Waste-minimized synthesis of C2 functionalized quinolines exploiting iron-catalysed C-H activation

Article abstract of DOI:10.1039/d0gc03351k

Herein we present an efficient and regioselective iron-catalyzed methodology for the external oxidant-free functionalization of quinoline-N-oxides. The protocol, based on the use of inexpensive and easily accessible FeSO4, showed broad applicability to a wide range of substrates. An additional green feature of this synthetic methodology is H2O being the only by-product. Experimental and computational investigations provide support to a mechanism based on a facile C-H activation event. The green efficiency of the process has also been carefully assessed using: (i) metrics related to the synthetic process (AE, Yield, 1/SF, MRP and RME); (ii) safety/hazard metrics (SHZI and SHI); and (iii) metrics related to the metal used as the catalyst (Abundance, OEL and ADP). In addition to the many advantages of this protocol related to the green iron catalyst used and the safety/hazard features of the process, an E-factor value of ca. 0.92 (84 to >99% reduction compared to known protocols) evidently confirms the sustainable efficiency of the procedure presented. Practical utility has also been demonstrated by performing the reaction efficiently on a multi-gram scale. This journal is

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DOI: 10.1039/D0GC03351K
ARTICLE
Waste-Minimized Synthesis of C2 Functionalized Quinolines
Exploiting Iron-Catalysed C–H activation
Received 00th January 20xx,
Accepted 00th January 20xx
Francesco Ferlin, a Agnese Zangarelli, a Simone Lilli, a Stefano Santoro, a and Luigi Vaccaro *a
DOI: 10.1039/x0xx00000x
Herein we present an efficient and regioselective iron-catalyzed methodology for the external oxidant-free functionalization
of quinoline-N-oxides. The protocol based on the use of inexpensive and easily accessible FeSO4, showed broad applicability
to a wide range of substrates. An additional green feature of this synthetic methodology is highlighted being H2O the only
by-product. Experimental and computational investigations provide support to a mechanism based on a facile C−H activation
event. The green efficiency of the process has been also carefully assessed using: i) metrics related to the synthetic process
(AE, Yield, 1/SF, MRP, RME; ii) Safety/Hazard metrics (SHZI, SHI); iii) metrics related to the metal used as catalyst (Abundance,
OEL, ADP). While the many advantages of this protocol related to the green iron catalyst used and the safety/hazard features
of the process, E-factor value of ca. 0.92 (84 to>99 % reductioncompared to known protocols) evidently confirms the
sustainable efficiency of the procedure presented. Practical utility has been also demonstrated by performing the reaction
efficiently on a multi-gram scale.
C−H functionalization processes, including allylation,11
alkylation,12 arylation,13 alkynylation14 and amination
reactions.15 Despite these considerable advances, iron
Introduction
The direct C–H functionalization of quinoline-N-oxides
represents an interesting synthetic strategy,1 offering the
possibility of a direct modification of an important heterocyclic
moiety, that can be found in different bioactive molecules
(Scheme 1a) and natural products.2 Moreover, quinoline-N-
oxides also offers the opportunity to realize “external oxidant-
free” oxidative functionalizations, exploiting the inherent ability
of the N-oxide to reoxidize the catalyst, other than serving as a
weakly-coordinating directing group.3
The direct C–H functionalization of quinoline-N-oxides has been
mainly reported using different transition metal catalysts.4
Among these, palladium,3b,3e rhodium,5 copper,6 and cobalt7
catalysis has been exploited to achieve either C2 or C8
olefination of quinoline-N-oxide, and in a unique case the C2
alkenylation has been performed using an heterogeneous
catalytic system.3a In addition, alkenylation strategies also
comprise metal-free or Brönsted acid catalyzed protocols.8 In
recent years, there has been a growing interest in the
development of efficient catalytic processes based on 3d
transition metals, in place of the more expensive 4d and 5d
elements.9 In this perspective, iron represents an ideal choice,
as one of the most abundant elements in the earth’s crust and
being associated with a very low toxicity.10 Excellent recent
contributions have reported the efficiency of iron to catalyze
catalyzed C−H bond alkenylation reaction remains limited to a
few examples,16 and specifically to the use of waste-producing
organo-zinc or Grignard reagents, but with no possibility for the
direct C−H bond alkenylation. Within our program aimed at the
definition on sustainable C−H activation reactions,17 we are also
interested in the use of earth-abundant non-toxic transition
metals and in this contribution we report our result on the
definition of the first iron-catalyzed C2-selective alkenylation of
quinoline N-oxides (Scheme 1b). In terms of sustainability, this
synthetic methodology features H2O as the sole by-product with
to an excellent atom economy.
