Organic Letters
Letter
neutral ligands such as bisphosphines and amines. Altogether
this would combine the reactivity and operational simplicity of
reactions using NMP and related additives with the ability to
modulate reactivity at the iron center afforded by directly
coordinating ligands. This could potentially, in turn, lead to a
more universal ligand platform for iron-catalyzed cross-
coupling reactions.
Table 1. Optimization of Reaction Conditions for the
Coupling of Methyl 4-Chlorobenzoate 1a and EtMgBr
a
Toward this goal, dilithium amides were chosen as the bis-
anionic ligands, with the ease of synthesis making them an
attractive and modular platform (Figure 1). These were also
b
Entry
Iron Source
Ligand (mol %)
Solvent
2a (%)
1
2
3
4
5
6
7
8
9
Fe(acac)3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Complex 1
FeCl3
L1 (5 mol %)
L1 (5 mol %)
L2 (5 mol %)
L3 (5 mol %)
L1 (10 mol %)
L1 (5 mol %)
L1 (5 mol %)
none
THF
THF
THF
THF
THF
Et2O
CPME
THF
THF
THF
68
83
75
74
75
trace
trace
trace
84
Figure 1. Design concept and rationale behind dilithium amides as
ligands for iron-catalyzed cross-coupling reactions.
none
L1 (5 mol %)
c
10
79
a
b
c
1a (0.34 mmol; 0.17 M), EtMgBr (0.4 mmol) added over ∼20 s.
selected owing to the facile deprotonation using organolithium
reagents, decreasing the potential for residual unreacted
organometallic reagents which could react with the iron
center. Additionally, the driving force of forming a lithium
halide salt could be advantageous in complexation with the
starting iron salt. A series of these dilithium amides were
investigated using the prototypical cross-coupling of methyl 4-
chlorobenzoate 1a and ethylmagnesium bromide (Table 1). In
all cases the ligand and iron salt were prestirred for only 1 min
prior to addition of the electrophile and Grignard reagent in
quick succession.
Determined by GC analysis using dodecane as internal standard.
Using EtMgCl.
cross-coupling reaction. The scope of this methodology was
examined under these conditions using L1 with a range of
electrophiles for which NMP and the aforementioned
alternatives have been applied (Figure 2).
The Grignard reagent chain length did not affect product
yields for the coupling of methyl 4-chlorobenzoate, with all
products being obtained in excellent yields (entries 1−3).
Notably, however, secondary and tertiary alkyl Grignard
reagents gave poor and negligible yields respectively (entries
4−5). A pronounced halogen effect was observed when
switching to methyl 4-bromobenzoate or methyl 4-iodoben-
zoate, resulting in a drastic drop in yield (entry 6−7). In these
cases, a mixture of unreacted electrophile and the product of
protodehalogenation resulted. Similarly poor reactivity was
observed for methyl 3- and 2-chlorobenzoates, resulting in
minimal product formation and a mixture of unreacted
electrophile and the product of protodehalogenation (see
to aryl amides similarly results in high yields (entries 8−9).
Facile and selective coupling at an acid chloride occurred
readily, even in the presence of an aryl bromide bond (entry
10). The coupling of alkenyl bromides and triflates also occurs
with excellent yields (entries 11−14), although this does not
occur with the retention of stereochemistry observed for
reactions using NMP. Quinoline- and pyrimidine-derived
electrophiles also gave moderate to excellent yields (entries
15−18). In the case of 2-haloquinolines, there was no
significant halogen effect observed (entries 15−16), contrast-
ing the aryl esters. The position of the halogen substituent
proved significant, with high yields maintained for 3-
bromoquinoline (entry 17) but diminished for 6-chloroquino-
line (entry 18). 2-Chloropyrimidine also proved effective,
resulting in good yields (entry 19). Perhaps surprisingly, given
the reactivity of haloquinolines, reaction of 2-chloropyridine
gave poor yields (entry 20). This represents an example of
The choice of iron salt in these reactions proved to be
significant, with an 83% yield of 2a obtained using FeCl3 and
L1 compared with 68% in the analogous reaction using
Fe(acac)3 (entries 1 and 2). Variations of the ligand did not
result in a significant change in yield, although bulkier L1
resulted in the highest yield with 83% of 2a (entries 2−4).
Increasing the loading of L1 from 1 to 2 equiv, with respect to
iron, resulted in a small decrease in the yield (entries 2 and 5).
Finally, changing the solvent from THF to other ethereal
solvents proved to have a dramatic effect, with negligible 2a
being observed when the reaction was conducted in diethyl
ether or cyclopentyl methyl ether (entries 6 and 7). In the
absence of any ligand, 2a was not observed in any appreciable
amount (entry 8). The L1−iron(III) chloride complex could
be isolated as the lithium chloride bridged dimer
[L1FeCl]2[LiCl(THF)2] from the reaction of L1 with FeCl3
in THF. Crystals suitable for single crystal X-ray diffraction
could be grown from pentane, and although they diffracted
weakly, the structure of the complex and formulation of the
crystals are unambiguous. This preformed complex gave
comparable yield to premixing L1 and FeCl3 (entry 9),
supporting the notion that the diamide does indeed act as a
ligand to iron. Finally, no significant halogen effect was
observed for the Grignard reagent (entry 10). Notably, these
reactions are complete within 15 min and did not require a
highly controlled and slow addition of the Grignard reagent. A
further advantage is that these reactions were run at 20 °C,
rather than the lower temperatures often used for this type of
5959
Org. Lett. 2021, 23, 5958−5963