N-Methylcaprolactam as a Dipolar Aprotic Solvent for Iron-Catalyzed Cross-Coupling Reactions: Matching Efficiency with Safer Reaction Media

Article abstract of DOI:10.1002/cctc.201802032

Although iron-catalysis provides a powerful alternative to the more conventional palladium and nickel in the cross-coupling arena, the major limitation is the necessity for carcinogenic N-methylpyrrolidone as a co-solvent in the vast majority of catalytic reactions. Herein, we introduce N-methylcaprolactam as an efficient, non-toxic and practical dipolar aprotic solvent for iron-catalyzed C(sp²)?C(sp³) alkylative cross-coupling of aryl chlorides and tosylates. The utility of this method is reflected by its wide substrate scope, high yields and capacity to cross-couple challenging alkyl organometallics prone to b-hydride elimination and homocoupling. Considering the broad utility of iron-catalyzed cross-coupling, we envision that N-methylcaprolactam will find wide application as a substitute for carcinogenic NMP.

Full text of DOI:10.1002/cctc.201802032

Accepted Article
Title: N-Methylcaprolactam as a Dipolar Aprotic Solvent for Iron-
Catalyzed Cross-Coupling Reactions: Matching Efficiency with
Safer Reaction Media
Authors: Elwira Bisz, Pamela Podchorodecka, and Michal Szostak
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To be cited as: ChemCatChem 10.1002/cctc.201802032
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10.1002/cctc.201802032
ChemCatChem
COMMUNICATION
N-Methylcaprolactam as a Dipolar Aprotic Solvent for Iron-
Catalyzed Cross-Coupling Reactions: Matching Efficiency with
Safer Reaction Media
Elwira Bisz,*[a] Pamela Podchorodecka[a] and Michal Szostak*[a,b]
practical substitute for NMP in iron-catalyzed C(sp2)–C(sp3)
Abstract: Although iron-catalysis provides a powerful alternative to
the more conventional palladium and nickel in the cross-coupling
arena, the major limitation is the necessity for carcinogenic N-
methylpyrrolidone as a co-solvent in the vast majority of catalytic
reactions. Herein, we introduce N-methylcaprolactam as an efficient,
non-toxic and practical dipolar aprotic solvent for iron-catalyzed
C(sp2)–C(sp3) alkylative cross-coupling of aryl chlorides and
tosylates. The utility of this method is reflected by its wide substrate
scope, high yields and capacity to cross-couple challenging alkyl
organometallics prone to -hydride elimination and homocoupling.
Considering the broad utility of iron-catalyzed cross-coupling, we
envision that N-methylcaprolactam will find wide application as a
substitute for carcinogenic NMP.
cross-coupling of aryl chlorides and tosylates (Figure 1). In
contrast to NMP, N-methylcaprolactam (N-Me-CPL) is not
mutagenic or reprotoxic.[14] According to the ECHA (European
Chemicals Agency), N-methylcaprolactam is classified at the
same level of hazard category as -caprolactam, which is in
sharp contrast to N-methylpyrrolidinone, which is a “substance
of very high concern” and may “damage fertility or the unborn
child.” [15]
As a product of N-alkylation of -caprolactam, one of the most
popular precursors for the production of plastics and fibers via
ring-opening polymerization, N-Me-CPL is cheap and available
in large quantities.[16] Processes for the production of N-Me-CPL
from -caprolactam on the industrial scale have been well-
established, notably by cheap and sustainable alkylation with
MeOH over acidic clay or alumina-based catalysts.[17]
Iron-catalysis has emerged as the dominant direction in
cross-coupling methods catalyzed by sustainable metals.[1–
3] Following the early studies,[4] iron-catalysis has evolved to
be among the most useful cross-coupling methods routinely
applied in large-scale pharmaceutical manufacturing,[5]
a
feat that is still elusive for other base metals, including
nickel.[6]
Despite tremendous progress in the field, iron-catalyzed
cross-coupling reactions typically employ carcinogenic NMP
(NMP = N-methylpyrrolidinone) as a co-solvent.[7,8] The use of N-
methylpyrrolidinone is especially pervasive in iron-catalyzed
C(sp2)–C(sp3) alkylative cross-coupling, which owing to mild
conditions and broad functional group tolerance have proven
indispensable in the preparation of complex architectures in the
synthesis of bioactive molecules.[5,9–11] The toxicity of NMP has
sparked the development of new alterative solvents for organic
synthesis.[12,13] In the present context, the potential of N-methyl-
caprolactam as a greener, non-toxic alternative solvent to NMP
in organic synthesis is the focus of a recent patent by BASF.[14]
Stimulated by the growing potential of iron-catalyzed cross-
coupling and serious toxicological concerns over NMP,[7,8] here,
we report N-methyl-caprolactam as an efficient, non-toxic and
Figure 1. Fe-catalyzed cross-coupling using N-methylcaprolactam (this study).