(a)
HO
N
HO
O
O
N
Cl
N
S
OH
N
O
Topotecan
(antineoplastic)
Montelukast
(anti-asthmatic)
F
HO
O
OH OH
O
OH
Pitavastatin
N
(ipercholesterol treatment)
(b)
R1
R
R
+
Fe
H
N
R1
N
O
H
2
3
a. Laboratory of Green S.O.C. – Dipartimento di Chimica, biologia e Biotecnologie,
Università degli Studi di Perugia, Via Elce di Sotto 8, 06123 – Perugia, Italy. E-
mail: luigi.vaccaro@unipg.it; http://www.dcbb.unipg.it/greensoc..
1
regioselective iron catalysis
external oxidant-free
mechanistic insight
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Scheme 1. Examples of biologically active molecules with a quinoline core and features
of iron-catalyzed C−H alkenylation.
entry
solvent
cat
C
[%]
selectivity
3a
[%]
View Article Online
b
c
DOI: 10.1039/D0GC03351K
(3a:4a)
1
2
Toluene
solvent-free
DMF
FeSO4
FeSO4
98
100:0
86
83
90
68
30
95
82
84
56
91
98
68
95:5
52:48
45:55
15:85
52:48
5:95
77
30
18
9
Results and discussion
We initially investigated various reaction conditions for the
envisioned iron-catalyzed C−H alkenylation of quinoline N-oxide
1a with methyl acrylate 2a (Table 1). After considerable
3
FeSO4
4
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
FeSO4
5
–
preliminary
experimentation
(see
also
Electronic
6
FeCl3
15
-
Supplementary Information for additional data), we observed
that FeSO4 is the most viable catalyst for the desired C−H
alkenylation of 1a. Optimal results were obtained using as little
as 1 mol% of FeSO4 in a highly concentrated toluene solution
[20M] at 100 °C for 16h (Table 1, entry 1). Very importantly, the
reaction afforded selectively the C2-alkenylated quinoline
(3a).18
Performing the reaction in solvent-free conditions or by
changing the medium to DMF or 1,4-dioxane resulted in lower
yields and most importantly in lower selectivity. In fact in these
latter cases, the formation of the hydroxylated product was
7
CuSO4
Cu(OAc)2
Pd(OAc)2
CoSO4
BrMn(CO)5
FePce
8
17:83
60:40
50:50
25:75
85:15
13
30d
23
18
12
9
10
11
12
a
Reaction conditions: 1a (1 mmol), 2a (2 mmol), catalyst (1 mol%), solvent (50 μL,
20M), 16h at 100° C. b GLC conversion has been determined using samples of pure
observed,
probably
derived
from
an
alternative
compound as reference standards. c Isolated yield. Degradation products have
d
cycloaddition/ring opening sequence.8 Conducting the reaction
without the catalyst led to very poor conversion. The use of
different iron, copper, palladium, cobalt or manganese catalysts
resulted in variable conversions and poor selectivities and
isolated yields.
been detected. e Iron(II) phthalocyanine.
Gratifyingly, quinoline-N-oxides containing either electron-
donating or -withdrawing groups were olefinated
regioselectively in good yields. Substitution at the C6 and C8
position by either methoxy or hydroxy groups, as well as 4,7-
dichlorosubstitution were tolerated, giving good results in
terms of selectivity and yields. It is worth-noting that methoxy,
chloride, and hydroxy groups are versatile functionalities that
allow for further transformations. Also, changing the alkyl
substituent on the acrylate only resulted in marginal differences
in product yields.
