N,N-Dimethylformamide as Hydride Source in Nickel-Catalyzed Asymmetric Hydrogenation of α,β-Unsaturated Esters

Article abstract of DOI:10.1021/acs.orglett.6b02662

Asymmetric transfer hydrogenation of α,β-unsaturated esters is realized by using a nickel/bisphosphine catalyst and N,N-dimethylformamide (DMF) as the hydride source.

Full text of DOI:10.1021/acs.orglett.6b02662

Letter
pubs.acs.org/OrgLett
N,N‑Dimethylformamide as Hydride Source in Nickel-Catalyzed
Asymmetric Hydrogenation of α,β-Unsaturated Esters
Siyu Guo and Jianrong (Steve) Zhou*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, 637371 Singapore
S
* Supporting Information
ABSTRACT: Asymmetric transfer hydrogenation of α,β-unsatu-
rated esters is realized by using a nickel/bisphosphine catalyst and
N,N-dimethylformamide (DMF) as the hydride source.
We discovered that a nickel catalyst supported by Me-
DuPhos, a chiral bisphopshine originally invented by Burk,15
afforded good stereoinduction in a model reaction (Scheme 1).
symmetric hydrogenation is an industrially important
Aprocess in the production of chiral drugs, fragrance, and
agrochemicals.1 Today, enantioselective hydrogenation of
prochiral olefins mostly relies on metal catalysts of heavy
noble metals including Rh,2 Ru,3 Ir,4 and lately Pd.5 The
expensive heavy metals not only incur high costs in the
production process but also require recovery and recycling of
the toxic metals for environmental reasons. In addition, these
noble metals are produced in small amounts each year and are
facing quickly depleting reserves. For example, only 3 tons of
iridium is produced a year worldwide, of which only 10% is
committed to chemical catalysis.
Scheme 1. Performance of Chiral Bisphosphines in a Model
Reaction of (E)-α,β-Methylcinnamate (Calibrated
GCYields)
In comparison, first-row metal catalysts of abundant metals
such as copper, nickel, and iron have gained renewed interest in
recent years. They are being produced in millions of tons every
year, and they are thousands-fold cheaper than noble metals.
Moreover, noble metals have much higher carbon footprints
than Earth-abundant metals due to complex extraction and
purification processes; for example, nickel and palladium have
carbon footprints of 7 and 6649 CO2 equiv, respectively.
Notably, oral exposure limits of metal residues in active
pharmaceutical ingredients are not very different, for example,
25 ppm for nickel and 10 ppm for palladium, respectively.6
In the past decade, Beller, Morris, and others reported iron
catalysts for asymmetric hydrogenation of ketones and
ketimines,7 but so far only asymmetric hydrogenation of
prochiral olefins has been reported.8 Recently, the Chirik group
disclosed cobalt−bisphosphine catalysts for asymmetric hydro-
genation of aryl olefins and enamides.9 Recently, the same
group also reported a nickel/DuPhos catalyst for hydrogenation
of α,β-unsaturated esters in good ee, but 33 bar of hydrogen gas
was needed.10 Our group recently reported nickel/bisphos-
phine catalysts for asymmetric transfer hydrogenation of
activated olefins, ketimines, and hydrazones.11 We used easy-
to-handle formic acid as a safe and cheap hydrogen source.12
Herein, we disclose our new finding that N,N-dimethylfor-
mamide (DMF) served as an alternative hydrogen source in
asymmetric hydrogenation of α,β-unsaturated esters. DMF is a
common solvent13 and was used in reductive synthesis of
nanoparticles of silver, gold, and platinum.14
The performance of other chiral bisphosphines was rather
unsatisfactory. For example, two related ligands, Me-BPE and
Ph-BPE, gave only 56% ee and 78% ee, respectively.
Additionally, P-chiral bisphosphines including TangPhos,
DuanPhos, and QuinoxP* provided less than 20% ee.16
Other less donating bis(arylphosphine)s such as BINAP,
chirophos, and segphos were completely inactive in the test
case.
We found that a 3:1 mixture of DMF and water was sufficient
to work as the hydrogen source in the model reaction (Table
1). If dry DMF was used, no conversion was seen (entry 1).
Additionally, when we changed the major solvent of DMF to
DMA, DMSO, dioxane, or alcohols, no reaction was detected
by GC, either (entries 2−4). We also changed the AlCl3
Received: September 5, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
unfortunately. Thus, the β-aryl rings also contributed to the
