Iron-Catalyzed C(sp2)?C(sp3) Cross-Coupling of Chlorobenzamides with Alkyl Grignard Reagents: Development of Catalyst System, Synthetic Scope, and Application

Article abstract of DOI:10.1002/adsc.201800849

Direct preparation of alkylated amide-derivatives by cross-coupling chemistry using sustainable protocols is challenging due to sensitivity of the amide functional group to reaction conditions. Herein, we report the synthesis of alkyl-substituted amides b

Full text of DOI:10.1002/adsc.201800849

Title: Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of
Chlorobenzamides with Alkyl Grignard Reagents: Development of
Catalyst System, Synthetic Scope and Application
Authors: Elwira Bisz and Michal Szostak
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of
Chlorobenzamides with Alkyl Grignard Reagents: Development
of Catalyst System, Synthetic Scope, and Application
Elwira Bisz,a and Michal Szostaka,b*
a
Department of Chemistry, Opole University, 48 Oleska Street, Opole, 45-052, Poland
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, United States
b
Fax: (+1)-973-353-1264; phone: (+1)-973-353-5329; e-mail: michal.szostak@rutgers.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
providing access to motifs of broad synthetic
by cross-coupling chemistry using sustainable protocols is interest.[3] As a consequence, new methods for the
Abstract. Direct preparation of alkylated amide-derivatives
challenging due to sensitivity of the amide functional group
to reaction conditions. Herein, we report the synthesis of
alkyl-substituted amides by iron-catalyzed C(sp2)–C(sp3)
cross-coupling of Grignard reagents with aryl chlorides.
The products of these reactions are broadly used in the
synthesis of pharmaceuticals, agrochemicals and other
biologically-active molecules. Furthermore, amides are
used as versatile intermediates that can participate in the
synthesis of valuable ketones and amines, providing access
to motifs of broad synthetic interest. The reaction is
characterized by its good substrate scope, tolerating a range
of amide substitution, including sterically-bulky, sensitive
and readily modifiable amides. The reaction is compatible
with challenging organometallics possessing -hydrogens,
and proceeds under very mild, operationally-simple
conditions. Optimization of the catalyst system
demonstrated the beneficial effect of O-coordinating
ligands on the cross-coupling. The reaction was found to be
fully chemoselective for the mono-substitution at the less
sterically-hindered position. Mechanistic studies establish
the order of reactivity and provide insight into the role of
amide to control mono-selectivity of the alkylation. The
protocol provides the possibility for convenient access to
alkyl-amide structural building blocks using sustainable
cross-coupling conditions with high efficiency.
synthesis of functionalized amides and their
analogues have a major impact on the development of
many pharmaceuticals, bioactive products and fine
chemicals.[4] The recent emergence of N–C amide
cross-coupling methods, wherein the amide bond can
be utilized as a synthetic acyl- or aryl equivalent,
offers additional opportunities in the capacity of
amides as versatile synthetic building blocks.[5]
The recent remarkable advances in homogeneous
iron-catalysis allow for mild, chemoselective access
to a wide array of C–C bond forming processes that
have found numerous applications in natural product
synthesis, drug discovery and organic materials.[6–8]
The increasing importance of sustainable methods in
modern cross-coupling chemistry has in particular
spurred the development of cost-effective protocols
using earth-abundant, sustainable iron catalysis.[9] In
this regard, cross-couplings using cheap and readily
available Grignard reagents offer unique mechanistic
opportunities to traditional protocols catalyzed by
precious metals.[10–12] However, the use of amides in
Kumada cross-cross coupling reactions is rare, most
likely due to sensitivity of the amide functional group
to reaction conditions.[13]
As part of our interest in iron catalysis and
functionalization of amides by selective cross-
coupling reactions,[14] herein, we report the synthesis
of alkyl-substituted amides by iron-catalyzed C(sp2)–
C(sp3) cross-coupling of Grignard reagents with aryl
chlorides (Scheme 1).