Herein, we demonstrate that N-methyl-caprolactam is a
new co-solvent for iron-catalyzed cross-coupling reactions
that retains many characteristics of NMP. Specifically, (1)
through examination of a series of challenging alkylation
reactions using organometallics prone to
-hydride
elimination,[18] we demonstrate that N-methyl-caprolactam
results in comparable or higher yields than those obtained
using reprotoxic N-methyl-pyrrolidone. (2) The method
shows excellent functional group tolerance, including
electrophilic functional groups that are incompatible with
other Fe/ligand catalysts.[19] (3) The practical utility has
[a]
[b]
Dr. E. Bisz, P. Podchorodecka, Prof. Dr. M. Szostak
Department of Chemistry, Opole University
48 Oleska Street, 45-052 Opole (Poland)
E-mail: ebisz@uni.opole.pl
Prof. Dr. M. Szostak
Department of Chemistry, Rutgers University
73 Warren Street, Newark, NJ 07102 (United States)
E-mail: michal.szostak@rutgers.edu
been highlighted in the synthesis of naftifine, a best-selling
[20]
antifungal drug.
Altogether, the study demonstrates N-
Homepage: http://chemistry.rutgers.edu/szostak/
Me-CPL as a highly effective green solvent alternative in
iron-catalyzed cross-coupling reactions.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201802032
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COMMUNICATION
Table 1. Optimization of Iron-Catalyzed Cross-Coupling [a]
Our study began by examining the reactivity of 1-chloro-
4-(trifluoromethyl)benzene with tetradecyl magnesium
chloride as our model system (Table 1). In this reaction, the
4-CF3-containing substrate serves as an electronically-
activated, non-coordinating arene. In the absence of co-
solvent, the reaction is inefficient (entry 1), affording
yield
(%)b
Fe(acac)3
(mol%)
entry
ligand
mol%
time
homocoupling, reduction and
-hydride elimination as the
1
2
5
5
5
5
5
5
5
5
-
-
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
41
56
65
77
88
96
>98
94
major products. We were pleased to find that under
optimized conditions as little as 50 mol% of N-Me-CPL
afforded a significant improvement in the cross-coupling
(entries 2-4). There is a linear correlation between the
quantity of N-Me-CPL used and the reaction efficiency
(entries 2-7, Figure 2). Typically, 200 mol% of N-Me-CPL
suffices to achieve close to quantitative conversions (entry
6). For comparison, the reaction using reprotoxic NMP (600
mol%) afforded the coupling product in 94% yield (entry 8).
The efficiency of N-Me-CPL supersedes the reactivity of
cyclic urea ligands[11a] despite much lower Nlp to C=O
donicity,[21] while the broad availability and low toxicity of
caprolactam[14–17] afford the key practical advantages.
N-Methylcaprolactam
N-Methylcaprolactam
N-Methylcaprolactam
N-Methylcaprolactam
N-Methylcaprolactam
N-Methylcaprolactam
N-Methylpyrrolidone
10
3
20
4
50
5
100
200
600
600
6
7
8c
[a] Conditions: ArCl (0.50 mmol), Fe(acac)3 (5 mol%), THF (0.15 M),
C14H29MgCl (1.20 equiv, 1.0 M, THF), 0 °C, 10 min. RMgCl added dropwise
over 1-2 s. [b] Determined by 1H NMR and/or GC-MS. [c] See refs. 9a,b.