stereodifferentiating process. In the hydrogenation of (E)-
phenylsuccinate, we obtained the product 2p in 95% ee after
the ancillary ligand was switched to TangPhos. When we
changed the ester group of 1a to other electron-withdrawing
groups such as aldehyde, ketone, and amide, only partial
conversion and moderate ee values were seen, for example, 40%
conversion and 78% ee for the methyl ketone after 12 h at 110
°C. We found that aryl nitriles and nitro groups were reduced
to a complex mixture. Moreover, simple aryl olefins did not
react.
DMF was known to undergo acidic hydrolysis to give rise to
N,N-dimethylammonium formate under heating.17 When we
heated a 3:1 mixture of DMF-d7 (99.5% D) and D2O (99.9%
D) in the presence of AlCl3 at 110 °C for 12 h, a small
percentage of the formyl signal of DMF (8.18 ppm) was
converted to a distinct signal at 8.49 ppm by proton NMR
spectroscopy, which corresponded to the formate ion (signal
for formic acid: 8.40 ppm).
Table 1. Effect of Solvents and Additives in a Model
Hydrogenation of Ethyl (E)-α,β-Methylcinnamate
(Calibrated GC Yields)
entry changes in standard conditions conv (%) yield (%) ee (%)
1
DMF as solvent
3:1 DMA/H2O
3:1 DMSO/H2O
3:1dioxane/H2O
BF3·OEt2
InCl3 (2×)
ZnCl2 (2×)
Zn(OTf)2 (2×)
p-tolSO3H (0.2×)
CF3SO3H (0.2×)
HCl (2×)
0
0
0
0
2
3
0
0
4
0
0
5
70
100
93
41
97
67
51
66
98
90
39
94
63
50
27
81
81
81
78
81
89
6
7
8
9
10
11
When we used a mixture of DMF and D2O in the model
reaction (Scheme 3a), the product was deuterated at both α
additive to other Lewis acids and Brønsted acids, but only
inferior results were obtained. Notably, in the presence of InCl3
and ZnCl2, the model reactions still proceeded in good yields,
but the ee values were only around 80% (entries 6 and 7).
When HCl was used as the additive, only half conversion was
detected under the same conditions, although the ee was almost
as good as the optimized conditions (entry 11).
Scheme 3. Deuterium-Labeling Experiments
With the optimized conditions in hand, we explored the
scope of olefins. α,β-Unsaturated esters having the aryl rings
trans to the ester groups reacted well and gave high ee values
(Scheme 2). Both electron-rich and -poor substituents were
tolerated on the aryl rings. The o-methoxy group (2j) can be
present on the aryl rings, while pyridyl and thienyl rings (2l and
2m) were tolerated, too. Additionally, two cyclic olefins were
also successfully hydrogenated with good ee values (2n and
2o). Replacement of the β-aryl rings with alkyl groups such as
benzyl and cyclohexyl led to moderate stereoselectivity,
Scheme 2. Examples of Transfer Hydrogenation (Isolated
Yields)
positions with combined 0.91 D. This is expected from non-
stereoselective α deuteration of the key nickel enolate18
produced via asymmetric hydride insertion.19 No deuteration
of starting material was detected under the same conditions.
The product also contained 0.31 D at the β position, probably
caused by a parasitic equilibrium between the nickel hydride/
deuteride and nickel(0) complexes. In another experiment
using DMF-d7 and H2O, only the β position was labeled with
0.77 D (Scheme 3b).
In summary, we report an asymmetric-transfer hydrogenation
of α,β-unsaturated esters using nickel catalysts and DMF as the
hydride source. DMF decomposed in the presence of water and
AlCl3 to give the formate ion. In a recent calculation, we
compared pathways of cationic hydridonickel(II) and neutral
hydridonickel(I) complexes in asymmetric-transfer hydro-
genation of ketimines.10 The latter was found to have an
exceedingly high barrier for the decarboxylation of formate to
generate metal hydride species.
B
DOI: 10.1021/acs.orglett.6b02662
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(g) Bernasconi, M.; Muller, M.-A.; Pfaltz, A. Angew. Chem., Int. Ed.
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02662.
■
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Experimental procedures (PDF)
Spectral data for all new compounds (1H and 13C NMR,
MS) (PDF)
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jrzhou@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank 2013 Singapore GSK-EDB Green and Sustainable
Manufacturing Award and Nanyang Technological University
for financial support.
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