Keywords: iron catalysis; cross-coupling; amides;
alkylation; sustainability; C(sp2)–C(sp3) Kumada coupling
The significance of the manuscript is as follows:
(1) this full paper demonstrates and investigates the
synthesis of alkylated benzamides. These derivatives
are among the most important compounds in organic
Introduction
Aromatic amides are among the most important and
prevalent building blocks in organic synthesis.[1–3]
Alkyl-substituted amides and derivatives are
extensively used in the synthesis of pharmaceuticals,
synthesis
with
applications
ranging
from
pharmaceuticals to organic materials owing to the
presence of the amide bond; (2) the manuscript,
through product manipulations, shows the utility of
the alkylated products to produce other important
compounds that (i) are inaccessible from other
agrochemicals
and
other
biologically-active
molecules.[4] Furthermore, amides are commonly
used as versatile intermediates that can participate in
the synthesis of valuable ketones and amines,
1
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
functional groups, including esters, (ii) thus far have
been prepared by much longer, more costly and less
sustainable synthetic routes. This clearly places the
subject into the broader scientific context and
demonstrates how the method can be productively
utilized by scientists in other fields.
conditions delivered the cross-coupling product in a
promising but unsatisfactory yield (entries 3-5).
Seminal studies by Fürstner and co-workers
established the potential of iron-catalyzed aryl–alkyl
C(sp2)–C(sp3) cross-coupling based on NMP (NMP =
N-methyl-2-pyrrolidone).[6a,b,7,11a,b, 21e] At present, this
catalytic system represents the catalyst of choice for
the vast majority of iron-catalyzed cross-couplings in
both academic and industrial settings.[18] Mechanistic
studies showed that NMP forms O-coordinated
catalytically active octahedral complexes of
iron(II).[19,20] We were delighted to find that addition
of NMP delivered the C4-alkylated product in
excellent 92% yield (Table 2, entry 1). Importantly,
under these conditions, the formation of ketone,
dehalogenated and homocoupling products was not
observed (<2%), consistent with the efficient
stabilization of the active low-valent iron species by
NMP. Further optimization revealed that temperature
had a significant effect on the reaction (entry 2).
The reaction is characterized by its good substrate
scope, tolerating a range of amide substitution,
including sterically-bulky, sensitive and readily
modifiable amides. The reaction proceeds under very
mild, operationally-simple conditions and is
compatible with challenging organometallics
possessing -hydrogens.[15] Through optimization, we
demonstrate the beneficial effect of O-coordinating
ligands on the cross-coupling. Intriguingly, we
demonstrate that the reaction is fully chemoselective
for the mono-substitution at the less sterically-
hindered position. Through mechanistic studies, we
establish the order of reactivity and provide insight
into the key role of amide to control mono-selectivity
of the alkylation. Finally, we demonstrate the
potential of this amide alkylation method to provide
direct access to functionalized amide, ketone and
amine building blocks. This protocol provides
convenient access to alkyl-amide structural building
blocks using sustainable cross-coupling conditions
with high efficiency.
Table 1. Optimization of Fe-Catalyzed Cross-Coupling:
Control Reactions.[a]
Entry
Fe(acac)3
[mol%]
Ligand
T
Time
Yield
[%][b]
[°C] [min]
1
2
3
4
5
-
-
5
1
1
-
-
-
-
-
0
23
0
0
23
10
3.5
10
60
3.5
<2
<2
55
56
54
[a]Conditions: 1 (0.50 mmol), Fe(acac)3 (1-5 mol%), THF
(0.15 M), C2H5MgCl (1.20 equiv, 2.0 M, THF), T, 3.5-60
min. Entries 1 and 3: RMgCl added dropwise over 1-2 s;
Entries 2 and 4-5: RMgCl added 0.10 mmol/30 s.
[b]Determined by 1H NMR and/or GC-MS.
Scheme 1. Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling
of Amides with Alkyl Grignard Reagents.
