High throughput mechanochemistry: Application to parallel synthesis of benzoxazines

Article abstract of DOI:10.1039/c7cc07758k

We describe herein an unprecedented mechanochemical "parallel synthesis" of 3,4-dihydro-2H-benzo[e][1,3]oxazine derivatives via a one pot three component reaction. The new milling system uses a multiposition jar (variable sizes are possible), allowing for the processing of up to 12 samples simultaneously, leading to the formation of a fungicide and a building block for polymer preparation with higher throughput compared to standard milling devices.

Full text of DOI:10.1039/c7cc07758k

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Rotolo, A. Porcheddu, F. Delogu, S. Bysouth, G. Cravotto and E. Colacino, Chem. Commun., 2017, DOI:
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DOI: 10.1039/C7CC07758K
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High Throughput Mechanochemistry: Application to Parallel
Synthesis of Benzoxazines
a
a
b
c
d
a,
Received 00th January 20xx,
Accepted 00th January 20xx
K. Martina, L. Rotolo, A. Porcheddu, F. Delogu, S. R. Bysouth, G. Cravotto, * E.
Colacinoa,e,
*
DOI: 10.1039/x0xx00000x
www.rsc.org/
We describe herein an unprecedented mechanochemical “parallel might also improve throughput protocols for the preparation of
synthesis” of 3,4-dihydro-2H-benzo[e][1,3]oxazine derivatives via a samples for parallel sequencing.
one pot three component reaction. The new milling system uses a
multiposition jar (variable sizes are possible), allowing to process successfully used for co-crystal screening
up to 12 samples simultaneously, leading to a fungicide and a dispersions of carbon black pigments. Besides these few
building block for polymer preparation with higher throughput examples, nothing is presently known about the use of this high
A
modified multisample planetary mill19 has been
20, 21
and to prepare
2
2
compared to standard milling devices.
throughput experimentation technique in mechanically
activated organic reactions. In this regard, we have developed a
new “parallel synthesis” via a mechanochemical approach” to
provide rapid and efficient synthesis of molecules of interest. To
demonstrate the usefulness of this technique to our ongoing
In the past decades, the search for cleaner and more sustainable
approaches to chemical synthesis has led to the rebirth of
1
,
2
interest mechanochemistry
for the preparation of
molecules3 and materials, as a fully effective key strategy for
-6
7, 8
23
research work, preparing added value products for industry,
9
new synthetic opportunities altering product selectivity or
23, 24
including Active Pharmaceutical Ingredients (APIs)
we
leading access to products elsewhere impossible to be obtained
synthesized library of substituted 3,4-dihydro-2H-
a
by other methods.1
0, 11
Tools for real-time mechanistic studies
benzo[e][1,3]oxazines by “parallel mechanochemistry”. 3,4-
Dihydro-2H-benzo[e][1,3]oxazines are scaffolds of industrial
relevance, which are widely used for preparing polymers, resins
(
by X-ray powder diffraction or Raman spectroscopy
1
2-14
15,
techniques)
1
or the use of extruders for scale-up purposes
6
were successfully achieved. While the investigation of kinetics
25
and cross-linking agents. These substrates are also suitable
and energetics17, 18 involved in mechanochemical processes are
still in infancy, with synthetic mechanochemistry, the main
limitation on the use of standard ball mills concerns their low
throughput. The development of advanced mechanochemical
devices, where many samples are milled in parallel will increase
throughput, enabling the rapid investigation of multiple
experimental parameters at the same time. In addition, they
26
building blocks for the design of biologically active compounds
from herbicides and fungicides to therapeutically usable
27
drugs.
The development of this new synthetic methodology will be
set-up in two distinct phases. First, the main advantages and
technical aspects of the new enabling device will be described,
whereas later the high throughput mechanochemical
preparation of 3,4-dihydro-2H-benzo[e][1,3]oxazine derivatives
via a one-pot three-component reaction will be examined. The
syntheses were executed using a new planetary milling system
where a standard milling jar was modified to process up to 12
a.Dipartimento di Scienza e Tecnologia del Farmaco and NIS, Centre for
Nanostructured Interfases and Surfaces, University of Turin, via P. Giuria 9, Turin,
1
0125, Italy. E-mail: giancarlo.cravotto@unito.it
19
samples simultaneously, depending on the size of the vial.
b.
c.
Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari,
Cittadella Universitaria, SS 554 bivio per Sestu, 09028 Monserrato (Ca), Italy
Dipartimento di Ingegneria Meccanica, Chimica, e dei Materiali, Università degli
Studi di Cagliari, via Marengo 2, 09123 Cagliari, Italy
Indeed, adapters with 4-, 8- and 12-positions can hold vials with
various capacity including 100 mL, 20 mL and 2 mL respectively
(Figure 1). This will allow a mill with four adapters, for example
to hold up to 48 samples which can be then milled in parallel
d.
e.
Automaxion SARL, L’Auvrairie, 50250 Varenguebec, France
Université de Montpellier, Institut des Biomolécules Max Mousseron (IBMM)
UMR5247 CNRS-UM-ENSCM, Université de Montpellier, cc1703, Place Eugène
Bataillon, 34095 Montpellier Cedex 05, France.
(see Supporting Information, Figure S1). All this translates in a
reduced effort and time for the screening of the optimized
reaction conditions and higher productivity of molecules per
unit of time.
Email :evelina.colacino@umontpellier.fr
Electronic Supplementary Information (ESI) available: Experimental procedures and
spectral data for compounds 1-14. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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The multisample device offers other advantages, such as: i) parameters for the preparation of three different compounds
View Article Online
DOI: 10.1039/C7CC07758K
(1-3, Table 1) significantly reduced the optimization time and
no cleaning or cross contamination of the jars, since the
reactants are milled directly in the vials, (in which the reaction costs associated therewith.
mixture can be also stored or analyzed directly through the vial
glass by Raman, avoiding loss of samples; ii) many small
amounts of samples (only 10’s of mg) can be reacted at the
same time; iii) the aluminum vial adapters serve as heat sinks,
minimizing sample heating and iv) vials can be periodically
loaded and unloaded during the experiment, thus processing
hundreds of samples per day. For the experiments described in
this study, 8- or 12-position vial adapters, to hold respectively
2
0 mL or 2 mL glass vials, were used (Figure 1b, c) and the
effectiveness of the planetary milling system was investigated
for the preparation of a library of substituted 3,4-dihydro-2H-
benzo[e][1,3]oxazines (Table 1). Hanusa’s formalism was used
to represent the reaction activated by mechanochemical
energy.28
Figure 2. Schematic representation of a) ‘lunar movement’19 and b) variation of force
intensity depending on the position of the vials.
Indeed, twelve experiments were performed at the same time,
by milling the reactants at 550 rpm for 4 hours, using four
different reaction conditions for preparing each benzoxazine 1-
3
(Table 1). All the experiments were performed in a 12-position
adapter holding 2 mL glass vials each one containing 60 stainless
steel balls (Ø 1 mm) using: i) stoichiometric quantity of
paraformaldehyde (2 equiv.); ii) an excess of paraformaldehyde
(
up to 4 equiv.); or in the presence of grinding additives such as
Figure 1. a)
A
multisample planetary mill. For more details visit
29
24, 30
http://www.automaxionltd.com/; b) 12 position jar hosting 2 mL GC/LC glass vials; c) 8 iii) NaCl (100 mg); or iv) polyethylene glycol
position jar hosting 20 mL glass vials.
