
purity (%)d
1
2
3
4
5
CH2CO2Me (2a)
CH2CO2Me (2a)
CH2CO2Me (2a)
H (2b)
2.5
2.5
1.5
2.5
2.5
rt
84
95
97
92
97
80
69
74
69
67
50 °C
50 °C
rt
H (2b)
50 °C
aConditions: 0.4 mL of a 0.5 M solution of azirine in acetone, bromoacetyl bromide injected as a 0.5 M solution. bTemperature for the reaction with
NaN3. cConversion for the nucleophilic displacement step. dDetermined by HPLC (254 nm) peak area integration.
The thermolysis of vinyl azide 1 was performed in a continu- 2b and 2c were also successfully generated from the corre-
ous flow reactor consisting of a perfluoroalkoxy (PFA) coil sponding vinyl azides (Table 4, entries 3–5).
(0.5 mL, 0.8 mm i.d.) immersed in a silicon bath at 150 °C. The
The continuous-flow setup was then extended by incorporating
a second reagent feed with a stream containing the bromoacetyl
bromide solution (0.5 M in acetone, Figure 3). A vessel was
placed between the two reaction zones to release the N2 gener-
ated during the azirine formation, which was maintained under
argon atmosphere. Using this system, the crude reaction mix-
ture obtained from the first reaction zone, containing the azirine
in acetone, was directly pumped into the second reaction zone
(500 µL/min), mixed with the bromoacetyl bromide stream in a
T-mixer, and reacted at 30 °C in a PFA tubing (1 mL volume).
Using a flow rate of 500 µL/min in the feed containing the
bromoacetyl bromide solution – corresponding to 1.0 equiv of
the bromide with respect to the starting vinyl azide – both
vinyl azide solution in acetone was introduced into the reactor
by a syringe pump (Syrris) with variable flow rates (Table 4) to
obtain different residence times. The system was pressurized
using a back-pressure regulator (BPR, Upchurch) at 17 bar
(250 psi). The reaction mixture was cooled by immersing a
second section of the coil reactor in an ice bath, to avoid
damage of the BPR by the hot reaction mixture and evapora-
tion of the solvent after the pressure release. Notably, flow rates
had to be reduced with respect to those calculated for a resi-
dence time of 1 min for the generation of azirine 2a, probably
due to an expansion of the reaction mixture from the N2 genera-
tion, which reduced the actual residence time within the coil
(Table 4, entries 1 and 2). Using the same flow setup azirines
Table 4: Continuous-flow generation of azirines 2 by thermolysis of vinyl azides 1.a
entry
R
flow rate (µL/min)b
time (min)
conv. (%)c
purity (%)c
1
2
3
4
5
CH2CO2Me (2a)
CH2CO2Me (2a)
H (2b)
500
250
250
167
500
1
2
2
3
1
98
100
91
100
100
92
H (2b)
95
94
CH2OH (2c)
100
94
aConditions: 0.5 M substrate in acetone, 5 mL reaction mixture (2.5 mmol) collected from the reactor output. bTheoretical residence time calculated
from the flow rate and reactor volume. cDetermined by HPLC (254 nm) peak area integration.
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Beilstein J. Org. Chem. 2018, 14, 506–514.
Figure 3: Continuous sequential thermolysis of vinyl azides 1 and ring expansion of azirines 2 with bromoacetyl bromide to give
2-(bromomethyl)oxazoles 6.
oxazoles 6a and 6b were obtained in full conversion, with 81% (Figure 4) containing an aqueous solution of NaN3 (1.5 M) and
and 59% purity (HPLC). Unfortunately, the oxazoles could not DIPEA, respectively. The three streams were mixed in a cross
be precipitated as hydrobromide salts even after cooling at mixer before entering a coil reactor at 50 °C (PFA tubing,
−20 °C and adding petroleum ether as co-solvent. The work-up 6 mL). While the vinyl azide thermolysis reactor zone was pres-
consisted in extraction with aqueous NaHCO3, evaporation of surized at 250 psi (17 bar), for this reactor zone 75 psi (5 bar)
the organic phase, and purification of the residue by column sufficed. Using this continuous-flow setup, azido oxazoles 7a
chromatography. Relatively poor isolated yields (42% and 35% and 7b were prepared from vinyl azides 1a and 1b in a three-
for compounds 6a and 6b, respectively) were achieved due to step sequence (azirine was not isolated, the solution of the
decomposition of the products during isolation. The decomposi- generated azirine was directly employed in the reaction de-
tion of the 2-(bromomethyl)oxazoles inside the column was scribed above). After reaction, 2-(azidomethyl)oxazoles 7a and
apparent, both when silica or neutral alumina were used as sta- 7b were purified by column chromatography, giving a three-
tionary phase.
step overall yield of 60% and 50%, respectively.
Decomposition of 2-(bromomethyl)oxazoles 6 was successfully The vinyl azide 1c was also subjected to the conditions de-
avoided by further integrating into the continuous-flow reactor scribed above. However, the reaction could not be completed
the final nucleophilic halide displacement step with NaN3. The due to solid generation in the second reactor zone (likely the
resulting 2-(azidomethyl)oxazole derivatives 7 presented higher hydrobromide salt of the oxazole). The reactor clogging could
stability and could be isolated without decomposition. Thus, not be avoided either by sonication of the tubing or increasing
two additional reagents streams were added to the flow setup the temperature to 50 °C. Thus, the reaction was performed em-
Figure 4: Continuous-flow three-step sequential synthesis of 2-(azidomethyl)oxazoles 7a–c from vinyl azides 1a–c. Yields refer to isolated yields.
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Beilstein J. Org. Chem. 2018, 14, 506–514.
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Conclusion
We have developed a continuous-flow protocol for the prepara-
tion of 2-(azidomethyl)oxazoles. The procedure consists of a
three-step sequential synthesis combining an initial thermolysis
of the starting vinyl azide to form an azirine intermediate, fol-
lowed by reaction with bromoacetyl bromide to generate the
oxazole moiety, and a final nucleophilic halide displacement
with NaN3 to give the desired product. After optimization of all
individual steps in batch and continuous-flow mode, the com-
plete sequence has been integrated in a single continuous-flow
reactor, in which the vinyl azide is fed as substrate and the final
2-(azidomethyl)oxazole is formed and collected from the
reactor output. The process avoids the isolation and handling of
the unstable 2-(bromomethyl)oxazole intermediates, thus
circumventing decomposition problems. The continuous reactor
has been tested for three different vinyl azide substrates. Good
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Acknowledgements
C.O.K acknowledges the Science without Borders program
(CNPq, CAPES) for a “Special Visiting Researcher” fellow-
ship. T.A.S. and N.S.S. are grateful to CAPES (Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior, Brazil) for
fellowships. Special thanks are due to CEBIME (Laboratorio
Central de Biologia Molecular e Estrutural, UFSC, Brazil) for
providing the mass spectra.
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