Results and Discussion
Optimization. Morpholinyl amide was selected as a
substrate for optimization studies (Table 1). While it
is well-established that amidic resonance in
morpholinyl amides is in the range expected for
planar amides (PhCON(CH2CH2)2O, RE = 19.6
kcal/mol, RE = resonance energy),[16] these amides
(1) are more sensitive to organometallic reagents due
to chelate formation with the morpholinyl oxygen,
and (2) are further useful in organic synthesis due to
Weinreb amide-type reactivity.[17]
At the outset, control reactions were conducted to
determine the effect of uncatalyzed background
process (Table 1). As shown, alkylation at the C4
position was not observed in the absence of the iron
catalyst under both rapid and slow addition protocols
(entries 1-2) (vide infra). Under these conditions, 7-
10% of the alkyl ketone product was formed,
consistent with the high capacity of the morpholinyl
amide to undergo nucleophilic acyl-type addition
with Grignard reagents.[17] Furthermore, control
reactions in the presence of iron under ligandless
Table 2. Optimization of Fe-Catalyzed Cross-Coupling:
Iron–NMP Catalytic System.[a]
Entry
Fe(acac)3
[mol%]
Ligand
T
Time
Yield
[%][b]
[°C] [min]
1
2
3
5
5
1
0.1
1
NMP
NMP
NMP
NMP
NMP
0
23
0
0
0
10
10
10
10
10
92
78
91
88
84
4
5[c]
[a]Conditions: 1 (0.50 mmol), Fe(acac)3 (0.1-5 mol%),
THF (0.15 M), NMP (600 mol%), C2H5MgCl (1.20 equiv,
2.0 M, THF), T, 10 min. RMgCl added dropwise over 1-2 s.
[b]Determined by H NMR and/or GC-MS. [c]NMP (10
1
mol%).
2
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
Moreover, the catalyst loading could be decreased to
1.0% (entry 3) and even 0.1% (entry 4) with a
minimal impact on the reaction efficiency. Finally,
the reaction with low NMP loading (entry 5) afforded
the desired product in high yield. Overall, these
results demonstrate that iron-NMP catalyst is highly
reactive for the coupling, and the by-products are not
formed under these conditions.
6
7
8
9
10
1
1
1
1
1
quinoline
styrene
SIPr
IMes
PPh3
23
23
23
23
23
3.5
3.5
3.5
3.5
3.5
84
51
78
74
62
[a]Conditions: 1 (0.50 mmol), Fe(acac)3 (1 mol%), THF
(0.15 M), ligand (10 mol%), C2H5MgCl (1.20 equiv, 2.0 M,
THF), T, 3.5 min. RMgCl added 0.10 mmol/30 s.
[b]Determined by 1H NMR and/or GC-MS.
Further optimization studies were conducted using
bidentate TMEDA (TMEDA
=
N,N,N’,N’-
tetramethylethylenediamine) as a ligand to iron
(Table 3). Fox and co-workers elegantly
demonstrated that TMEDA serves as an efficient
ligand in iron-catalysis;[21] however, these reactions
are less convenient due to sequential addition
protocol. Nevertheless, considering the importance of
alkylated amide derivatives in organic synthesis, we
were interested to fully examine the effect of the
reaction conditions using iron-TMEDA catalysis.
As shown in Table 3, the reaction conducted with
TMEDA as a ligand (entry 1) generated the desired
coupling product in excellent 90% yield with minor
quantities of ketone and dehalogenation side-products.
The temperature (entries 2-3) and the slow addition
protocol (entry 4) had a major effect on the reaction
efficiency. Furthermore, the reaction was found to be
quite sensitive to the amount of TMEDA (entries 5-8)
and iron (entry 9) used. Finally, the catalyst loading
could be decreased to 0.1%, while maintaining high
Table 3. Optimization of Fe-Catalyzed Cross-Coupling:
Iron–TMEDA Catalytic System.[a]
Table 5. Optimization of Fe-Catalyzed Cross-Coupling:
Additional Optimization.[a]
Entry Fe(acac)3
[mol%]
Ligand
T
Time
Yield
[%][b]
[°C] [min]
Entry
Catalyst
[mol%]
Ligand
T
[°C]
Time
[min]
Yield
[%][b]
1
2
1
1
TMEDA
TMEDA
TMEDA -78
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
23
0
3.5
3.5
3.5
1
3.5
3.5
3.5
3.5
3.5
3.5
90
89
38
73
77
81
82
80
60
85
1[c]
2[c]
3[d]
4[e]
5[f]
6[f]
1
5
5
5
1
5
TMEDA
NMP
DMPU
DMI
TMEDA
NMP
23
0
0
0
23
0
3.5
10
10
10
3.5
10
92
91
93
92
<2
<2
3
1
4[c]
5[d]
6[e]
7[f]
8[g]
9
1
1
1
1
1
5
23
23
23
23
23
23
23
[a]Conditions: 1 (0.50 mmol), Fe(acac)3 (1-5 mol%), THF
(0.15 M), ligand (10-600 mol%), C2H5MgCl (1.20 equiv,
2.0 M, THF), T, 3.5-10 min. Entries 1 and 5: RMgCl added
0.10 mmol/30 s; Entries 2-4 and 6: RMgCl added dropwise
over 1-2 s. TMEDA (10 mol%); NMP, DMPU, DMI (600
10
0.1
[a]Conditions: 1 (0.50 mmol), Fe(acac)3 (0.1-5 mol%),
THF (0.15 M), TMEDA (10 mol%), C2H5MgCl (1.20
equiv, 2.0 M, THF), T, 1-3.5 min. RMgCl added 0.10
mol%). [b]Determined by H NMR and/or GC-MS. [c]2-
1
mmol/30 s. [b]Determined by H NMR and/or GC-MS.
