A continuous flow approach for the C-H functionalization of 1,2,3-triazoles in γ-valerolactone as a biomass-derived medium

Article abstract of DOI:10.1039/c8gc01115j

Herein we report an efficient procedure for the C-H functionalization of 1,2,3-triazoles in a continuous flow regime applied to a variety of functionalities and to the inter- or intramolecular versions of the process. The continuous-flow protocol is based

Full text of DOI:10.1039/c8gc01115j

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A continuous flow approach for the C–H functionalization of 1,2,3-
triazoles in γ-valerolactone as biomass-derived medium
Francesco Ferlin,a Lorenzo Luciani,a Stefano Santoro,a Assunta Marrocchi,a Daniela Lanari,b
Alexander Bechtoldt,c Lutz Ackermann,c Luigi Vaccaro *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Herein we report an efficient procedure for the C–H functionalization of 1,2,3-triazoles in continuous flow regime applied
to a variety of functionalities and to the inter- or intramolecular versions of the process. The continuous-flow protocol is
based on the use of an heterogeneous catalyst (Pd/C), a soluble organic base and GVL as reaction medium. Flow
conditions allow an optimal recovery/reuse and durability of the catalyst that combined with the simple purification of the
products and the recovery of the reaction medium, make the proposed protocol operationally simple and very efficient in
terms of waste minimization as proven by low metal leaching and low associated E-factor.
www.rsc.org/
most powerful tools for the selective construction of C–C
bonds.7General approaches to metal-catalysed direct
arylations via C–H bond cleavage are generally based on the
Introduction
The 1,2,3-triazole moiety is widely represented in
pharmaceutical compounds as well as in synthetic materials.1
Therefore, it is not surprising that there is a great interest for
the development of scalable, safe and effective synthetic
protocols that would efficiently allow to access fully and
diversely decorated 1,2,3-triazoles. Heterocyclic systems fused
with a triazole ring are possibly even more interesting, as they
use of homogeneous metal catalysts and often of hazardous
organic solvents, which makes the available protocols
relatively unappealing from the sustainability point of view.
Additionally, large amounts of waste are often produced to
eliminate the high metal content from the products, in order
to fulfil the requested level of purity for the targeted
application.
find
application
in
different
fields.2
1,2,3-
Our research program aims at developing innovative C–H
functionalization methodologies8 and defining environmentally
and chemically efficient synthetic protocols to access highly
valuable materials while minimizing the waste production.9 To
this end, in recent years we made extensive use of safer
media10 and heterogeneous catalytic systems,11 often
combining these approaches using flow conditions.
triazolobenzoheterocycles represent a notable example, with
their increasing applications in drug discovery and chemical
biology.3
Regioselective syntheses of fully decorated 1,2,3-triazoles
has been made possible by the definition of effective protocols
for the azide-alkyne cycloaddition (AAC) reaction, or by using
halogenated or metalated alkynes.4 Extensive optimization has
been done and single regioisomers can be accessed by
carefully choosing the catalyst and the reaction conditions.5
Alternatively, efficient methodologies have been also
developed by exploiting the consecutive AAC reaction of
terminal alkynes and the direct C–H bond functionalization on
the pre-formed 1,4-disubstituted triazoles.6
The great advancements of the last decade in C–H
activation technologies led to the definition of some of the
Figure 1. Features of current work.
Solvents used as reaction media are responsible for
producing the largest part of the waste generated in chemical
productions.12 Therefore, the choice of a particular reaction
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medium plays a pivotal role in the search for environmentally- Furthermore, in this reaction we started to observe the
sustainable chemical methodologies.13
formation of dehalogenated product 5a. These unsatisfactory
Recently, researchers’ attention has directed towards the results prompted us to test the use of other bases, in
use of more sustainable substitutes to replace fossil derived otherwise optimal reaction conditions, namely, 5 mol % of
and toxic solvents.14 In this contest, we have been pioneering Pd/C in the presence of 30 mol % of pivalic acid in 0.5M GVL at
the use of γ-valerolactone (GVL), a chemical typically produced 120 °C (Table 2).
by hydrogenation of lignocellulosic biomass-derived levulinic
acid15 and possessing very intriguing physical-chemical
Table 1.
