2-Methyltetrahydrofuran: A Green Solvent for Iron-Catalyzed Cross-Coupling Reactions

Article abstract of DOI:10.1002/cssc.201800142

Iron-catalyzed cross-coupling reactions allow sustainable formation of C?C bonds using cost-effective, earth-abundant base-metal catalysis for complex syntheses of pharmaceuticals, natural products, and fine chemicals. The major challenge to maintain full sustainability of the process is the identification of green and renewable solvents that can be harnessed to replace the conventional solvents for this highly attractive reaction. Herein, iron-catalyzed cross-coupling of aryl chlorides and tosylates with challenging organometallic reagents possessing β-hydrogens is found to proceed in good to excellent yields with the green, sustainable, and eco-friendly 2-methyltetrahydrofuran (2-MeTHF) as solvent. The reaction operates with excellent functional group tolerance under very mild conditions. Furthermore, large-scale cross-coupling, cross-coupling of heteroaromatic substrates, and cross-coupling of challenging aryl tosylates and carbamates mediated by Fe–N-heterocyclic carbene catalytic systems in eco-friendly 2-MeTHF were also carried out. The developed method was applied to the key cross-coupling in the synthesis of a fibrinolysis inhibitor, further highlighting the potential of 2-MeTHF as a general solvent for sustainable iron-catalyzed cross-coupling reactions.

Full text of DOI:10.1002/cssc.201800142

Accepted Article
Title: 2-Methyltetrahydrofuran: A Green Solvent for Iron-Catalyzed
Cross-Coupling Reactions
Authors: Elwira Bisz and Michal Szostak
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2-Methyltetrahydrofuran: A Green Solvent for Iron-Catalyzed
Cross-Coupling Reactions
Elwira Bisz[a] and Michal Szostak*[a,b]
Abstract: Iron-catalyzed cross-coupling reactions allow for
sustainable formation of C–C bonds using cost-effective, earth-
abundant base-metal catalysis in complex areas of pharmaceutical
development, natural product and fine chemical synthesis. The
major challenge to maintain full sustainability of the process is the
identification of green and renewable solvents that can be harnessed
to replace the conventional solvents in this highly attractive manifold.
Herein, we report that the iron-catalyzed cross-coupling of aryl
chlorides and tosylates with challenging organometallics possessing
-hydrogens that proceed in good to excellent yields using green,
sustainable and eco-friendly 2-methyltetrahydrofuran (2-MeTHF).
The protocol operates with excellent functional group tolerance
under very mild conditions. Furthermore, large scale cross-coupling,
cross-coupling of heteroaromatic substrates, and cross-coupling of
challenging aryl tosylates and carbamates mediated by Fe-NHC
catalytic systems in eco-friendly 2-MeTHF are reported. The
developed method was applied to the key cross-coupling in the
synthesis of a fibrinolysis inhibitor, further highlighting the potential of
2-MeTHF as a general solvent for sustainable iron-catalyzed cross-
coupling reactions.
the conventional solvents in this highly attractive cross-
coupling manifold.[1–5]
Herein, we report that the iron-catalyzed cross-coupling
of aryl chlorides and tosylates with challenging
organometallics possessing 
-hydrogens[12] that proceed in
good to excellent yields using green, sustainable and eco-
friendly 2-methyltetrahydrofuran as a solvent (Figure 1).
Considering the key importance of renewable solvents, the
method constitutes a valuable addition to the growing
arsenal of iron-catalyzed cross-couplings for sustainable
chemical synthesis.
Figure 1. Iron-catalyzed cross-coupling reactions in 2-MeTHF (this work).