1
[c]
MeTHF instead of THF. [d]DMPU instead of NMP. [e]DMI
instead of NMP. [f]Co(acac)3 instead of Fe(acac)3.
RMgCl added dropwise over 1-2 s. [d]TMEDA (50 mol%).
[e]TMEDA (20 mol%). [f]TMEDA (5 mol%). [g]TMEDA (1
mol%).
activity (entry 10). Collectively, the optimization
studies with iron-TMEDA demonstrate that TMEDA
can be used as a ligand in this cross-coupling;
however, the protocol is less appealing due to the
necessity for slow addition.
Table 4. Optimization of Fe-Catalyzed Cross-Coupling:
Effect of Ligands.[a]
Subsequently, we evaluated the effect of different
ligands on the cross-coupling (Table 4). Previous
studies have demonstrated the viability of various N-,
C- and P-based ligands in iron-catalyzed cross-
coupling reactions.[6,7,11,12] In the event, in a screen of
amine-based ligands we found that while Et3N (entry
1), HMTA (HMTA = hexamethylenetetramine)
(entry 2) and DIPA (DIPA = diisopropylamine)
(entry 3) did not promote the desired coupling
Entry Fe(acac)3
[mol%]
Ligand
T
Time Yield
[°C] [min] [%][b]
1
2
3
4
5
1
1
1
1
1
Et3N
HMTA
DIPA
DABCO
isoquinoline
23
23
23
23
23
3.5
3.5
3.5
3.5
3.5
65
67
42
84
69
efficiently,
DABCO
(DABCO
=
1,4-
a
diazabicyclo[2.2.2]octane) was identified as
potentially suitable ligand (entry 4). This reactivity
3
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
Table 6. Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of
as a highly suitable, renewable solvent for iron-
catalyzed cross-coupling reactions.[22] Next, we were
pleased to find that urea ligands, DMPU and DMI
Amides with Alkyl Grignard Reagents.[a]
(DMPU
=
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
DMI 1,3-dimethyl-2-
pyrimidinone,
=
imidazolidinone), afforded the coupling product with
efficiency comparable to NMP (entries 3-4). This
reactivity further demonstrates the prospect of fine-
tuning of benign O-coordinating ligands in iron-
catalysis.[23] Finally, control reactions using Co
instead of Fe (entries 5-6) demonstrate the essential
catalytic role of iron.[24] In these cases, the Co catalyst
did not promote any conversion to the desired
product, and only dehalogenation was observed as a
major side reaction.[25]
Scope Studies. With optimized conditions in hand,
we next explored the scope of this iron-catalyzed
alkylation (Table 6). In particular, we were interested
to define the range of sterically- and electronically-
differentiated amides that could participate in this
cross-coupling protocol. These reactions were
routinely conducted using both iron-NMP and iron-
TMEDA reagent systems for comparison purposes.
As shown in Table 6, the reaction tolerates a wide
range of amides, including simple (entries 1-4) as
well as extremely sterically-hindered amides (entry 5-
6). The broad applicability is further demonstrated by
coupling of cyclic amides, including the morpholinyl
amide and common piperidinyl amide (entries 7-10)
(vide infra). Furthermore, sensitive azetidinyl amide
was found to be a good substrate for this coupling
(entries 11-12) despite high ring strain and propensity
for C-cleavage. Importantly, the high efficiency of
the coupling in this case provides an alternative
approach to ketone synthesis by stable tetrahedral
intermediates of azetidinyl amides.[26] Moreover, we
were pleased to find that activated amides, such as
anilides, which are effective precursors for metal-
catalyzed N–C cross-coupling[5] due to lower amidic
resonance (PhCONMePh, RE = 13.5 kcal/mol),[27]
coupled with high reaction selectivity (entries 13-14).
