Asymmetric Transfer Hydrogenation of Ketones with Well-Defined Manganese(I) PNN and PNNP Complexes

Article abstract of DOI:10.1021/acs.organomet.8b00625

Three new manganese complexes trans-[Mn(P-NH-NH-P)(CO)₂][Br], (14) P-NH-NH-P = (S,S)-PPh₂CH₂CH₂NH-CHPhCHPhNHCH₂CH₂PPh₂), fac-[Mn(P′-NH-NH₂)(CO)₃][Br], (15) P′-NH-NH₂ = (S,S)-PPh₂(C₆H₄)NHCHPhCHPhNH₂, and syn-mer-Mn(P-NH-NH₂)(CO)₂Br, (16) P-NH-NH₂ = (S,S)-PPh₂CH₂CH₂NHCHPhCHPhNH₂ were synthesized and tested for the asymmetric transfer hydrogenation (ATH) of acetophenone in 2-PrOH. The ligands have stereogenic centers derived from the starting diamine, (S,S)-DPEN. Complex 16 was shown by NOE NMR experiments to have Mn-Br syn to the N-H of the secondary amine. Only the precatalyst 16, upon reaction with potassium tert-butoxide (KO^tBu) in 2-PrOH, generated an active system at 80 °C for the ATH of acetophenone to 1-phenylethanol in an enantiomeric excess (ee) of 42% and thus was selected for further investigation into the mechanism of transfer hydrogenation. The corresponding amido complex Mn(P-N-NH₂)(CO)₂ (17), a borohydride complex syn-mer-Mn(P-NH-NH₂)(CO)₂(BH₄) (18), and an ethoxide complex anti-mer-Mn(P-NH-NH₂)(CO)₂(OEt) (19′) were independently synthesized and tested in the ATH of acetophenone. The amido complex 17 and the borohydride complex 18 displayed similar activity to 16 activated in basic 2-PrOH, but the anti NH OEt complex 19′ was completely inactive. This result suggested that the NH effect, as described by Noyori, was required to obtain catalytic activity. The syn NH BH₄ manganese complex is one of the most active manganese ATH catalysts to date and can hydrogenate a variety of aromatic ketones, including base-sensitive substrates such as p-acetylbenzoate ethyl ester.

Full text of DOI:10.1021/acs.organomet.8b00625

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
Asymmetric Transfer Hydrogenation of Ketones with Well-Defined
Manganese(I) PNN and PNNP Complexes
Karl Z. Demmans, Maxwell E. Olson, and Robert H. Morris*
Department of Chemistry, University of Toronto, 80 Saint George Street, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
ABSTRACT: Three new manganese complexes trans-
[Mn(P−NH−NH−P)(CO)2][Br], (14) P−NH−NH−P =
(S,S)-PPh2CH2CH2NH−CHPhCHPhNHCH2CH2PPh2),
fac-[Mn(P′−NH−NH2)(CO)3][Br], (15) P′−NH−NH2
=
(S,S)-PPh2(C6H4)NHCHPhCHPhNH2, and syn-mer-Mn(P−
NH−NH2)(CO)2Br, (16) P−NH−NH2 = (S,S)-
PPh2CH2CH2NHCHPhCHPhNH2 were synthesized and
tested for the asymmetric transfer hydrogenation (ATH) of
acetophenone in 2-PrOH. The ligands have stereogenic
centers derived from the starting diamine, (S,S)-DPEN.
Complex 16 was shown by NOE NMR experiments to have Mn−Br syn to the N−H of the secondary amine. Only the
precatalyst 16, upon reaction with potassium tert-butoxide (KOtBu) in 2-PrOH, generated an active system at 80 °C for the
ATH of acetophenone to 1-phenylethanol in an enantiomeric excess (ee) of 42% and thus was selected for further investigation
into the mechanism of transfer hydrogenation. The corresponding amido complex Mn(P−N−NH2)(CO)2 (17), a borohydride
complex syn-mer-Mn(P−NH−NH2)(CO)2(BH4) (18), and an ethoxide complex anti-mer-Mn(P−NH−NH2)(CO)2(OEt)
(19′) were independently synthesized and tested in the ATH of acetophenone. The amido complex 17 and the borohydride
complex 18 displayed similar activity to 16 activated in basic 2-PrOH, but the anti NH OEt complex 19′ was completely
inactive. This result suggested that the NH effect, as described by Noyori, was required to obtain catalytic activity. The syn NH
BH4 manganese complex is one of the most active manganese ATH catalysts to date and can hydrogenate a variety of aromatic
ketones, including base-sensitive substrates such as p-acetylbenzoate ethyl ester.
