Angewandte
Communications
Chemie
We ultimately elected FeCl as our catalyst of choice,
3
a THF/NMP ratio of 7.5:1, and a reaction temper-
ature of À788C as our most general reaction
conditions to apply to a broad range of (E)-enol
carbamates. Interestingly, as will be discussed later,
we found that NMP was not required as a co-solvent
to obtain high yields and stereoselectivities when
(Z)-enol carbamates were employed.
Table 2 summarizes our substrate scope to date
with more elaborate (E)-enol carbamates and a vari-
ety of Grignard reagents. A wide range of functional
groups were tolerated, including acetals (27), ethers
(37), silanes (38), primary bromides (39), terminal
alkynes and alkenes (20, 40, 41), and protected
amines (42). What perhaps is most important to
highlight is that the current method is very amend-
able to the stereoselective synthesis of acyclic
tetrasubstituted acrylates (i.e., 20–24, 31, 32) where
other Fe-catalyzed methods have yet to show their
full potential. Whereas most of the products shown
in Table 2 have no precedence in the literature,
several of them had been synthesized previously but
with very poor stereoselectivity. For example, the
synthesis of 13 has previously been achieved in 80% yield and
an E/Z ratio of 3.8:1 by employing a solvent-free Horner–
Scheme 2. Selected examples for the stereoselective synthesis of highly substi-
tuted (E)- and (Z)-enol carbamates from readily available acetoacetate deriva-
tives.
[
16a]
work.
Scheme 2.
A few representative examples are shown in
[
17]
With a stereoselective synthesis of enol carbamates in
hand, we embarked on a systematic screening approach to
identify optimized reaction conditions for the Fe-catalyzed
cross-coupling with Grignard reagents. A summary of these
efforts using (E)-1 as the model substrate and n-hexylmagne-
sium bromide as the cross-coupling partner is presented in
Wadsworth–Emmons approach.
The Fe-catalyzed cross-
coupling between (E)-1 and hexylmagnesium bromide, for
comparison, gave 13 in an E/Z ratio of 65:1 and 96% yield
(Table 2). Olefin 26 is an important precursor to the
fragrances phenoxanol, citralis, and citralis nitrile, and the
starting olefin geometry plays a critical role in the asymmetric
III
[18]
Table 1. We were pleased to find that several Fe salts were
synthesis of these chiral fragrant molecules. The highest
effective in catalyzing the cross-coupling reaction, with the
only exception being FeF ·3H O. Furthermore, as originally
discovered by Cahiez and Avedissian, the addition of NMP
as a co-solvent provided a noticeable increase in yield and had
an even more dramatic positive impact on stereoselectivity.
stereoselectivity for the synthesis of 26 that we could find was
achieved by a reductive debromination of the corresponding
vicinal dibromide with an E/Z ratio of 5.25:1 with an overall
yield of 65%. As can be seen in Table 2, the Fe-catalyzed
cross-coupling between (E)-1 and phenethylmagnesium chlo-
ride gave 26 in an E/Z ratio of > 50:1 and 82% yield. Finally,
this method is readily scalable, with a 20 mmol scale reaction
yielding almost identical yields and stereoselectivities as the
same reaction on 1 mmol scale (see compound 18 in Table 2).
Next, we turned our attention to exploring the scope with
3
2
[
6]
[19]
Table 1: Selected optimization results for the iron-catalyzed cross-
[
a]
coupling between (E)-1 and hexylmagnesium bromide.
(
Z)-enol carbamates. The culmination of our efforts with
these substrates is summarized in Table 3. We are pleased to
report that all of the fully substituted acyclic (Z)-carbamates
that we have explored to date reacted with a very high level of
stereoselectivity in the Fe-catalyzed cross-coupling reaction
with alkyl Grignard reagents. In fact, the reaction is stereo-
specific for many of the products as we were unable to detect
[
d]
Entry
Catalyst
Solvent
Yield [%]
E/Z
[
[
b]
b]
1
2
3
4
5
Fe(acac)3
FeCl3
Fe(acac)3
FeBr3
THF
THF
81
74
90
91
trace
94
96
1:1
2:1
15:1
45:1
N/A
>50:1
>50:1
[
c]
c]
THF/NMP
THF/NMP
THF/NMP
THF/NMP
THF/NMP
[
1
the corresponding E isomers by H NMR spectroscopy or LC/
[
c]
FeF ·3H O
3
2
MS. Furthermore, we observed that NMP is not required to
[
e]
[c]
6
FeCl (99.99%)
[20]
3
obtain high yields or stereoselectivities for these substrates.
[
c]
7
FeCl3
We believe that the proximity of the carbonyl oxygen atom in
the Z stereoisomers plays a similar role as NMP in stabilizing
an intermediate organoiron species, thus obviating the need
for any co-solvent. As a result, all of the products shown in
Table 3 except for 53, 54, and 55 did not require any
chromatographic purification. At this point, we would also
like to highlight several products that demonstrate the
[
(
[
0
a] Reactions were performed at À788C with the Fe catalyst (5 mol%),
E)-1 (1 equiv), and n-hexylMgBr (2 equiv) unless otherwise stated.
b] Reactions were performed at 0.8m. [c] Reactions were performed at
.07m with a THF/NMP ratio of 7.5:1. [d] Determined by HPLC analysis.
e] The success of high-purity FeCl supports the notion that other low-
[
3
level metal impurities (e.g., Pd) are not responsible for catalysis.
acac=acetylacetonate, NMP=N-methyl-2-pyrrolidinone.
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 6689 –6693