Finally, cross-coupling of N-benzyl amide was well-
tolerated under standard conditions (entries 15-16).
These amides provide rapid access to secondary
amides after N-Bn hydrogenolysis.[28] While both
catalytic systems, namely iron-NMP and iron-
TMEDA, performed efficiently with the exception of
a sterically-hindered N,N-i-Pr2 amide, the former
system is vastly preferred due to operational
simplicity of the coupling. Overall, the scope of the
amide component in this coupling is broad and bodes
well for an array of synthetic applications.
[a]Conditions: Iron–NMP: 1 (0.50 mmol), Fe(acac)3 (5
mol%), THF (0.15 M), NMP (600 mol%), C2H5MgCl
(1.20 equiv, 2.0 M, THF), 0 °C, 10 min. RMgCl added
dropwise over 1-2 s. Iron–TMEDA: 1 (0.50 mmol),
Fe(acac)3 (1 mol%), THF (0.15 M), TMEDA (10 mol%),
C2H5MgCl (1.20 equiv, 2.0 M, THF), 23 °C, 3.5 min.
RMgCl added 0.10 mmol/30 s. See SI for details.
could be rationalized by steric interaction with the
low-valent iron species. Moreover, comparison of
isoquinoline (entry 5) and quinoline (entry 6) proved
the latter to be more efficient. Electron-deficient
ligand, styrene, (entry 7) had no effect on the
coupling efficiency. Interestingly, strongly -
donating NHC (NHC = N-heterocyclic carbene)
ligands (entries 8-9) did not furnish the desired
product in improved yields. Similarly, PPh3 (entry
10) was found to have a negligible effect on the
coupling. Overall, the studies with different ligands
emphasize the high efficiency of NMP as the
preferred ligand to iron in this coupling.
Next, we sought to define the scope of the alkyl
coupling partner. Mechanistically, the cross-coupling
with alkyl Grignard reagents is challenging due to
slow transmetalation as well as competing -hydride
elimination and dimerization processes.[11,15] We were
pleased to find that the coupling was compatible with
various 1° and 2° alkyl Grignard reagents (Table 7),
including long-chain 1° Grignard reagents (entries 2-
Additional optimization studies were conducted
(Table 5). First, the coupling could be conducted in a
sustainable solvent, 2-MeTHF, with no detectable
decrease in the reaction efficiency (entries 1-2). This
finding further establishes the potential of 2-MeTHF
4
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
Table 7. Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of
Scheme 5. Large Scale Cross-Coupling.
Amides with Alkyl Grignard Reagents.[a]
3), more-sterically congested 2° alkyl Grignard
reagents (entries 4-5), and activated Grignard
reagents prone to -hydride elimination (entry 6). Of
note, isomerization of i-Pr to n-Pr was not observed
under the reaction conditions (entry 4), attesting to
the mild nature of this catalytic system (cf. iron-
NHC). Moreover, both alkyl-magnesium chlorides
and alkyl-magnesium bromides could be utilized with
similar high levels of efficiency (entry 3), which is in
contrast to several other iron-catalyzed cross-
coupling protocols.[6f]
Furthermore, we were delighted to find that cross-
coupling at the meta-position is also feasible (Scheme
2). This reactivity pattern delivers valuable meta-
alkyl-substituted amide derivatives and is not reliant
on the conjugation with the amide carbonyl. As
expected, the reaction underscores the high efficiency
of NMP as a ligand to iron (cf. TMEDA).
Intriguingly, full substrate recovery of the ortho-
substituted amide was observed under the developed
reaction conditions (Scheme 3). This is likely due to
rigidity of the six substituents comprising the amide
bond due to resonance,[1,16] which prevents oxidative
addition at the sterically-hindered position.