at 70 °C in 2-PrOH, producing a racemic mixture of alcohols
in 24 h.35 For the DH of esters, Pidko and co-workers
synthesized achiral Mn(P−N)(CO)3Br and [Mn(P−
N)2(CO)2][Br] precatalysts, while Milstein and co-workers
made achiral Mn(P−N−N)(CO)2Br precatalysts containing a
methylene-pyridine moiety to take advantage of their well-
known dearomatization-rearomatization mechanism (3 and 4
Figure 1).36 Clarke and co-workers reported a chiral [Mn(P−
NH−N)(CO)3][Br] precatalyst with a ferrocenyl backbone of
the P−NH−N ligand for the ADH of ketones (5, Figure 1).37
For the TH of ketones, Sortais synthesized Mn(N−Y)-
(CO)3Br (where Y = N, O) precatalysts (6a,b, Figure 1).30
Sortais probed the ATH of ketones by stirring bromopenta-
carbonylmanganese with a variety of chiral diamines in a 1:1
ratio to produce the active species in situ. While the exact
structures of the precatalysts were not known, this study
demonstrated that manganese catalysts with bidentate chiral
diamines yield an ee of the product alcohols of up to 64%.38
The most active and enantioselective manganese ATH catalyst
to date was synthesized by Zirakzadeh and co-workers
(characterized as diastereomeric hydrides species 7 and 7′,
Figure 1).31 These hydride species required basic conditions to
INTRODUCTION
■
Finding catalysts for the asymmetric hydrogenation of ketones,
imines, and alkenes is a valuable pursuit as the enantiomerically
pure products are of utmost importance to the fragrance,
flavor, and pharmaceutical industries.1−6 These products can
be synthesized via asymmetric direct hydrogenation (ADH)
under hydrogen gas, and ATH using ethanol or 2-PrOH as
sacrificial alcohols. Other synthetic routes include ammonia-
borane, sodium formate in water, or azeotropic mixtures of
formic acid and triethylamine.6−9 Ruthenium, rhodium, and
iridium remain the most studied transition metals for the ATH
of ketones, but there has been a recent push to use well-defined
catalysts based on first-row transition metals..10−28 To date,
there are a rapidly growing number of well-defined iron ATH
catalysts but only a few examples based on other first-row
transition metals such as nickel,23 cobalt,29 or manganese.30,31
Notable among well-defined manganese hydrogenation
catalysts are Beller’s recently reported achiral Mn(P−N−
P)(CO)2Br and [Mn(P−N−P)(CO)3][Br] (1, Figure 1)
precatalysts for the direct hydrogenation (DH) of nitriles,
ketones, esters, and aldehydes,32,33 as well as a one example for
the ADH of ketones with a [Mn(P*−N−P*)(CO)3][Br]
precatalyst containing stereogenic phospholane rings on the
phosphorus donors (2, Figure 1).34 Beller’s achiral precatalysts
also functioned in the transfer hydrogenation (TH) of ketones
Received: August 29, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Figure 1. Well-defined manganese precatalysts.
achieve catalytic turnover. In optimized conditions with 0.5
mol % of precatalyst, alcohols with an ee of up to 85% could be
obtained at room temperature in only 2 h.31
Reported herein are the syntheses, characterizations, and
catalytic activities in the ATH of ketones for three new
manganese catalysts based on previously reported tetradentate
P−NH−NH−P and tridentate P′−NH−NH2, P−NH−NH2
ligands 8−10 (see Figure 2) derived from (S,S)-DPEN.11,12,14
RESULTS AND DISCUSSION
■
Improved Synthesis of the P−NH−NH−P Ligand. The
previously reported synthesis of the P−NH−NH−P ligand 8
required four steps over 7 days, including a protection of the
phosphine by oxidation and subsequent deprotection with
trichlorosilane in basic conditions resulting in a very poor yield
of 8 (Scheme 1).11
The new synthetic protocol was adapted from the synthesis
of the P−NH−NH2 ligand (10, Figure 2).12 The air- and
moisture-stable phosphonium dimer 12 (Scheme 2) was
synthesized from the acetal 11 according to the literature.17
All of the subsequent steps were then performed in a single-
pot. The dimer 12 was deprotonated in basic methanol to
release a diphenylphosphinoacetaldehyde, which undergoes an
iron-templated condensation reaction with (S,S)-DPEN to
produce the [Fe(P−N−N−P)(MeCN)2]2+ intermediate 13, as
previously reported.17 Upon addition of lithium aluminum
Figure 2. P−NH−NH−P, P′−NH−NH2, and P−NH−NH2 ligands.
Scheme 1. Previous Synthesis of the P−NH−NH−P Ligand 8
B
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Scheme 2. New Synthetic Protocol for the Synthesis of the P−NH−NH−P Ligand 8
Scheme 3. Synthesis of New Manganese Complexes 14−16 with Ligands 8−10
hydride (LiAlH4), the iron(II) was reduced to iron(0), and the
imines of the P−N−N−P ligand were reduced to release the
P−NH−NH−P ligand 8. The extraction in the workup may be
performed open to air and, if completed in less than 2 h, gives
8 with no observable oxidation of the 2-(diphenylphosphinyl)-
ethyl group as confirmed in the 31P{1H} NMR spectrum. For
long-term storage, however, the ligand must be placed under
an inert atmosphere.
This alternative synthetic protocol reduced the total amount
of time to synthesize the product by 5 days, replaced the
energy-intensive hydroamination step with a simple con-
densation reaction performed at 28 °C (Scheme 2), and
afforded the ligand 8 in moderate yield.
C
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Table 1. IR Data for the Manganese Complexes 14−16 and Comparison with those of Reported Compounds
a
manganese complex
CO stretches (cm−1
)
reference
trans-[Mn(P−NH−NH−P)(CO)2][Br], 14
fac-[Mn(P′−NH−NH2)(CO)3][Br], 15
fac-[Mn(P−N−P)(CO)3][Br], 1
mer-[Mn(P*−N−P*)(CO)3][Br], 2
fac-[Mn(P−N)(CO)3][Br], 6b
1930, 1854
2032, 1955, 1914
2007, 1933, 1891
2009, 1908, 1821
2029, 1936, 1911
1921, 1842
this work
this work
33
34
30
fac-[Mn(P−N−N)(CO)3][Br], 5
mer-Mn(P−NH−NH2)(CO)2Br, 16
mer-Mn(P−N−N)(CO)2Br, 3
37
1915, 1828
1916, 1829
this work
40
mer-Mn(P−N−N)(CO)2Br, 4
1909, 1828
39
a
P* indicates stereogenic phospholane rings on the phosphorus donors.
1
Figure 3. H NMR resonances for 14 and 16 in DMSO-d6. Selected 2D NOESY correlations are shown with arrows.