Comparison of bases in the cyclization of 1a.a
properties, to replace toxic polar aprotic solvents such as DMF,
DMAc and NMP in metal catalysed cross-coupling and C–H
functionalization reactions.16
We have proven that GVL is not only a safer, non-toxic and
more sustainable chemical, but it also features peculiar
chemical behaviors, such as the tendency to minimize metal
leaching from a heterogeneous catalyst, thus improving the
catalyst-recyclability.16
Entry
Base
C (%)b
Yield (%)c
In this context, we have also proven that flow chemistry can
lead to additional benefits in terms of waste minimization and
preservation of the catalyst stability and longevity.11,16a
In this contribution we report our results on the definition of
an effective, waste minimized and safe protocol for the large
scale continuous-flow preparation of fully decorated 1,2,3-
triazoles, including benzochromeno- and indolino-fused
triazoles, based on inter- or intramolecular C–H
functionalization reactions.
1
2
3
KTFA
K2CO3
TBAAc
89
90
94
82
85
87
a
Reaction conditions: 1a (1 eq, 0.5 mmol), Pd/C (5 mol %, 0.025 mmol),
MesCO2H (30 mol %, 0.15 mmol), base (2 eq, 1 mmol), GVL (1 mL).
Conversion to 2a, measured by GC analyses using samples of pure compounds as
reference. c Isolated yield of the pure product.
b
We have developed our protocol by exploiting GVL as reaction
medium and by setting custom-made flow reactors, packed
with commercially available and cheap heterogeneous Pd/C
catalyst. We have also optimized our conditions in order to set
the recovery and reuse of the metal catalyst, minimizing its
leaching into the product, and of the reaction medium, in
order to minimize dramatically the waste production.
Table 2.
Comparison of bases in the cyclization of 3aBr.a
Results and Discussion
Entry
Base
C (%)b
4a/5a
Yield (%)c
We started our investigation by testing different bases in the
representative C–H activation/intramolecular cyclization of
substrate 1a promoted by Pd/C in GVL (Table 1). Commonly
used potassium trifluoroacetate (KTFA) and potassium
carbonate gave good results in terms of reactivity (Table 1,
entries 1 and 2), but their solubility in GVL is very limited.
Moreover, the stoichiometry of the process leads to the
formation of the corresponding highly insoluble potassium
iodide. This is an important issue in the design of flow
conditions, since insoluble species would result in undesired
clogging of the system. Therefore, we shifted our attention to
tetrabutylammonium acetate (TBAAc), since alklylammonium
bases certainly feature higher solubility in organic
environments.8b TBAAc has already proved to be effective as
promoter in C–H activation processes.17 Under the selected
conditions, tetrabutylammonium acetate is effective in the
cyclization of 1a giving slightly higher yield (Table 1, entry 3)
compared to KTFA and K2CO3, with the additional advantage of
a high solubility in GVL.
1
2
3
4
5
6
7
8
KTFA
K2CO3
85
92
62
14
48
76
90
97
88/12
87/13
89/11
14/86
0/100
55/45
78/12
100/0
67
69
43
N.D.
-
TBAAc
DABCO
DBU
BEMP
38
64
87
Me-TBD
TBAAc:TBAI (1:0.6)
a Reaction conditions: 3aBr (1 eq, 0.5 mmol), Pd/C (5 mol %, 0.025 mmol),
MesCO2H (30 mol %, 0.15 mmol), base (2 eq, 1 mmol), GVL (1 mL)
b
.
Conversion to products, measured by GC analyses using samples of pure
compounds as reference. c Isolated yield of the pure product 4a.
Using bicyclic nitrogen containing bases as DBU or DABCO little
or no conversion to 4a was observed, with the main formation
of dehalogenated 5a (Table 2, entries 4 and 5). Slightly better
results were obtained using BEMP and Me-TBD (Table 2,
entries 6 and 7, respectively), but still yields were not
As expected, moving from iodinated 1a to the equivalent
brominated substrate 3aBr, lower reactivity was observed and
the use of K2CO3, KTFA or TBAAc resulted in 67%, 69% and 43%
isolated yield of 4a, respectively (Table 2, entries 1-3).
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satisfactory. A very good result was then obtained by using a in the reaction mixture traces of dehalogenated starting
combination of TBAAc and tetrabutylammonium iodide (TBAI) material (compound 5a) was also detected, suggesting that
in a 1:0.6 ratio (2 and 1.2 equivalents, respectively, relative to 100 min residence time is too long. The conditions adopted
substrate 3a), achieving a conversion to the desired product 4a ensure homogenous conditions and no clogging of the system
of 97%, with an isolated yield of 87% (Table 2, entry 8). It is was experienced.
noteworthy that under these conditions no formation of 5a
was observed.