Accordingly, we hypothesized that selective mono-
alkylation at the less sterically-hindered position
could be achieved using this mild protocol. In the
event, excellent selectivity was observed in the
coupling of the 2,4-disubstituted precursor (Scheme
4).[29] The product 4-alkyl-2-chloro-benzamides are
common intermediates in the synthesis of
pharmaceuticals (vide infra).
[a]Conditions: 1 (0.50 mmol), Fe(acac)3 (5 mol%), THF
(0.15 M), NMP (600 mol%), C2H5MgCl (1.20 equiv, 2.0
M, THF), 0 °C, 10 min. RMgCl added dropwise over 1-2 s.
[b] Yield using n-Hex-MgBr. See SI for details.
Cross-coupling of other halide precursors was
evaluated using our model morpholinyl amide (not
shown). We found that the 4-bromo analogue gave
low yield of the desired product (TMEDA: 36%
yield; NMP: 13% yield), while the 4-fluoro analogue
gave little to no conversion (TMEDA: 13%; NMP:
<2%). Thus, the use of cheap and readily available
aryl chlorides is another advantage of this protocol.
The scalability of this sustainable iron-catalyzed
cross-coupling method was evaluated. The alkylation
of a model N,N-Me2 amide could be conveniently
carried out on a gram scale and afforded the desired
product in 82% isolated yield (Scheme 5), attesting to
the synthetic utility of the method.
Limitations of the current cross-coupling method
are presented in Figure 1. We note that the method
does not work with alkyl-Grignard reagents that
cannot promote the formation of low-valent iron
species, including MeMgBr. Furthermore, the method
is chemoselective for benzamide substrates in that
aliphatic amides are recovered unchanged from the
cross-coupling conditions. In general, we focused on
benzamide substrates because these substrates are not
Scheme 2. Cross-Coupling of meta-Substituted Amides.
Scheme 3. Cross-Coupling of ortho-Substituted Amides.
Scheme 4. Chemoselective Mono-Cross-Coupling.
5
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
studies emphasize the role of chelation and amide
rigidity in this iron-catalyzed alkylation of amides.
Further studies on the mechanism are ongoing.
Figure 1. Limitations of the Iron-Catalyzed C(sp2)–C(sp3)
Cross-Coupling of Amides with Alkyl Grignard Reagents.
Note that the reactants are shown below the structures of
starting materials. Np = neopentyl.
activated and therefore best suited for examination of
the reaction scope and limitations. Heteroaromatic
and polyaromatic substrates are well-known to be
activated in iron-catalyzed cross-couplings. Studies to
address the cross-coupling of heteroaromatic and
polyaromatic substrates as well as conjugated amides
are currently ongoing. Likewise, future studies will
address the use of functionalized Grignard reagents in
this and related iron-catalyzed cross-couplings.
Studies to address the current limitations of iron-
catalysis in cross-coupling of substrates containing
polar functional groups are currently underway in our
laboratories.
Scheme 6. Intermolecular Competition Experiments:
Amides.
Mechanistic Studies. Considering the unique
features of this iron-catalyzed alkylation method,
several studies were performed to gain insight into
the reaction mechanism. The well-established kinetic
analysis by intermolecular competition experiments
was used to determine relative reactivity rates.[30]
First, intermolecular competition studies established
that the electronic nature of the amide bond does not
affect the reactivity (N,N-Me2:N,N-Ph/Me
=
1.10:1.00, Scheme 6A), despite significant
a
difference in resonance stabilization of the amide
bond. Second, morpholinyl amides were found to be
inherently more reactive (N,N-morpholine:N,N-Me2
= 2.60:1.00, Scheme 6B). Collectively, this suggests
coordination to the amide bond during the reaction by
a -coordination of the oxygen (cf. -coordination of
the amide bond). Based on relative energetics of the
amide bond (RE = 19.6 kcal/mol vs. RE = 13.5
kcal/mol), as measured by resonance energies,
morpholinyl amides should not be more reactive than
anilides. Moreover, intermolecular competition
studies determine that esters (CO2Me:N,N-Me2 = 9:1)
and trifluoromethyl arenes (CF3:N,N-Me2 = 4.4:1)
couple preferentially to amides (Scheme 7). This
establishes the following order of reactivity of aryl
electrophiles in the iron-catalyzed cross-coupling:
ester > CF3 > amide, and is broadly consistent with
electronic stabilization of the aromatic ring.[31] Finally,
control experiments with ortho-substituted ester and
trifluoromethyl electrophiles demonstrate that these
substrates undergo cross-coupling under the
developed reaction conditions (Scheme 8), indicating
a key role of amide bond conformation to control to
alkylation mono-selectivity. Overall, the mechanistic
Scheme 7. Intermolecular Competition Experiments:
Esters and Trifluoromethyl Arenes.