Iron-catalyzed cross-coupling has recently become an
important strategy for the formation of C–C bonds using
cost-effective, sustainable, earth-abundant iron-catalysis,
while providing new opportunities for organic synthesis.[1–5]
Meanwhile, selective methods for the cross-coupling using
green, renewable solvents are essential to reduce
environmental damage.[6–8] As such, the combination of
base-metal catalysis[1–5] with green solvents offers unique
prospects within the field of organic synthesis with
multidimensional practical industrial applications.[9]
Obtained from furfural or levulinic acid, 2-MeTHF is a
very attractive solvent for organometallic reactions.[13] In
contrast to THF, the production of 2-MeTHF utilizes
renewable lignocellulosic biomass,[14] which is critical to
decrease waste generation in chemical industry and
pharmaceutical manufacturing. Important from the point of
iron-catalysis, 2-MeTHF is a strong Lewis base (2-MeTHF:
143.7 kcal/mol; THF: 137.2 kcal/mol; Et2O: 139.7 kcal/mol,
LiCB, lithium cation basicity scale).[15] Accordingly, we
hypothesized that despite increased steric hindrance at the
2-position, the high basicity of 2-MeTHF (relative to THF)
should facilitate its coordination to iron and promote the
generation of catalytically active, solvent-coordinated
iron(II) species.[16]
In this regard, it is remarkable that organic solvents
constitute up to 90% of the non-aqueous waste used in the
synthesis of pharmaceuticals.[8] In light of the limited
abundance of precious metals in the Earth’s crust,[4,5] iron
catalysis offers
a
distinct sustainability paradigm in
chemical synthesis.[10,11] The major challenge to maintain
full sustainability of the process is the identification of green
and renewable solvents that can be harnessed to replace
Table 1. Optimization of Iron-Catalyzed Cross-Coupling: Control Reactions[a]
[a]
[b]
Dr. E. Bisz, Prof. Dr. M. Szostak
Department of Chemistry, Opole University
48 Oleska Street, 45-052 Opole (Poland)
Prof. Dr. M. Szostak
Department of Chemistry, Rutgers University
73 Warren Street, Newark, NJ 07102 (United States)
E-mail: michal.szostak@rutgers.edu
Homepage: http://chemistry.rutgers.edu/szostak/
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201800142
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Table 2. Scope of Fe-Catalyzed Coupling using Ecofriendly 2-MeTHFa]
2-MeTHF
THF
Entry
T (°C)
Time
Yield (%)[b]
Yield (%)[b]
1
2
3
4
5
6
7
0
23
-78
0
10 min
10 min
10 min
10 min
60 s
37
34
41
23
8
Yield
<5
>95
91
Entry
1
Substrate
1
Products
2
(%)
94[c]
94
93
87
96
(94)
0
1a
2a
0
30 s
85
0
10 s
86
92
(91)
2
3
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
[a] 1 (0.50 mmol), Fe(acac)3 (5 mol%), 2-MeTHF or THF (0.15 M), C14H29MgCl
(1.20 equiv, 1.0 M, THF), T, 10 min. RMgCl added dropwise over 1-2 s;
Entries 4-7: NMP/solvent. Entries 5-7: C12H25MgBr (1.20 equiv, 0.50 M, 2-
MeTHF). [b] Determined by 1H NMR and/or GC-MS. See SI for details. [c] Ref.
10a.
86
(91)
Our studies commenced with an examination of the
cross-coupling of 1-chloro-4-(trifluoromethyl)benzene with
tetradecyl magnesium chloride in 2-MeTHF as a solvent
using rapid addition of the Grignard reagent at 0 °C (Table
1). The model CF3-substrate was selected for optimization
studies to test non-coordinating arene in the coupling.[10a]
For comparison, all runs were performed using THF as a
solvent under otherwise identical reaction conditions. We
were delighted to find that 2-MeTHF and THF show similar
profiles in the cross-coupling of the model substrate at 0 °C
and 23 °C (entries 1-2), with negligible conversion observed
at -78 °C for both solvents (entry 3), in the absence of O-
coordinating ligand.[10a,16] Under the optimized conditions
(entry 4), the cross-coupling proceeded in a quantitative
yield at 0 °C using 2-MeTHF as a green solvent. To our
knowledge, this is the first example described in the
literature for a high yielding cross-coupling using iron-
catalysis in 2-MeTHF.[1–5,10,11] Several control reactions
were conducted (entries 5-7). Overall, the results
demonstrate that 2-MeTHF is comparable in the reaction
efficiency to the conventional THF in the coupling (vide
infra). Remarkably, the reactions result in an almost
69
(58)
4[b]
87
(94)
5
92
(81)
6
[a] 1 (0.50 mmol), Fe(acac)3 (5 mol%), 2-MeTHF (0.15 M), NMP, C14H29MgCl
(1.20 equiv, 1.0 M, THF), 0 °C, 10 min. Yield in brackets corresponds to the
yield reported using THF as a solvent. See, refs. 10a,b. [b] 60 min.