Pd/C
Before moving towards the definition of the flow reactor
system, we also studied the recovery and reuse of the
heterogeneous catalyst. Using the optimized conditions, the
palladium leaching was quantified in each reaction run to
evaluate possible durability of the catalyst (Table 3). We
MesCO2H
base
N
R
N
N
N
R
N
N
flow reactor
X
GVL
O
H
O
120 °C
base: a TBAAc; b TBAAc/TBAI (1:0.6)
1a-d or 1a-dBr
2a-d
consistently observed
a negligible leaching of palladium
I
O
I
O
I
O
H
H
H
N
species in the reaction mixture. The good recyclability of the
catalyst was also confirmed by the constantly good product
yields obtained in five consecutive reaction runs (Table 3).
N
N
N
N
N
4-OMeC6H4
Bn
4-MeC6H4
N
N
N
a
a
a
1b
2b
, Y for
84%
1a
2a
1c
2c
, Y for
87%
, Y for 85%
Table 3.
Catalyst reuse in the cyclization of 1a.a
Br
O
Br
O
Br
O
H
H
N
H
N
N
N
N
N
Run 1
2.1
Run 2
1.8
Run 3
2.3
Run 4
1.4
Run 5
1.8
N
N
4-OMeC6H4
Bn
4-MeC6H4
N
Leaching
(ppm)
b
a
b
1aBr
, Y for
2a
82%
1bBr
, Y for
2b
80%
1cBr
, Y for 79%
2c
Yield
87 %
87 %
85 %
85 %
83 %
I
O
Br
O
H
N
H
a Conversion of 1a consistently above 95%. Reaction conditions: Pd/C (5 mol
%), MesCO2H (30 mol %), TBAAc (2 eq), GVL (0.5M)
N
N
N
nC5H11
nC5H11
N
N
.
1d, Y for 2d 91%a
b
1dBr
2d
87%
, Y for
Table 4.
Optimization of flow conditions for the cyclization of 1a.a
Scheme 1. Synthesis of chromeno-fused triazoles 2a-d in flow. Data
reported refer to the isolated yield of the pure product. Reaction
conditions: Pd/C (packed in coil flow reactor), MesCO2H (30 mol %),
TBAAc (2 eq), GVL (0.15M).
N
R
N
N
O
Pd/C
N
MesCO2H
TBAAc
R
N
N
H
flow reactor
GVL
O
I
120 °C
2a
1a R = 4-MeOC6H4
Flow rate
(mL/min)
Residence time
(min)
C
Entry
(%)b
1
2
3
4
5
1.0
0.75
0.5
20
30
65
83
40
93
0.25
0.1
80
100c
100c
100
a Reaction conditions: Pd/C (packed in coil flow reactor), MesCO2H (30 mol
b
%), TBAAc (2 eq), GVL (0.15M). Conversion of 1a to the corresponding 2a,
the remaining material was 1a, measured by GC analyses using samples of pure
compounds as referencec 87% isolated yield of the pure product.
Scheme 2. Scope of isoindoline-fused triazoles 4a-g. Data reported
refer to the isolated yield of the pure product. Reaction conditions:
Pd/C (packed in a coil flow reactor), MesCO2H (30 mol %), TBAAc (2
eq), GVL (0.15M). a A combination of TBAAc:TBAI (1:0.6) was used.
Encouraged by these results, a customized 2m coil reactor
packed with 2 grams of Pd/C catalyst dispersed in glass beads
was set in order to investigate the most adequate residence
time. The results, reported in Table 4, show that in our flow
reactor conversion is complete in 80 min of residence time.
Shorter residence time led to a mixture of product 2a with
unreacted starting material 1a. In the case of longer residence
time (100 min), conversion was complete with almost identical
results in terms of isolated yield of the pure product (87%) but
Using the same coil reactor different substrates were reacted
under the tested conditions. Our optimized flow reaction
conditions proved to be effective for a variety of iodide and
bromide substrates (1a-d and 1aBr-1dBr) leading to the
formation of different dihydrochromeno-fused triazoles
(Scheme 1) in very good yields.