6
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
Scheme 8. Cross-Coupling of ortho-Substituted Esters and
Trifluoromethyl Arenes.
reactivity of the alkylated products. For example,
iron-catalyzed cross-coupling of n-hexyl group
followed by phenyllithium addition affords
a
functionalized diaryl ketone that has been used as an
intermediate in the synthesis of biologically-active
anthracene derivatives (Scheme 10).[33] Moreover,
similar hydrophobic ketones are broadly used as
fluorescence quenchers.[34] Finally, iron-catalyzed
alkylation/reduction of a piperidinyl amide furnishes
benzyl piperidines, which are used as pesticides and
drug pharmacophores (Scheme 11).[35] Overall, the
presented reactions highlight the potential of this
amide alkylation method to provide direct access to
functionalized molecules of broad synthetic interest.
Application. As noted in the introduction, the
alkylated amide products obtained in this process are
valuable intermediates extensively used in the
synthesis of pharmaceuticals, agrochemicals and
functional materials. To demonstrate the versatility of
the amide products, we conducted a series of
transformations (Schemes 9-11).
Conclusions
In summary, we have reported the synthesis of alkyl-
substituted amides by iron-catalyzed C(sp2)–C(sp3)
cross-coupling of Grignard reagents with aryl
chlorides. The reaction occurs in high yield, under
very mild, operationally-simple conditions, and
provides valuable alkyl-amide products, which have
Scheme 9. Synthesis of 5-HT Receptor Agonists.
useful
applications
in
the
synthesis
of
pharmaceuticals, agrochemicals and functional
materials. This sustainable, iron-catalyzed alkylation
method is characterized by a broad scope, tolerating a
wide range of amides, including sterically-bulky,
sensitive and readily modifiable amides. The reaction
is compatible with challenging organometallics
possessing -hydrogens.
We
have
further
demonstrated the advantage of using O-coordinating
ligands in iron-catalyzed cross-coupling, which
allows for the rapid addition of Grignard reagents
during the process. The reaction was successfully
applied to the synthesis of functionalized amide,
ketone and amine building blocks, illustrating broad
applicability of this approach. Mechanistic and
control experiments outlined the reactivity trends in
iron-catalyzed cross-coupling and clearly indicated
the key importance of the amide bond to control
chemoselectivity of the substitution at the less
sterically-hindered position. The subtle effect of the
morpholinyl amide uncovered in this study provides
further evidence for chelation as an effective method
in iron-catalyzed cross-coupling. This mild protocol
is practical, sustainable and cost-effective. Given the
importance of functionalized amides in organic
synthesis, we anticipate that this process will find
wide application. Further work to expand the scope to
other substrates and base metal catalysts are ongoing
and these studies will be reported in due course.
Scheme 10. Synthesis of Functionalized Ketones via Iron-
Catalyzed Cross-Coupling/Weinreb-Amide-Type Addition.
Scheme 11. Synthesis of Functionalized Amines via Iron-
Catalyzed Cross-Coupling/Reduction.
First, the selective mono-alkylation provides direct
access to chloro-containing alkyl-amide building
blocks that have been broadly utilized in the
pharmaceutical industry. For example, iron-catalyzed
n-propylation affords the corresponding N,N-
diethylamide derivative, which has been employed as
an intermediate in the synthesis of 5-HT receptor
agonists (Scheme 9).[32] The traditional route involves
the Pd-catalyzed Stille coupling of the more
expensive 4-Br-derivative, clearly establishing
advantage of the iron-catalyzed method. Second, the
facility of cross-coupling of morpholinyl amides in
the current protocol offers a unique access to alkyl-
aryl ketones by exploiting the Weinreb amide-type
Experimental Section
General Information. General methods have been
published.[23]
Materials. Iron(III) acetylacetonate (CAS: 14024-18-1)
was purchased from Sigma-Aldrich (cat. no. F300, 97%)
and used as received. Cobalt(III) acetylacetonate (CAS:
21679-46-9) was purchased from Sigma-Aldrich (cat. no.