Synthesis of Manganese Complexes. Treatment of
Mn(CO)5Br with each ligand 8−10 in toluene at 110 °C
afforded the corresponding manganese complexes 14−16 in
moderate to high yields as shown in Scheme 3.
protons (Figure 3), as outlined in the Supporting Information.
The isomer of 16 shown in Scheme 3 is calculated by use of
density functional theory (DFT) to be 1.4 kcal/mol more
stable than the one with Mn−Br anti to NH of the secondary
amine (labeled 16′ in the Supporting Information). The NMR
spectra for manganese complex 15 indicated the presence of a
minor diastereomer. Upon heating to 65 °C the 31P NMR
signal of the minor diastereomer disappears, concomitantly
Over the course of the reaction in toluene, complexes 14
and 15 precipitated out of solution to yield the manganese(I)
di- or tricarbonyl bromide salt, respectively. These complexes
are greater than 92% pure based on elemental analysis done
three times but could not be crystallized to complete purity.
Complex 14 has C2 symmetry, making the two diphenylphos-
phino donors spectroscopically equivalent and producing a
singlet in the 31P{1H} NMR spectrum. This symmetry, as
1
with the emergence of a new set of H NMR signals (see the
Supporting Information). This suggested the formation of a
manganese complex bearing an uncoordinated phosphine
1
donor which may broaden the H NMR spectrum. A rapid
1
indicated also by the H NMR data, suggested that a trans-
acid−base equilibrium between the highly acidic protonated
amino donor bearing a bromo counteranion 15 and the
deprotonated manganese complex with hydrogen bromide may
carbonyl complex was isolated, and indeed the infrared (IR)
spectrum displays the asymmetric and symmetric stretches of
the carbonyl ligands at 1930 and 1854 cm−1, respectively. The
IR spectrum of complex 15 displayed three stretches for the
carbonyl ligands at 2032, 1955, and 1914 cm−1, which
suggested the isolation of the fac-isomer as the IR data
matched closely to those of the precatalyst fac-[Mn(P′−N−
P)(CO)3][Br] that was crystallographically characterized by
Beller and co-workers (1, Figure 1).33−35 Our precatalysts cis-
β-[Fe(P′−NH−NH−P)(CO)(Br)][BPh4] (P′−NH−NH−P
= 9 with an 2-(diphenylphosphinyl)ethyl arm) also preferen-
tially bend at this aniline nitrogen.14 Reaction of ligand 10 with
Mn(CO)5Br initially formed a precipitate, but after stirring the
solution for 4 h at 110 °C, it redissolved. The complex Mn(P−
NH−NH2)(CO)2Br (16) was isolated after removal of the
toluene in vacuo and washing with pentane and drying as an
analytically pure mixture of diastereomers as indicated by the
31P{1H} and 1H NMR spectra and elemental analysis. The mer-
(P−NH−NH2)-cis-dicarbonyl structure of the diastereomers
was suggested on comparison with the IR spectrum known
mer-Mn(P−N−N)(CO)2Br complexes (Table 1).31,39,40
The 2D NMR spectra for the manganese complexes 14 and
16 were used to assign each proton, excluding aromatic
1
also lead to the broadening of the H NMR spectrum in this
case.
Activity in the ATH of Acetophenone. Manganese
complexes 14−16 were tested in the ATH of acetophenone
under optimized conditions to compare their catalytic activity.
The results are shown in Table 2.
The catalytic activity of these manganese complexes
activated in basic 2-PrOH was sluggish at 28 °C, prompting
an increase in the temperature of the reaction vessels to 80 °C.
Fac-[Mn(P′−NH−NH2)(CO)3][Br] 15 did not catalyze the
ATH of acetophenone under these forcing conditions. trans-
[Mn(P−NH−NH−P)(CO)2][Br] 14 produced 1-phenyletha-
nol in a 3% yield, while mer-Mn(P−NH−NH2)(CO)2Br 16
displayed high activity in basic 2-PrOH with a poor ee of 37%.
Precatalyst 16 contains a bromo ligand which can be labilized
upon addition of base to produce an amido manganese
complex and potassium bromide, while the manganese salt
complexes 14 and 15 do not contain a halide to allow for the
facile formation of an open site on the manganese center
Activation Studies of Manganese Precatalyst. Further
reactions were performed with 16 to detect possible catalytic
D
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
formation of this amido complex by deprotonation of the
secondary amine of 16, rather than the primary amine, was
established by analysis of the 1H NMR resonances (Scheme 4),
Table 2. Catalyst Screen for Activity in the ATH of
Acetophenone at 28 and 80 °C
a
1
1
which were assigned by using 2D H−1H COSY, 2D H−1H
NOESY, and 1H−13C HSQC NMR experiments. The IR
spectrum of 17 displayed two carbonyl stretches at 1890 and
1808 cm−1, which are comparable to those of Mn(P−N−
P)(CO)2 and Mn(P−N−N)(CO)2 complexes found in the
literature.41,42,40
complex
none
temperature (°C)
conversion (%)
ee (%, (R)-alcohol)
28
80
28
80
28
80
28
80
0
0
0
3
0
0
56
>99
-
-
-
68
-
-
Several attempts were made to isolate a hydride species by
mimicking catalytic conditions without the addition of the
substrate. Three hydride species in minute amounts were
14
15
16
1
2
observed by H NMR spectroscopy at −4.12 (d, JPH = 72
2
2
Hz), − 4.63 (d, JPH = 36 Hz), and −4.73 (d, JPH = 38 Hz),
but the structures of these hydride species could not be
discerned because of their low concentration in solution. The
attempted direct synthesis of a hydride species via a reaction of
16 with sodium triethylborohydride at −78 °C in toluene
initially formed a bright yellow solution, but upon warming to
28 °C the solution immediately turned red. Removal of the
solvent in vacuo indicated the presence of the amido complex
17 as confirmed in the 31P{1H} NMR spectrum. It is proposed
that the hydride was formed, but preferentially releases
hydrogen gas at 28 °C to form the more stable amido
complex. Changing to a less reactive hydride source, sodium
borohydride, and stirring the solution for 1.5 h produced the
manganese borohydride complex containing the Mn−BH4 syn
to the NH of the secondary amine (18 in Scheme 5). The
yellow powder of 18 was very sensitive to oxygen and was
characterized solely by NMR and IR spectroscopy. The syn
isomer is calculated by use of density functional theory to be
3.8 kcal/mol more stable than the one with Mn−BH4 anti to
NH of the secondary amine (labeled 18′ in the Supporting
Information). If the reaction was stirred for 16 h, then the
isolated product was a manganese ethoxide complex containing
the Mn−OEt anti to the NH of the secondary amine (19′ in
Scheme 5, wherein the apostrophe denotes the anti
conformation). The yellow powder of 19′ was also very
sensitive to the air and was characterized solely by NMR and
IR spectroscopy.