Table 2. Scope of Fe-Catalyzed Cross-Coupling using N-Methylcaprolactam
(N-Me-CPL) as Ligand[a]
With the optimized conditions in hand, we next
examined the scope and generality of this method (Table
2). We were pleased to find that N-methylcaprolactam
serves as an effective ligand to iron in a series of
challenging cross-couplings, including substrates bearing
sensitive electrophilic functional groups, such as ester
(entry 2), nitrile (entry 3), halide (entry 4), and sulfonamide
(entry 5). Furthermore, various N-heterocycles, including
simple (entry 6) and electronically-deactivated pyridine
(entry 7) as well as quinoline (entry 8) afforded the coupling
ligand
yield
(%)
entry
1
substrate
2
(mol%)
2a
600
200
600
98 (94)
96 (91)
93 (91)
products in high yields. It is worthwhile to note that
-
2
3
2b
2c
hydride elimination from the challenging organometallic[18]
was not observed. Importantly, the efficiency of cross-
coupling using N-methylcaprolactam was found to be higher
or comparable than when using toxic N-methyl-pyrrolidone
(entries 1-8, brackets).
Pleasingly, the reaction of a tosyl electrophile afforded
the cross-coupling product with high C–O coupling
selectivity (Scheme 1), demonstrating that after suitable O-
activation phenols can be used as alternative electrophile
sources to aryl chlorides in this cross-coupling.[1k]
4b
5
2d
2e
600
200
48 (58)
98 (94)
A brief examination of alkyl Grignard nucleophiles was
conducted (Scheme 2). Most importantly, challenging
secondary Grignard reagents, such as cyclohexyl and
isopropyl, are suitable nucleophiles for this coupling.
Isomerization to the linear Grignard reagent was not
observed, which is the major side reaction in Fe/NHC-
6c
7
2f
2g
2h
600
200
200
89 (81)
93 (95)
95 (92)
catalysis.[19] Moreover, electronically-activated towards
-
hydride elimination, phenethyl Grignard underwent smooth
coupling, demonstrating another benefit of this mild cross-
coupling using benign N-methylcaprolactam as a ligand.
The cross-coupling using N-methylcaprolactam could be
readily performed on a gram scale to deliver the coupling
product without modification of the reaction conditions (Scheme
3), attesting to the scalability of the method.
8
[a] Conditions: ArCl (0.50 mmol), Fe(acac)3 (5 mol%), THF (0.15 M),
C14H29MgCl (1.20 equiv, 1.0 M, THF), 0 °C, 10 min. Yield in brackets
corresponds to the yield reported using NMP (600 mol%). See, refs. 9a,b. [b]
60 min. [c] C14H29MgCl (2.0 equiv), 60 min. See SI for details.
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ChemCatChem
COMMUNICATION
Plot of conversion vs. ligand for 1a
Plot of conversion vs. time for 1a
100
90
80
70
60
50
40
30
100
80
60
40
20
0
NMP
N-Me-CPL
N-Me-CPL
0
100
200
300
400
500
600
0
100
200
300
400
500
600
700
ligand (mol %)
time [s]
Figure 2. Plot of conversion vs. ligand for 1a (4-CF3-C6H4-Cl). Conditions: n-
C14H29 (1.20 equiv), Fe(acac)3 (5 mol%), ligand, THF, 0 °C.
Figure 3. Kinetic profile of 1a (4-CF3-C6H4-Cl). Conditions: n-C14H29 (1.20
equiv), Fe(acac)3 (5 mol%), ligand (200 mol%), THF (0.15 M), 0 °C.
Scheme 1. Aryl tosylate C(sp2)–C(sp3) cross-coupling.
Scheme 6. Synthesis of naftifine (Exoderil).