7
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10.1002/adsc.201800849
Advanced Synthesis & Catalysis
494534, 99.99%). All Grignard reagents were purchased
from Sigma-Aldrich and titrated prior to use.[36]
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Note regarding the rate of addition and definition of
“dropwise addition.” It is well-established that the rate of
addition of the Grignard reagent may be critical to the
outcome of iron-catalyzed cross-couplings. For the purpose
of developing methods that are highly operationally-
convenient, we prefer the rapid addition protocol using
NMP as a ligand. In this protocol, the Grignard reagent is
added rapidly in one-shot to the reaction mixture. We also
recognize that in some cases “slow addition protocol” may
be preferred. In the case of TMEDA as a ligand, the
Grignard reagent is added at a rate of 0.10 mmol every 30 s.
In some protocols, the use of slow-addition syringe pump
protocol is preferred. We recommend that screening of the
rate of addition of the Grignard reagent is included during
the optimization of iron-catalyzed cross-coupling reactions
to expedite reaction development.
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General Procedure for Iron-Catalyzed Cross-Coupling
using NMP as a Ligand. An oven-dried vial equipped
with a stir bar was charged with an amide substrate (neat,
typically, 0.50 mmol, 1.0 equiv) and Fe(acac)3 (typically, 5
mol%), placed under a positive pressure of argon and
subjected to three evacuation/backfilling cycles under
vacuum. THF (0.15 M) and ligand were sequentially added
with vigorous stirring at room temperature, the reaction
mixture was cooled to 0 °C, a solution of Grignard reagent
(typically, 1.2 equiv) was added dropwise with vigorous
stirring and the reaction mixture was stirred for the
indicated time at 0 °C. After the indicated time, the
reaction mixture was diluted with HCl (1.0 N, 1.0 mL) and
Et2O (1 x 30 mL), the organic layer was extracted with
HCl (1.0 N, 2 x 10 mL), dried and concentrated. The
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1
sample was analyzed by H NMR (CDCl3, 400 MHz) and
GC-MS to obtain conversion, yield and selectivity using
internal standard and comparison with authentic samples.
Purification by chromatography on silica gel
(EtOAc/hexanes) afforded the title product.
Representative Procedure for Iron-Catalyzed C(sp2)–
C(sp3) Cross-Coupling. 1.0 g Scale. An oven-dried, two-
necked flask (250 mL) equipped with a stir bar was
charged with 4-chloro-N,N-dimethylbenzamide (1.00 g,
5.45 mmol, 1.0 equiv) and Fe(acac)3 (96.2 mg, 0.27 mmol,
5 mol%). THF (0.35 M) and ligand (600 mol%) were
sequentially added with vigorous stirring at room
temperature, the reaction mixture was cooled to 0 °C, a
solution of n-C6H13MgCl (2.0 M in THF, 3.27 mL, 1.20
equiv) was added dropwise with vigorous stirring and the
reaction mixture was stirred for 10 min at 0 °C. After the
indicated time, the reaction mixture was diluted with HCl
(1.0 N, 3 mL) and Et2O (1 x 100 mL), the organic layer
was extracted with HCl (1.0 N, 2 x 10 mL), dried and
concentrated. The sample was analyzed by 1H NMR
(CDCl3, 400 MHz) and GC-MS to obtain conversion, yield
and selectivity using internal standard and comparison with
authentic samples. Purification by chromatography on
silica gel (EtOAc/hexanes) afforded the title product; 82%
(1.04 g).
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) for generous financial support.
[7] For a leading perspective on homogeneous iron
catalysis, see: A. Fürstner, ACS Cent. Sci. 2016, 2, 778-
789.
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Advanced Synthesis & Catalysis
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FULL PAPER
Iron-Catalyzed C(sp2)–C(sp3) Cross-Coupling of
Chlorobenzamides with Alkyl Grignard Reagents:
Development of Catalyst System, Synthetic Scope
and Application
Adv. Synth. Catal. Year, Volume, Page – Page
Elwira Bisz, Michal Szostak*
11
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