40
37
a
Reactions performed under argon at 28 °C for 24 h or 80 °C for 1 h.
Acetophenone:KOtBu:manganese complex ratio was 100:1:1. Volume
of 2-PrOH = 8 mL. [acetophenone] = 0.312 M; [KOtBu] = 6.25 ×
10−4 M; [Mn complex] = 3.13 × 10−4 M; [2-PrOH] = 13.1 M. (R)-1-
Phenylethanol was the major product. Conversions and ee were
determined using a gas chromatograph containing a chiral column.
Di-tert-butylbenzene was used as an internal standard.
intermediates and synthesize a borohydride complex which
enters the catalytic cycle without the addition of KOtBu. The
first step in the activation of 16 was the deprotonation of an
amine to form a manganese amido complex as shown in
Scheme 4.
Scheme 4. Synthesis of the 5-Coordinate Mn(P−N−
1
NH2)(CO)2 Complex 17. Assignment of H NMR (C6D6)
Resonances Made Using 2D NOESY Correlations (Arrows)
An ethoxide complex is proposed to form by the loss of BH3
and H2 from 18 to produce the amido complex 17, which then
heterolytically cleaves the H−O bond of ethanol to form 19
with a Mn−OEt group syn to the NH of the secondary amine.
This complex rearranges to the anti isomer 19′, which is
calculated by use of density functional theory to be 4.0 kcal/
mol more stable than 19 (see Supporting Information). The
1H NMR resonances of 18 and 19′ could be assigned through
Upon addition of KOtBu to a bright yellow solution of 16 in
THF, there was an immediate color change to deep red, which
is characteristic of 5-coordinate manganese amido com-
plexes.41 The isolated red solid was very oxygen sensitive
and characterized only by IR and NMR spectroscopy. The
Scheme 5. Synthesis of the Syn Manganese Borohydride Isomer and the Anti Manganese Ethoxide Isomer; Assignment of the
1H NMR (Toluene-d8) Resonances and 2D NOESY Correlations (Arrows)
E
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Scheme 6. Proposed Catalytic Cycle for the ATH of Ketones with 16, 17, and 18
analysis of the 2D NMR spectra as outlined in Scheme 5. The
31P{1H} NMR spectrum and CO stretches in the IR spectrum
of 19′ are similar to the manganese bromide complex 16, while
the CO stretches in the IR spectrum of 18 at 1920 and 1836
cm−1 were comparable with those of a mer-Mn(P−NH−
P)(CO)2(BH4) complex bearing cis-carbonyl ligands which
was characterized by X-ray crystallography by Gauvin et al.41
Proposed Catalytic Cycle. The borohydride complex 18
and ethoxide complex 19′ were independently tested in the
ATH of acetophenone at 80 °C without the addition of KOtBu
and only 18 produced 1-phenylethanol. The proposed catalytic
cycles are presented in Scheme 6 and Scheme 7, respectively.
Scheme 7. Proposed Formation of an Inactive Hydride
Species 20′ from 19′
The manganese precatalyst 16 reacts with KOtBu to produce
an amido manganese complex 17, potassium bromide, and tert-
butanol. In an outer-sphere, six-membered transition state, a
proton and hydride are transferred from 2-PrOH to the amido
complex to produce the uncharacterized syn NH hydride
complex 20, which may benefit from the NH Effect.43 The
active hydride may also be accessed by stirring a solution of the
borohydride complex 18 or amido complex 17 in 2-PrOH
without the need for KOtBu. In this manner, ketones bearing
base-sensitive functional groups could also be asymmetrically
reduced (p-acetylbenzoate ethyl ester, Figure 4). In the
subsequent step, the manganese hydride species 20 transfers
a hydride and proton in either a concerted or stepwise outer-
Figure 4. ATH of various ketones with precatalyst 18. Reactions
performed under argon at 80 °C. Ketone:18 ratio was 100:1. Volume
of 2-PrOH = 8 mL. [ketone] = 0.312 M; [18] = 3.13 × 10−4 M; [2-
PrOH] = 13.1 M. (R)-Alcohol was the major species in all cases.
Conversions and ee were determined using a gas chromatograph
containing a chiral column. Di-tert-butylbenzene was used as an
internal standard.
sphere mechanism to the ketone substrate to release the (R)-
enantiomerically enriched alcohol product and regenerate the
amido complex 17.
F
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
Garcia et al. studied the use of several alcohols as sacrificial
reductants in the transfer hydrogenation of acetophenone with
a nickel catalyst prepared in situ.44 Using ethanol, they
observed the initial production of acetaldehyde which reacts
with ethanol to produce ethyl acetate. In a similar manner, the
ethoxide complex 19′ is postulated to release acetaldehyde to
produce an anti Mn−H and NH hydride species 20′ (Scheme
7), which is proposed to be unreactive with respect to the
hydride transfer to the ketone due to the lack of carbonyl
activation by an NH group.