Table 3. Scope of Fe-Catalyzed Coupling using Ecofriendly 2-MeTHFa]
Yield
Entry
1
Substrate
1
Products
2
(%)
1a
2g
93
instantaneous coupling, with
a
complete conversion
observed in <1 min. The high reactivity of 2-MeTHF bodes
well for the development of a range of iron-catalyzed cross-
couplings in this alternative solvent.[1,2]
2
3
1b
1c
1d
1e
1f
2h
2i
98
88
66
92
88
With the optimized conditions in hand, the scope of the
coupling was next explored (Tables 2-3). The scope was
first investigated using tetradecyl magnesium chloride as a
nucleophile (Table 2). For comparison, yields obtained
using THF as a solvent are presented in brackets. As
shown, the reaction showed an excellent chemoselectivity
profile (1a-1f). Notably, a wide range of reactive functional
handles, such as esters (entry 2), nitriles (entry 3),
chlorides(entry 4), sulfonamides (entry 5) are competent
electrophiles in this mild alkylation. This provides versatile
4[b]
2j
5
2k
2l
6
handles
for
product
derivatization.
Furthermore,
coordinating heterocycles, such as pyridine (entry 6), cross-
[a] 1 (0.50 mmol), Fe(acac)3 (5 mol%), 2-MeTHF (0.15 M), NMP, C12H25MgBr
(1.20 equiv, 0.50 M, 2-MeTHF), 0 °C, 10 min. [b] C12H25MgBr (2.0 equiv), 60
min. See SI for details.
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10.1002/cssc.201800142
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couple with good levels of efficiency. Note that in all cases,
the reaction efficiency is comparable or even higher than in
THF as a solvent. We were further intrigued by the fact that
the cross-coupling could be performed using dodecyl
magnesium bromide in 2-MeTHF (Table 3). Of note, this
coupling utilizes commercially available Grignard solution in
2-MeTHF. Remarkably, all substrates bearing sensitive
PrMgBr is selective for the branched product (2n, B:L
>20:1). In contrast, isomerization of secondary nucleophiles
is a major side-reaction using other Fe-based catalytic
systems, highlighting benefits of this method.[2e,f]
Furthermore, short-chain
(
2o), activated
(
2p
)
and
functionalized 2q Grignard reagents are suitable
(
)
nucleophiles. Of particular note, alkylated pyridines, such
as 2o serve as common precursors in natural product and
ligand synthesis,[19] while in the cross-coupling of an
activated Grignard reagent containing a benzylic position
functional groups
(1a-f) could be perfectly tolerated,
furnishing the desired cross-coupling products in high
yields. Comparison of the results (Tables 2-3) clearly
indicates that 2-MeTHF serves as a very effective solvent
for the cross-coupling even in the absence of trace
quantities of THF. Since many Grignard reagents are
commercially available as solutions in 2-MeTHF as part of
green chemistry initiative,[6–8] the incorporation of 2-MeTHF
as a green solvent for iron-catalyzed cross-couplings
(
2p), -hydride elimination to the thermodynamically-
favoured styrene[2i] was not observed, revealing the mild
nature of our protocol.
The scalability of the protocol was assessed (Scheme
3). As shown, the reaction could be readily performed on a
gram-scale without any modification of the reaction
conditions, furnishing the desired product in 84% yield.