With the optimized reaction conditions in hand we explored its
scope (Scheme 2) by reacting a variety of quinoline-N-oxides (1)
with different acrylates (2).
Table 1. Optimization of iron-catalyzed C−H alkenylation of 1a.a
O
cat (1 mol%)
OH
+
OMe
+
H
OMe
OMe
Solvent [20M]
100 °C, 16 h
N
N
O
H
N
O
O
1a
2a
3a
4a
Next, we investigated whether the methodology is compatible
with different alkenes, other than acrylates. Indeed, the
reaction is very efficient on substituted or unsubstituted
styrene derivatives, showing also in this case excellent
compatibility with different functionalities present on the
quinoline-N-oxide, within this protocol, acid labile substrates
(6m and 6n) have been also obtained in excellent yields
(Scheme 3).
2 | J. Name., 2012, 00, 1-3
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ARTICLE
View Article Online
N
N
FeSO4 (1 mol%)
R1
FeSO4 (1 mol%)
R1
R
R
+
DOI: 10.1039/D0GC03351K
H
+
N
R1
H
Toluene [20M]
100° C, 16h
R1
N
O
H
Toluene [20M]
100° C, 16h
N
N
O
H
1 or 5
8
7
1
2
3
N
N
N
N
N
OMe
OBn
OBu
OEt
O
N
OMe
N
OBu
N
OEt
O
N
O
O
3a: 86%
3c: 88%
3b: 82%
O
O
8c:78%
8b: 75%
8a: 80%
MeO
MeO
OMe
O
OEt
N
N
N
N
N
N
N
N
O
3d: 80%
3e: 82%
O
3f: 85%
N
O
Cl
MeO
MeO
Cl
O
8d: 90%
8e: 88%
8f 92%
OBu
OBn
N
OMe
N
Cl
N
O
O
O
Scheme 4. Scope of C-H alkenylation of quinoxalines 7 and acrylates 2 or styrene 5.
3g: 78%
3h: 70%
O
3i: 87%
Cl
Cl
FeSO4 (1 mol%)
OR
OEt
OBu
N
Cl
N
N
O
H
Cl
N
N
R
Toluene [20M]
100° C, 16h
OH
O
O
3j: 85%
3k: 82%
R= Me (3l): 88%
R= Et (3m): 85 %
1a
R
R = CO2Me, 3a, 90% yield (2.78 g)
R = Ph, 6a, 98% yield (3.40 g)
(15.0 mmol, 2.25 g)
Scheme 2. Scope of C−H alkenylation of quinoline-N-oxides 1 with acrylates 2
Scheme 5. Gram-scale reactions
Mechanistic studies of iron-catalyzed reactions are particularly
challenging, for both experimental and computational
methods. Intrigued by the efficiency of the proposed
methodology, we decided to investigate its mechanism
(Scheme 6). First, we heated substrate 1a in D2O in the presence
of 1 mol% of the catalyst, observing an almost complete
deuteration of C2 in 5 hours (Scheme 6a). This result suggests
that the C−H activation event should be relatively fast. Next, we
measured the deuterium kinetic isotope effect of the reaction
by subjecting 1a and the completely deuterated anolgue 1ad7,
either in separate reactions or in one pot, to the optimized
reaction conditions (Scheme 6b and c). In both cases we
obtained a KIE ≈ 2.1. Overall, these results are compatible with
a mechanism involving a relatively fast and reversible C−H
activation step preceding an irreversible rate-determining
step.19 Furthermore, we also conducted the reaction between
1a and 2a in the presence of 1 equivalent of TEMPO and
otherwise standard reaction conditions (Scheme 6d). The
alkenylation product 3a was formed in very small amount
(12%), with the major product being quinoline 1a’. This might
indicate that the inhibiting effect of TEMPO is exerted through
a cleavage of the directing group, rather than through an
inhibition of a radical pathway.