(PEG) HO-PEG-
2
000-OH (450 mg/mmol of substrate). Full conversion of
starting materials was observed after 4 hours of milling at 550
The motion of the vials differs from the motion of the vessel in rpm with a two-fold excess of paraformaldehyde. Lower
a conventional planetary mill, where the jar is located in the rotation speeds or shorter reaction times were detrimental,
center and it turns around its own axis and simultaneously leading to partial conversion of the reactants and uncomplete
counter-clockwise around the principal wheel axis. With a intramolecular cyclization reactions. ‘Diluted solid solutions’ of
multi-position jar or adapter, the movement was referred to as reactants, in the presence of NaCl, required longer reaction
‘
lunar’:19 vials are distributed around the jar periphery and times (6-8 hours) to achieve a full conversion of substrates,
experience a degree of rotation around an axis which is while the conversion, reaction time and yields were not
different from the vial axis, while counter-rotating around the affected or improved when HO-PEG-2000-OH was used as
same principal ‘sun’ wheel axis (Figure 2a). The force on a additive, except for benzoxazine
3, obtained in traces in the
bead in the vial varies during the rotation: when the vials are absence of PEG polymer. In a second set of experiments, the
closer to the center of the sun wheel, the force is less, when preparation of benzoxazines 1-3 was investigated using an 8-
closer to the outer edge, the force is greater and equal to those position adapter holding 20 mL glass vials, with 60 glass balls (Ø
in a conventional planetary system where the beads are always 3 mm), milling at 550 rpm for 4 h. The aim was to study not only
towards the outer edge of the sun wheel and therefore the scalability of the reaction, but also its outcome as a function
experience constant force (Figure 2b). 3,4-Dihydro-2H- of the size and the nature of material used (stainless steel or
benzo[e][1,3]oxazines were prepared in a one-pot cascade glass) for the milling balls and the geometry of the milling jars.
sequence by condensation/Mannich base ring-closure reactions We found that the same yields were obtained for benzoxazines
involving stoichiometric quantity of phenol (or o-allyl phenol), 1-3, independently on the process parameters used to achieve
paraformaldehyde and a primary amine (aromatic, allylic or the condensation/Mannich base ring-closure reactions. The
benzylic). The possibility to screen simultaneously four different
2
| J. Name., 2012, 00, 1-3
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multisample planetary mill allowed the optimization of the benzoxazines in solution, depending on the nature of the
View Article Online
DOI: 10.1039/C7CC07758K
reaction conditions by processing more than 60 experiments in product to be obtained.
less than one week compared to 6-8 weeks expected when
using a conventional mill. Once the general protocol was
Table 1. Comparative data for mechanochemical and solution synthesis of 3,4-dihydro-
2H-benzo[e][1,3]oxazines 1-14.
developed, it was extended to other substrates allowing faster
and more efficient preparation of library of diverse
a
benzoxazines 1-14 (Table 1). Worthy of note is N-
allylbenzozaxine 13, an attractive scaffold used as starting
material for the preparation of polybenzoxazines, which are
interesting polymers with excellent mechanical properties and
high thermal stability.3
1, 32
Contrary to methods in solution,
33
Yield (%)a
Multiposition
the reaction yield using mechanochemistry is not influenced by
the effect of the electronic or steric nature of R substituents on
2
In
R1
R2
Compound
1
Ball-milling
solution
5643
the primary amine, for both series having R = H (Table 1,
H
C
4
H
6
-p-NO
2
1
45
65
compounds 1-6
compounds 9-12 and 14), with the exception of benzoxazines
and 10. In the last case, the modest yields in both series are
, 8
and 13) or R1 = allyl group (Table 1,
H
H
H
H
C
4
H
6
-p-OCH
-p-Br
-p-CH
3
2
3
4
5
6
7
8
9
10
11
12
13
14
7444
32
63
62
52
51
n.d.
n.d.c
n.d.
72
7
,
b
44
C
C
4
H
6
67
1
4
5
5
4
H
6
3
65
73
75
50
77
43
23
58
50
45
37
likely due to the presence of electron withdrawing nitro group,
reducing the nucleophilicity of the nitrogen atom of the
substituted aniline, involved in the first step of the mechanism,
where a condensation reaction with the aldehyde occurs.
Nevertheless, for the same R substituents, yields depended of
the nature of R ortho-substitution on starting phenol (R = H or
4
H
H
CH
-p-CH
-o-I
2
Ph
CH
2
CH=CH
H
CH CH=CH2
2
C
4
H
6
3
c
C
4
H
6
2
2
C H -o-I
4
6
1
1
c
CH
CH
CH
2
2
2
CH=CH
CH=CH
CH=CH
H
2
2
2
C
4
H
6
-p-NO
Ph
2
1
31
allyl), leading to better yields when R = H (compounds
1
,
2
,
4
,
6
c
CH
CH CH=CH
-p-OCH
2
Ph
n.d.