Substrate Scope. With the manganese borohydride
complex 18, the ATH of various ketones was performed in
heated 2-PrOH without the addition of KOtBu. The optimized
catalysis results are shown in Figure 4.
The reduction of acetophenone was rapid at 80 °C, only
requiring 1 h to produce 1-phenylethanol with a poor ee of
42% (R). The addition of electron -donating groups in the para
position to the acetyl group on the benzene ring placed
electron density near the ketone carbonyl, thus decreasing the
electrophilicity of the acetyl carbon and decreasing the rate of
catalysis. In contrast, addition of electron-withdrawing groups
in the meta position of the benzene ring to the acetyl group,
enhanced catalytic activity by increasing the electrophilicity of
the acetyl carbon. This was observed in both cases for the
bromo- and chloro-substituted acetophenone derivatives.
Increasing the bulk of the R group of the acetophenone
derivative led to lower rates of catalysis (Figure 4), as observed
with the lower activity of the catalyst in the reduction of
cyclohexylphenylketone or the bromo-substituted acetophe-
none in contrast to the chloro-substituted acetophenone. The
catalyst was also efficient for the hydrogenation of base-
sensitive substrate p-acetylbenzoate ethyl ester,45 producing
the ethyl ester alcohol without observation of the trans-
esterification product (see SI).
EXPERIMENTAL SECTION
■
General Experimental Considerations. All manipulations were
performed under an inert atmosphere of argon using Schlenk or
standard glovebox techniques, unless otherwise stated. Solvents and
liquid substrates were dried and degassed via distillation prior to use.
All solid substrates were heated to 80 °C under vacuum to remove
any traces of water before being stored in the glovebox. The P−NH−
NH2 ligand 1012 and the orthophenylene P′−NH−NH2 ligand 914
were synthesized according to literature. NMR spectra were recorded
at ambient temperature and pressure using an Agilent 600 MHz, and
500 MHz spectrometer as well as Bruker Avance-III 400 MHz
autosampler. The conversions and ee, using di-tert-butylbenzene as an
internal standard, for each reaction were obtained on a PerkinElmer
Clarus 400 Chromatograph equipped with a chiral column (CP
chirasil-Dex CB 25 m x 2.5 mm), using hydrogen gas as the mobile
phase. The IR spectra were recorded on a Bruker Alpha with an ATR-
platinum diamond attachment. All experiments were repeated three
times for accuracy.
Alternative Synthesis of the P−NH−NH−P Ligand (8). This
procedure was adapted from the synthesis of (1S,2S)-N1-(2-
(diphenylphosphinyl)ethyl)-1,2-diphenylethane-1,2-diamine (P−
NH−NH2 ligand, 10).12
In separate vials, the diphenylphosphonium dimer (291 mg, 0.471
mmol, 1 equiv) and sodium methoxide (51 mg, 0.942 mmol, 2 equiv)
were dissolved in methanol (8 mL), iron(II) tetrafluoroborate
hexahydrate (239 mg, 0.707 mmol, 1.5 equiv) was dissolved in
methanol (4 mL), and DPEN (100 mg, 0.471 mmol, 1 equiv) was
dissolved in MeCN (4 mL). All solutions were stirred for 2 min and
then combined in a 100 mL Schlenk flask to produce a purple
solution. After the solutions were stirred for 16 h, they became red,
indicating the formation of [Fe(P−N−N−P)(MeCN)2][BF4]2 (P−
N−N−P = Ph2PCH2CHNCH(Ph)CH(Ph)NCHCH2PPh2).17 The
solvent was removed in vacuo to leave a red residue. LiAlH4 (89 mg,
2.36 mmol, 5 equiv) was added as a powder, and then the mixture was
dissolved in THF (20 mL) and allowed to stir for 1 h until the
solution turned gray and gas evolution ceased. The Schlenk flask was
brought from the glovebox to the Schlenk line and placed under a
continuous flow of argon. It was placed in an ice bath, and the excess
LiAlH4 was quenched by injecting water (deionized, not degassed) via
a syringe dropwise to the solution. After 2 mL of water was added in
this manner, the solution was dried in vacuo to leave a gray residue.