FeSO4 (1 mol%)
R1
R
+
H
N
R1
Toluene [20M]
100° C, 16h
N
O
H
1
5
6
N
N
N
6a: 88%
6b: 86%
6c: 75%
Cl
Br
MeO
MeO
N
O
N
N
6d: 77%
O
6e: 81%
6f: 80%
Cl
Cl
MeO
Cl
N
O
Cl
N
Cl
N
O
6g: 74%
Cl
6h: 91%
6i: 86%
Cl
N
Cl
N
N
Br
OH
6k: 74%
6j: 88%
6l: 88%
N
N
O
O
OSiMe3
6n: 86%
6m: 90%
O
Scheme 3. Scope of C−H alkenylation of quinoline-N-oxides 1 with styrene 5
Furthermore, the methodology also enabled the direct
alkenylation of isoquinoline N-oxide, with excellent level of
selectivity, allowing to obtain 1-styrylisoquinoline 6k. Notably,
this iron catalyzed process has been found enable to allow the
direct alkenylation of quinoxaline N-oxide 7, and the
methodology herein reported offers, to the best of our
knowledge, a very rarely explored and step economical access
to C2-functionalized quinoxalines (Scheme 4).
The practical usefulness of the methodology is also
demonstrated by its prompt scalability, which allowed us to
perform multigram scale reactions on two differents substrates,
further improving the associated yields (Scheme 5).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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a) H/D scrambilng
DOI: 10.1039/D0GC03351K
FeSO4 (1 mol%)
+
N
H
N
O
H
D2O [5M]
100° C, 5h
N
O
D
O
3a
1a
b) Intermolecular KIE (independent reactions)
FeSO4 (1 mol%)
1a: 12%
1a-D: 88%
TS1C2
N
1a
O
O
O
Fe
O
O
N
H2O
S
H2O
D7/H7
D7/H7
B
N
O
H/D
Toluene [20M]
CO2Me
N
CO2Me
O
MeO
H2O
N
O
HO
Fe
OH
O
3a/3ad7
2a
S
Fe
1a/1ad7
O
OSO2OH
O
H2O
OH2
kH/kD= 2.09
H
H2O
C
TS3C2
c) Intermolecular KIE (one pot)
FeSO4 (1 mol%)
Toluene [20M]
D7/H7
D7/H7
N
O
H/D
N
CO2Me
N
CO2Me
2a
N
3a/3ad7
1a/1ad7
HO
Fe
kH/kD= 2.10
O
MeO
HO Fe
OH2
OSO2OH
OH2
OH
OSO2OH
HO
G
d) Radical scavenging
D
FeSO4 (1 mol%)
TEMPO 1 equiv.
N
O
H
+
N
Toluene [20M]
100°C, 16h
N
N
CO2Et
N
H
OH
OSO2OH
HO Fe
MeO2
C
CO2Me
1a'
: 88%
3a: 12%
1a
OH
OSO2OH
2a
OH2
2a
HO Fe
OH2
E
Scheme 6. Mechanistic investigation on the iron-catalyzed C−H alkenylation.
F
To gain more insight, we also studied the complete reaction
mechanism by means of DFT calculations (see Scheme 7 and
ESI). The most energetically favorable pathway involves a
reversible ligand-promoted C2 deprotonation mediated by
sulfate (TS1C2), followed by the oxidation of iron, a plausibly
rate-determining insertion of the olefin into the C2-Fe bond
(TS2C2) and a final H-abstraction to regenerate the double bond
(TS3C2). Very importantly, this mechanistic proposal is also able
to account for the experimentally observed regioselectivity,
since the pathway for the reaction to occur on C8 is associated
to significantly higher energy barriers. Furthermore, our DFT
calculations suggest that alternative mechanistic scenarios
involving an initial [3+2] cycloaddition8 are associated to
significantly higher energy barriers, essentially ruling out this
possibility for the present reaction (additional details are
available in ESI section).
TS2C2
Scheme 7. Proposed mechanism based on DFT calculations.
Finally, we have analyzed in deep the greenness of our protocol
by using radial polygons (Figure 1).
We have been carefully assessed three categories of metrics: i)
metrics related to the synthetic process (AE, Yield, 1/SF, MRP,
RME; ii) Safety/Hazard metrics (SHZI, SHI); iii) metrics related to
the metal used as catalyst (Abundance, OEL, ADP).