62
35
and
8 vs compounds 7, 9, 10, 12 and 14). This is in agreement
46
2
2
with previous reports on the synthesis of benzoxazines in
solution, highlighting the key role played by both the reactivity
of phenolic hydroxyl as well as the electron density of the
CH
2
CH=CH
2
C
4
H
6
3
a
Isolated yield. The reaction scale was: a) for 2 mL glass vials (each vial containing
aromatic carbon atom at the free ortho-position in the phenol 60 stainless steel balls of Ø 1 mm): alcohol (0.53 mmol), paraformaldehyde (2.12
3
4, 35
mmol), amine (0.53 mmol), b) for 20 mL glass vials (each vial containing 60 glass
ring.
To investigate the effect of forces generated during
balls of Ø 3 mm): alcohol (3.19 mmol), paraformaldehyde (12.74 mmol), amine
milling and how the total mechanical energy transferred to the
powder influence the outcome of a mechanochemical
reaction,3
b
(
3.19 mmol); HO-PEG-2000-OH (450 mg/mmol of substrate) was used; c n.d. =
never described.
, 4, 36-38
benzoxazines 1 and 2 were also prepared by
milling the reactants for 4 hours in a vibrational (VBM, at 30 Hz)
Table 2. Influence of the technical parameters for the preparation of benzoxazines 1
or in a classic planetary mill (PBM, at 550 rpm). Stainless steel and 2.
or zirconia jars were used and the results were compared with
those obtained when the reactants were milled in 20 mL glass
vials, using the multiposition mill (Table 2). As we observed
when using the multisample mill, full conversion of the starting
Yield (%)a
Planetary
Ball Mill (PBM)
Multiposition
Glass vialsb
Vibrating
Ball Mill (VBM)
Classic
materials was observed when using VBM or classic PBM.
Benzoxazine was recovered in 88% after precipitation in
water, while benzoxazine was obtained in 20% after
jarc
Stainless steel jarsd
Compound
ZrO
2
1
1
2
45
65
0
0
88
20
2
extraction and purification on column chromatography. In the
last case, yield was hampered by the formation of many polar
unidentified by-products, never observed when using glass vials
which produce cleaner reaction profiles, even with glass or
Isolated yield; b,c,d The reaction was performed for 4 hours in: b 20 mL jars
c
containing 60 glass balls (Ø 3 mm) each at 550 rpm 45 mL jar with 11 balls (Ø 12
d
mm) at 550 rpm; 10 mL jar containing 6 balls (Ø 5 mm) at 30 Hz.
stainless steel balls (Table 2). Benzoxazines
1
and
2
could not be
Attempts to prepare benzoxazines by solventless methods
obtained when the milling was performed in a zirconia jar, upon heating,47 by microwaves 45 or using more eco-friendly
despite the full conversion of substrates, maybe due to the procedures in alternative solvents such as PEG48 (yields were
formation of polybenzoxazine network via a thermally induced not given) were also described, but no examples of
ring-opening polymerization side-reaction.3
9-41
The reversible
mechanochemical activation were reported so far.
heterolytic scission of the cyclic N,O-acetal moiety is thermally
or catalytically induced, leading to phenolic structures by a
We strongly hope that our contribution will stimulate the
2
Mannich base bridge [-CH
2
-N(R )-CH
2
-], very similar to development of this high-throughput device enabling a time-
42
traditional phenolic resin network polymer. It is also worth efficient approach for data gathering and a higher productivity
noticing that diverse procedures (choice of the solvent, reaction for the preparation of libraries, compared to classic planetary
time, temperature) were reported for the preparation of mills.
This journal is © The Royal Society of Chemistry 20xx
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,
2014, 16, 1628−1632.
DOI: 10.1039/C7CC07758K
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