Ease of execution (bench-top set-up), ready scalability and
the combination of sustainable iron catalysis with a green
solvent are notable features of this protocol.
represents
a significant benefit from practical green
chemistry standpoint.
Pleasingly, the reaction conditions could be directly
applied to the cross-coupling of aryl tosylates to accomplish
challenging C–O alkylation under sustainable conditions
(Scheme 1). The use of phenol electrophiles further
demonstrates practicality of this protocol.[17,18]
Gratifyingly, the method could be further extended to the
C(sp2)–C(sp2) cross-coupling (Scheme 4), demonstrating
generality of the method. The product biaryl quinolines,
such as 2r, constitute privileged scaffolds in medicinal
chemistry.[20]
Scheme 1. Aryl tosylate C(sp2)–C(sp3) cross-coupling.
Scheme 4. Cross-coupling or aryl Grignard.
Scheme 5. Cross-coupling of heteroaromatic tosylate.
Scheme 2. Cross-coupling of Grignard reagents.
The elegant 2009 report by Skrydstrup and co-workers
established the utility of iron-catalyzed alkylation of
heterocyclic tosylates.[21] We were intrigued to find that the
excellent chemoselectivity profile also allowed the use of 2-
MeTHF as environmentally-benign, renewable solvent for
the cross-coupling of a model 4,6-dimethyl-pyrimidin-2-yl
tosylate in excellent yield (Scheme 5). This together with
the C(sp2)–Cl/C(sp2) coupling (Scheme 4), clearly
demonstrates the potential of the present method in the
cross-coupling of heteroaromatic electrophiles.
Scheme 3. Large scale cross-coupling.
We were delighted to find that challenging secondary
Grignard reagents are competent substrates in this
alkylation, furnishing the sterically-hindered products with
high efficiency (2m-n) (Scheme 2). The reaction using i-
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general fashion. The protocol occurs with excellent
functional group tolerance under very mild, operationally-
convenient conditions. The potential of these couplings has
been demonstrated by large scale cross-coupling, cross-
coupling of heteroaromatic substrates, and cross-couplings
of challenging aryl tosylates and carbamates mediated by
Fe-NHC catalytic systems. The practical utility was
highlighted in the key cross-coupling in the synthesis of a
fibrinolysis inhibitor. To the best of our knowledge, these
results represent the first examples of highly efficient iron-
catalyzed cross-couplings in 2-MeTHF. Considering the
pivotal role of sustainable iron-catalysis and the essential
use of green solvents, in particular within industrial settings
where solvents constitute up to 90% of non-aqueous waste,
we anticipate that the method will be of broad interest.
Scheme 6. Application to Fe-NHC catalysis.
Acknowledgements
We gratefully acknowledge Narodowe Centrum Nauki (grant no.
2014/15/D/ST5/02731, E.B., M.S.) and Rutgers University (M.S.)
for generous financial support.
Keywords: iron catalysis • cross-coupling • sustainability • green
solvents • 2-methyltetrahydrofuran
Scheme 7. Key cross-coupling in the synthesis of a fibrinolysis inhibitor,
AZD6564.
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toxic and renewable solvent can be applied to the iron-
catalyzed cross-coupling of aryl chlorides and tosylates with
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This article is protected by copyright. All rights reserved.

10.1002/cssc.201800142
ChemSusChem
COMMUNICATION
COMMUNICATION
2-Methyltetrahydrofuran: A Green
Solvent for Iron-Catalyzed Cross-
Coupling Reactions
Elwira Bisz, Michal Szostak*
Page No. – Page No.
Herein, we report that the iron-catalyzed cross-coupling of aryl chlorides and
tosylates with challenging organometallics possessing -hydrogens that proceed in
good to excellent yields using green, sustainable and eco-friendly 2-
methyltetrahydrofuran (2-MeTHF) in a general fashion. The protocol operates with
excellent functional group tolerance under very mild conditions.
Keywords: iron catalysis, cross-coupling, sustainability, green solvents, 2-methyltetrahydrofuran
This article is protected by copyright. All rights reserved.