First of all, it is worthy to note that our protocol has an
associated E-factor value of 0.92 which is very low compared to
other protocols available in the literature (an 84->99 %
reduction considering values from 6 to 37 of the catalysts free
protocols, to 131-457 of the palladium catalyzed protocols, see
ESI). This result is evidently due to the use of highly
concentrated conditions and to the small amounts of solvent
needed for the work-up procedure. As consequence also the
other mass related metrics support the efficiency and the
greenness of the process.
Furthermore, analyzing the safety/hazard metrics, we found
that the Safety Hazard index (SHZI) related to the input and to
the excess of starting materials, which finally results in waste,
are in the case of our protocol, the lowest resulting in an
optimal Safety Hazard Impact (SHI) for the process newly
developed.
4 | J. Name., 2012, 00, 1-3
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allowed us to propose a mechanism based on anViienwitAiratilclleigOanlninde
promoted C−H activation, followed by internal metal oxidation,
J.Am.Chem.Soc. 2009
Tetrahedron Lett. 2016
DOI: 10.1039/D0GC03351K
AE
AE
1
0.8
0.6
0.4
0.2
0
1
insertion and H-abstraction. Further studies on the
environmental and hazard impact showed that the iron-
catalyzed process allowed an environmentally benign access to
widely interesting C2 alkenylated quinolines and quinoxaline
with a consistent waste minimization. The E-factor value of ca.
0.92 evidently confirm the sustainable efficiency of the
procedure presented.
0.8
SHIexcreag
SHIimput
Rxn Yield
1/SF
SHIexcreag
Rxn Yield
0.6
0.4
0.2
0
SHIimput
1/SF
RME
MRP
RME
MRP
Org.Biomol.Chem. 2016
Org. Lett. 2016
AE
AE
1
1
0.8
0.8
0.6
0.4
0.2
0
SHIexcreag
Rxn Yield
0.6
0.4
0.2
0
SHIexcreag
SHIimput
Rxn Yield
1/SF
Acknowledgements
The research leading to these results has received funding from
the NMBP-01-2016 Programme of the European Union's
Horizon 2020 Framework Programme H2020/2014-2020/
under grant agreement nº [720996]. The Università degli Studi
di Perugia and MIUR are acknowledged for financial support to
the project AMIS, through the program “Dipartimenti di
SHIimput
1/SF
RME
MRP
RME
MRP
This work
AE
1
0.8
0.6
0.4
0.2
0
SHIexcreag
SHIimput
Rxn Yield
Eccellenza
- 2018-2022”.S.S. acknowledges CINECA for
computational resources provided in the framework of ISCRA
calls (project IsC64_AMUCHFR).
1/SF
RME
MRP
Figure 1. Radial polygons for metrics evaluation
Notes and references
These results and also the green features of iron the metal used
as catalyst, reported in Table 2, strongly support the
sustainability of the green iron-catalyzed process, indeed being
iron decisively more abundant in the earth crust compared to
palladium and its very low depletion (ASP).
1
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Catalyst Metal Abundance (%)
RPP
1.56
1.73
1.85
OEL (mmol/m3)
0.17
ADP
0.00035
0.32
FeSO4
PdOAc2
PdCl2
5.6
0.015
0.015
0.004
0.004
0.32
RPP: Risk phrases potential; OEL: Occupational exposure limits; ADP: Abiotic
Resource Depletion.
4
In addition, by combining the toxicity data present in the
literature (exposure limits, risk phrases and acute toxicity) it can
be quantified the expected reduced hazard impact of iron
compared to palladium.
Conclusions
In conclusion, here we reported the first examples of external
oxidant-free, C2-selective iron-catalyzed C−H alkenylation of
quinolines. The methodology makes use of inexpensive, earth
abundant FeSO4 catalyst and N-oxides as directing group and
internal oxidant. The power of this approach was demonstrated
by the efficient, chemo- and regioselective coupling of variously
substituted quinoline-N-oxides with acrylates and styrenes,
even on a gram-scale. Experiments and DFT calculations
5
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