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Similarly, several isoindoline-fused triazoles were Finally, in order to define a truly waste-minimized protocol for
additionally prepared with highly satisfactory yields, ranging the synthesis of fully decorated 1,2,3-triazoles, we have also
from 82% to 93%. (Scheme 2). It is noteworthy that substrate optimized the recovery of GVL by distilling the solvent from
3g was also compatible with the reaction conditions without the reaction mixture coming out of the flow reactor. At
leading to the dehalogenated product, and therefore opening reduced pressure (0.3 mbar) and 150-170 °C temperature,
the possibility for a late stage functionalization of product 4g using a Kugelrohr apparatus, GVL was recovered almost
1
quantitatively (ca. 95%). Its purity was confirmed by H- and
(Scheme 2).
We also tested our reactor and flow conditions in the inter- 13C-NMR analyses. The recovered solvent was re-used in
molecular C–H activation process leading to the continuous- subsequent reaction runs without further purification.
flow synthesis of fully decorated 1,4,5-trisubstituted 1,2,3-
Isolation of the pure product was conducted on the oily
triazoles. The results are summarized in Scheme 3. Also for this residue coming from the distillation of GVL, by re-
intermolecular process, optimal results were obtained using crystallization from acetone/water (1:20) (see ESI). It is
TBAAc as base in combination (for bromide 6b) or not with noteworthy that the entire substrate scope was performed
TBAI. In all the cases very good yields for the representative using the same coil reactor packed with Pd/C (10 % w/w
fully decorated triazoles 7a,b were accomplished (Scheme 3).
loading) (see ESI) and also with almost the same GVL
To evaluate the durability of our catalytic system we have recovered by distillation.
also measured the amounts of palladium species leached in
The use of a soluble organic base allowed performing the
the solvent passing through the packed coil reactor and it is reaction in operationally simple flow conditions and in addition
worth-noting that the amount of leached palladium is led to a considerable waste reduction compared to similar
constantly low with an average value of ca. 0.3 ppm. This methodologies employing inorganic bases. In fact, the latter
result is very valuable, since it means that the purification of inevitably require the separation of the solids from the
the product from metal residues is easier and also that the reaction mixture using classic filtration techniques and an
catalyst is very stable when packed in the flow reactor and additional aqueous washing of the solid catalyst to clean it
when operating under flow conditions. In fact, this conclusion from the inorganic salts formed. We calculated for our
is also supported by the experimental evidence given by the continuous flow protocol an E-factor as low as 24 (see ESI), a
continuous operation of our system with no reduction in result that also confirms that the flow approach combined
efficiency, change in metal leaching, or in product formation with heterogeneous catalysis can be very effective for
after more than 100 mmol, yield being constantly 87%. In flow improving the greenness of a process by minimizing waste
conditions, loss of palladium measured as leached palladium in production and make the synthetic procedure operationally
solution, represents 0.0015% of the total palladium used per 1 simpler.
mmol of substrate processed, while under batch conditions
this value is 0.16% per mmol processed (see ESI). These data Conclusion
confirm the efficiency of the flow approach in preserving the In conclusion, in this contribution we have reported a very
efficiency of a solid catalyst as it remains packed into the chemically efficient and waste-minimized procedure for the C–
reactor.
H functionalization of 1,2,3-triazoles in continuous flow
regime. The utility of the protocol is also confirmed by its
applicability to a variety of functionalities and also to the inter-
and intramolecular versions of the process.
The use of the heterogeneous catalyst (Pd/C) in combination
with a soluble organic base and GVL as reaction medium,
allowed obtaining the desired products in excellent yields and
good hourly productivity. The recovery and reuse of the
reaction medium and the durability of the catalyst make our
protocol also very efficient in terms of waste minimization as
proven by the low associated E-factor.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
Scheme 3. Scope of intermolecular C–H activation in flow. Data
reported refer to the isolated yield of the pure product.
Reaction conditions: 6a or 6b (3 eq), Pd/C (packed in coil flow
reactor), MesCO2H (30 mol %), TBAAc (2 eq), GVL (0.15M).
The Università degli Studi di Perugia is acknowledged for
financial support under the program “Ricerca di Base 2015”.
The research leading to these results has received funding
from the NMBP-01-2016 Programme of the European Union's
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ARTICLE
Journal Name
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Vaccaro, in Advanced Green Chemistry: Part 1: Greener
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