The following extraction can be performed in air in under 2 h to
ensure that the phosphine does not become oxidized. DCM (not dry
or degassed, 50 mL) and water (not degassed, 50 mL) was added to
the Schlenk flask in order to dissolve the residue. A DCM/water
extraction was performed in a 250 mL separatory funnel, extracting
the water layer with DCM (50 mL × 2). All of the DCM fractions
were combined, dried with magnesium sulfate, filtered through Celite,
and then dried in vacuo to isolate the PNNP ligand as a brown oil in a
95% purity as indicated by the singlet in the 31P{1H} NMR spectrum
at −20.3 ppm. Yield: 185 mg (62%). Full characterization for 8 can be
found in the literature.11
Synthesis of trans-[Mn(P−NH−NH−P)(CO)2][Br] (14). The chiral
P−NH−NH−P ligand (1S,2S)-N1,N2-bis(2-(diphenylphosphinyl)-
ethyl)-1,2-diphenylethane-1,2-diamine 8 (185 mg, 0.290 mmol, 1
equiv) was dissolved in toluene (5 mL) and placed into a 50 mL
Schlenk flask. In a separate vial, bromopentacarbonylmanganese(I)
(80 mg, 0.290 mmol, 1 equiv) was dissolved in toluene (8 mL) and
then added to the Schlenk flask. This was brought out of the glovebox,
placed on the Schlenk line, and then heated at 110 °C under Ar. After
4 h, the reaction was removed from the oil bath and allowed to cool to
28 °C. The solution was freeze−pump−thawed two times, then
brought back into the glovebox. The solution was filtered to collect
the precipitate. The precipitate was washed with toluene (2 mL × 2),
dried in vacuo for 10 min, placed in a vial, and then stirred in diethyl
ether (15 mL) for 16 h. The solid was collected via filtration, stirred in
diethyl ether (5 mL × 2) for 16 h, and then dried in vacuo to isolate
the product as a yellow powder. Several attempts were made to
CONCLUSIONS
■
New manganese complexes 14−16 were synthesized and
tested in the ATH of acetophenone. Only the mer-Mn(P−
NH−NH2)(CO)2Br complex 16 displayed moderate activity at
80 °C and was therefore selected to further investigate the
mechanism of transfer hydrogenation. The active hydride
species could not be isolated, but the 5-coordinate amido
complex Mn(P−N−NH2)(CO)2 17 and the borohydride
complex syn-mer-Mn(P−NH−NH2)(CO)2(BH4) 18 were
isolated and demonstrated to be active in the ATH of
acetophenone without the addition of KOtBu for the first time
with manganese. An ethoxide isomer anti-mer-Mn(P−NH−
NH2)(CO)2(OEt) 19′ was independently synthesized and
found to be inactive for ATH of acetophenone. The proposed
catalytic cycle for 18 and 19′ relies on the production of a syn
Mn−H and NH manganese hydride species for the catalysis to
proceed. The borohydride complex 18 is one of the most
active manganese ATH catalysts to date and can catalyze the
hydrogenation of a variety of ketone substrates including the
base-sensitive substrate p-acetylbenzoate ethyl ester. Com-
pared to Sortais and co-worker’s manganese ATH catalysts
prepared in situ, the catalyst presented herein displayed similar
activity and enantioselectivity.38 The manganese catalyst
prepared by Zirakzadeh remained the most active and
enantioselective manganese ATH in the literature to date,
with an impressive rate of catalysis at 25 °C and an unmatched
enantioselectivity.31
1
crystallize the product to no avail. Yield: 160 mg (67%). H NMR
G
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
spectrum (600 MHz, DMSO-d6) δ 8.13−6.18 (30H, aromatic
protons), 3.76 (br, 2H, NH), 3.57 (br, 2H, PPh2CH2), 3.19 (br,
2H, NHCH2), 3.04 (br, 2H, CHPh), 3.00 (br, 2H, PPh2CH2), 2.94
(br, 2H, NHCH2). 31P{1H} NMR spectrum (243 MHz, DMSO-d6) δ
the solvent was removed in vacuo. The residue was redissolved in
benzene (3 mL), filtered through Celite to remove any solid
impurities, and then the filtrate was removed in vacuo. The dark
red residue was stirred in pentanes for 16 h. The solid was filtered out
and dried under vacuum to isolate the product as a dark red powder.
Several attempts were made to crystallize the product to no avail.
1
80.8 (s). The 2D H−13C HSQC spectrum (500 MHz, DMSO-d6)
showing correlations for the two CHPh protons at (3.04, 67.57), the
four protons of the NHCH2 at (3.19, 49.67) and (2.94, 49.69), and
the four protons of the CH2PPh2 at (3.57, 22.93) and (3.00, 22.82).
IR ATR (CO ligand): 1930 and 1854 cm−1. ESI+ high-resolution
mass spec [M − Br]+: calcd, 747.2102; found, 747.2099.
1
Yield: 320 mg (87%). H NMR spectrum (600 MHz, C6D6) δ 7.71
3
(dt, JHH = 24, 8 Hz, 4H, aromatic protons), 7.30−6.85 (m, overlaps
3
with benzene solvent peak, aromatic protons), 6.58 (d, JHH = 7 Hz,
3
2H, aromatic protons), 4.02 (d, JHH
= 7 Hz, 1H,
Synthesis of fac-[Mn(P′−NH−NH2)(CO)3][Br] (15). The chiral P′-
NH-NH2 ligand (1S,2S)-N1-(2-(diphenylphosphinyl)phenyl)-1,2-di-
phenylethane-1,2-diamine 9 (58 mg, 0.123 mmol, 1 equiv) was
dissolved in toluene (5 mL) and placed into a 50 mL Schlenk flask. In
a separate vial, bromopentacarbonylmanganese(I) (34 mg, 0.123
mmol, 1 equiv) was dissolved in toluene (8 mL) and then added to
the Schlenk flask. This was brought out of the glovebox, placed on the
Schlenk line, and heated at 110 °C under Ar. After 16 h, the reaction
was removed from the oil bath and allowed to cool to 28 °C. The
solution was freeze−pump−thawed two times, then brought back into
the glovebox. The workup was the same as that of 14 to produce a
yellow powder. Several attempts were made to crystallize the product
to no avail. Yield: 48 mg (56%). 1H NMR spectrum (600 MHz,
DMSO-d6) δ 7.81−6.83 (20H, aromatics from CHPh and PPh2),
6.81−6.17 (4H, aromatics from orthophenylene), 6.03−5.57 (br,
2H), 4.77 (br, 1H), 4.49 (br, 1 H), 4.15 (br, 1H) .Because of the
fluctional behavior of the complex, all of the peaks were broad.
31P{1H} NMR spectrum (243 MHz, DMSO-d6) δ 63.9 (s). IR ATR
(CO ligand): 2032, 1955, and 1914 cm−1. ESI+ high-resolution mass
spectrometry [M − Br]+: calcd, 611.1296; found, 611.1299.