The practical utility was further highlighted in the alkenyl–alkyl
cross-coupling of
a model alkenyl bromide selected for
comparison with the Fe/NMP-catalyzed cross-coupling (Scheme
5). 1,1-Disubstitued olefins are particularly challenging
substrates for iron-catalyzed alkenylation of Grignard
nucleophiles,[22] which demonstrates a significant potential of N-
methylcaprolactam for organic synthesis.
Scheme 2. Cross-coupling of Grignard reagents.
Finally, to highlight the practical value of this method, we have
demonstrated a short synthesis of naftifine, a best-selling
antifungal drug (Scheme 6).[20] The use of a benign ligand N-
Scheme 3. Large scale cross-coupling.
Scheme 4. Cross-coupling of aryl Grignard.
Scheme 5. Cross-coupling of alkenyl halide.
methylcaprolactam presents
a
key advantage from the
environmental and operational standpoints.[23]
To gain insight into the efficiency of N-Me-CPL,
preliminary kinetic studies were conducted (Figure 3).
Pleasingly, these investigations revealed similar kinetics to
Fe-NMP, attesting to the high reactivity of the iron/N-Me-
CPL catalyst system.
In summary, we have reported N-methylcaprolactam as
an efficient, non-toxic and practical substitute for N-methyl-
pyrrolidone in iron-catalyzed cross-coupling reactions of
aryl chlorides and tosylates. N-methyl-caprolactam is
available in large commercial quantities, is not mutagenic or
reprotoxic, and has been shown to promote iron-catalyzed
cross-couplings in yields higher or comparable to NMP. The
practical value has been demonstrated in the cross-
coupling of a broad range of electrophiles bearing sensitive
functional groups using challenging alkyl organometallics
Importantly, this benign cross-coupling method is not limited
to C(sp2)–C(sp3) disconnection as demonstrated in the C(sp2)–
C(sp2) biaryl coupling to afford 2-phenylquinoline with high
reaction efficiency (Scheme 4).
prone to
-hydride elimination. Furthermore, this benign
method has been showcased in the synthesis of a
pharmaceutical agent. Considering the broad utility of iron-
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COMMUNICATION
[7]
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table (accessed 30 Oct, 2018).
catalyzed cross-coupling, notably, in pharmaceutical and
natural product research, this study offers a new option to
synthesize biologically-active compounds in
a
green
manner, matching or superseding the previous-state-of-art
method using co-solvent with unfavourable toxicological
and environmental profile. Further studies on the
development of green ligands for iron-catalyzed cross-
couplings and reaction conditions for coupling of additional
classes of substrates are ongoing in our laboratory and
these results will be reported in due course. Given the
broad utility of iron-catalyzed cross-couplings in modern
organic synthesis, structural modifications of O-coordinating
ligands offer new vistas to improve the efficiency and safety
profile of this important catalysis manifold.
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Acknowledgements
We gratefully acknowledge Narodowe Centrum Nauki (grant no.
2014/15/D/ST5/02731, E.B., M.S.), Rutgers University (M.S.)
and the NSF (CAREER CHE-1650766, M.S.) for generous
financial support.
Keywords: iron catalysis • cross-coupling • sustainability • green
solvents • catalysis
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10.1002/cctc.201802032
ChemCatChem
COMMUNICATION
COMMUNICATION
N-Methylcaprolactam as a Dipolar
Aprotic Solvent for Iron-Catalyzed
Cross-Coupling Reactions: Matching
Efficiency with Safer Reaction Media
Elwira Bisz,* Pamela Podchorodecka,
Michal Szostak*
Page No. – Page No.
Herein, we introduce N-methyl-caprolactam as an efficient, non-toxic and practical
dipolar aprotic solvent for iron-catalyzed C(sp2)–C(sp3) alkylative cross-coupling.
The utility of this method is reflected by its wide substrate scope, high yields and
capacity to cross-couple challenging alkyl organometallics.
Keywords: iron catalysis, cross-coupling, sustainability, green solvents, catalysis
This article is protected by copyright. All rights reserved.