H2NCHPhCHPhN), 3.31 (m, 1H, H2NCHPh), 2.84 (m, 1H,
NCH2), 2.77 (m, 1H, NCH2), 2.47 (m, 1H, NH2CHPh), 2.45 (dt,
2JHH = 13 Hz, 3JHH = 7 Hz, 1H, CH2PPh2), 2.41 (m, 1H, CH2PPh2),
2.05 (m, 1H, NH2CHPh). 31P{1H} NMR spectrum (243 MHz,
1
C6D6) δ 102.8 (s). The 2D H−13C HSQC spectrum (500 MHz,
C6D6) displays the two CHPh protons at (4.02, 79.76) and (3.31,
69.32), the two protons of the CH2 adjacent to the amino donor are
found at (2.84, 54.03) and (2.77, 54.03), and the two protons of the
CH2 adjacent to the diphenylphosphino donor at (2.47, 35.22) and
(2.41, 35.20). There is no cross peak for the amino group proton at
2.05 ppm, while no conclusion can be drawn for the amino proton at
2.45 ppm since it is shrouded by the CH2 proton at 2.47 ppm. IR
ATR (CO ligand): 1890 and 1808 cm−1. DART Mass Spec [M]+:
calcd, 534.1269; found, 534.2. High-resolution mass spectroscopy and
elemental analysis could not be performed as the product degrades
quickly upon exposure to air.
Synthesis of syn NH BH4 Isomer mer-Mn(P−NH−NH2)(CO)2(BH4)
(18). Mn(P−NH−NH2)(Br)(CO)2 16 (50 mg, 0.081 mmol, 1 equiv)
was weighed out in a vial, then dissolved in ethanol (4 mL) with
toluene (1.3 mL). Sodium borohydride (15 mg, 0.405 mmol, 5 equiv)
was added portion-wise. The solution was stirred for 1.5 h, then
filtered through Celite to remove any solid impurities. The filtrate was
removed in vacuo to yield a yellow-orange powder. The residue was
redissolved in THF (5 mL) and filtered to remove excess NaBH4. The
filtrate was concentrated to approximately 1 mL, then pentanes was
added dropwise to cause precipitation of the product. The product
was isolated via filtration, washed with pentanes (2 mL × 3), then
Synthesis of syn NH Br mer-Mn(P−NH−NH2)(CO)2(Br) (16). The
chiral PNN ligand (S,S)-Ph2PCH2CH2NHCHPh−CHPhNH2 10
(620.5 mg, 1.461 mmol, 1 equiv) was dissolved in toluene (15 mL)
and placed into a 100 mL Schlenk flask. In a separate vial,
bromopentacarbonylmanganese(I) (401.8 mg, 1.461 mmol, 1 equiv)
was dissolved in toluene (20 mL) and then added to the Schlenk flask.
This was brought out of the glovebox, placed on the Schlenk line and
heated at 110 °C under Ar. After 4 h, the reaction was removed from
the oil bath and allowed to cool to 28 °C. The solution was freeze−
pump−thawed two time and then brought back into the glovebox.
The solution was filtered to remove any salt impurities, and then the
filtrate was removed in vacuo to yield a bright yellow residue. The
residue was stirred in diethyl ether (20 mL) for 16 h, filtered, then
dried in vacuo to isolate the product as a yellow powder. Several
attempts were made to crystallize the product to no avail. Yield: 800
1
dried in vacuo to obtain a yellow powder. Yield: 38 mg (85%). H
NMR spectrum (600 MHz, toluene-d8) δ 7.95 (t, 2H, aromatic
3
3
protons, JHH = 9 Hz), 7.31 (t, 2H, aromatic protons, JHH = 9 Hz),
7.22−6.74 (24H, aromatic protons), 6.66 (d, 2H, aromatic protons,
3JHH = 5 Hz), 5.06 (t, 1H, NHCH2, JHH = 12 Hz), 4.08 (t, 1H,
3
3
NH2CHPh, JHH = 10 Hz), 3.82 (pseudo t, 1H, NH2CHPhCHPh,
3JHH = 12 Hz), 3.09 (pseudo t, 1H, NH2CHPh, JHH = 10 Hz), 2.77
2
3
(m, 1H, NHCH2), 2.44 (t, 1H, PPh2CH2, JHH = 15 Hz), 2.31 (m,
1
mg (89%). H NMR spectrum (600 MHz, DMSO-d6) δ 7.80−7.00
1H, NHCH2), 2.09 (m, 1H, NH2CHPh, buried under toluene signal),
1.80 (m, 1H, PPh2CH2), −1.21 to −1.60 (br, BH4). 31P{1H} NMR
spectrum (243 MHz, toluene-d8) δ 89.2 (s). 11B NMR spectrum (192
MHz, toluene-d8) δ −23.9 (br). 2D 1H−13C HSQC spectrum displays
the two CHPh at (4.08, 65.01) and (3.82, 74.24), the two protons of
the CH2 adjacent to the secondary amino donor at (2.77, 50.39) and
(2.31, 49.58), the two protons of the CH2 adjacent to the
diphenylphosphino donor at (2.44, 31.67) and (1.80, 31.64). There
is no cross peak for the three amino protons at 6.14, 5.40, and 2.07
ppm in the HSQC spectrum. IR ATR (CO ligand): 1920 and 1836
cm−1. High-resolution mass spectroscopy and elemental analysis
could not be performed as the product degrades quickly upon
exposure to air.
3
(br, 40H, aromatic protons), 6.14 (t, 1H, PPh2CH2CH2NH, JHH
=
12 Hz), 5.40 (m, 1H, NH2CHPh), 3.95 (m, 1H, NH2CHPh), 3.81
3
(pseudo t, 1H, NH2CHPhCHPh, JHH = 12 Hz), 3.36 (m, 1H,
PPh2CH2), 2.79 (m, 1H, NHCH2), 2.48 (m, 1H, NHCH2, buried
under the DMSO-d6 signal), 2.42 (m, 1H, PPh2CH2, buried under the
3
DMSO-d6 signal), 2.07 (pseudo t, 1H, NH2CHPh, JHH = 12 Hz).
31P{1H} NMR spectrum (243 MHz, DMSO-d6) δ 83.1 (s). 2D
1H−13C HSQC spectrum (500 MHz, DMSO-d6) displays the two
CHPh at (3.95, 66.88) and (3.81, 66.97), the two protons of the CH2
adjacent to the amino donor at (2.79, 45.28) and (2.48, 44.99), the
two protons of the CH2 adjacent to the diphenylphosphino donor at
(3.36, 29.10) and (2.42, 29.23). There is no cross peak for the three
amino protons at 6.14, 5.40, and 2.07 ppm in the HSQC. IR ATR
(CO ligand): 1915 and 1828 cm−1 and a slight impurity at 2023 cm−1
which suggests a side-product. ESI+ high-resolution mass spectrom-
etry [M − Br]+: calcd, 535.1347; found, 535.13. Elemental Analysis
[M] Calcd: C, 58.55%; H, 4.75%; N, 4.55%. Found: C, 58.24%; H,
5.12%; N, 4.54%.
Synthesis of anti NH OEt Isomer mer-Mn(P−NH−NH2)(CO)2(OEt)
(19′). Mn(P−NH−NH2)(Br)(CO)2 16 was reacted with NaBH4 as
above, but stirred for 16 h. The workup was the same as for 18 to
obtain a yellow powder. Yield: 34 mg (75%). 1H NMR spectrum (600
MHz, toluene-d8) δ 8.03 (t, 2H, aromatic protons, 3JHH = 9 Hz), 7.37
3
(t, 2H, aromatic protons, JHH = 9 Hz), 7.22−6.74 (24H, aromatic
Synthesis of Mn(P−N−NH2)(CO)2 (17). Mn(P−NH−NH2)(Br)-
(CO)2 16 (425 mg. 0.69 mmol, 1 equiv) was weighed out in a vial
and dissolved in THF (8 mL). In a separate vial, KOtBu (85.2 mg,
0.76 mmol, 1.1 equiv) was weighed out and dissolved in THF (2 mL).
The KOtBu solution was added dropwise to the vial containing 16 to
form a dark red solution. The solution was stirred for 1 h, and then
protons), 6.60 (m, 2H, aromatic protons), 4.37 (t, 1H, NHCH2, 3JHH
= 12 Hz), 3.94 (t, 1H, NH2CHPh, 3JHH = 10 Hz), 3.89 (pseudo t, 1H,
NH2CHPhCHPh, 3JHH = 12 Hz), 3.33 (br, 2H, OCH2CH3), 2.79 (m,
2
1H, NHCH2), 2.62 (pseudo t, 1H, NH2CHPh, JHH = 10 Hz), 2.54
3
(t, 1H, PPh2CH2, JHH = 14 Hz), 2.45 (m, 1H, NHCH2), 2.27 (m,
1H, NH2CHPh, buried under toluene signal), 1.87 (m, 1H,
H
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
PPh2CH2), 0.97 (br, 3H, OCH2CH3), − 1.41 (br, 3H, BH3). 31P{1H}
NMR spectrum (243 MHz, toluene-d8) δ 84.1 (s). 2D 1H−13C
HSQC spectrum displays the two CHPh at (3.94, 64.30) and (3.86,
73.36), the two protons of the CH2 adjacent to the secondary amino
donor at (2.80, 49.30) and (2.44, 49.15), the two protons of the CH2
adjacent to the diphenylphosphino donor at (2.54, 30.58) and the
Extended experimental section; summary of 31P{1H}
NMR spectra and IR spectra; NMR spectra of newly
synthesized compounds and activated complexes; gas
chromatograph readouts for the product alcohols,
including an NMR spectrum of the base-sensitive p-
acetylbenzoate ethyl ester for confirmation of the
product alcohol; and DFT calculations for the structures
of the bromide manganese, borohydride manganese, as
well as the ethoxide manganese structures (PDF).
1
proton at 1.86 was not found in the 2D H−13C HSQC spectrum.
There is no cross peak for the three amino protons at 4.36, 2.63, and
2.27 ppm in the HSQC spectrum. IR ATR (CO ligand): 1916 and
1830 cm−1. High-resolution mass spectroscopy and elemental analysis
could not be performed as the product degrades quickly upon
exposure to air.
xyz coordinate file of the calculated structures (XYZ).
Testing the Activity of the Compounds 14, 15, and 16 for
the ATH of Acetophenone (Table 2). By the Schlenk line, an oil
bath was kept at 28 °C or heated to 80 °C. Concurrently, in the
glovebox, Stock Solution 1 (SS1) containing a manganese precatalyst
14, 15, or 16 (0.025 mmol) was prepared with DCM (1 mL) and
quickly placed into a 1 mL syringe. A 10 mL Schlenk flask was
charged with 0.1 mL of SS1 and a magnetic stir bar. The solvent was
removed in vacuo to obtain 0.0025 mmol of manganese precatalyst in
the Schlenk flask. A syringe was filled with 2-PrOH (7 mL) and the
needle was stabbed into a rubber stopper. A second syringe was filled
with the acetophenone (0.25 mmol), diluted with 2-PrOH (0.5 mL),
and the needle was stabbed into the rubber stopper. A third syringe
was filled with KOtBu (0.56 mg, 0.005 mmol) dissolved in 2-PrOH
(0.5 mL). Once the temperature of the oil bath was stable, the
Schlenk flask was brought out of the glovebox and attached to the
Schlenk line under Ar. The three syringes were taken out of the
glovebox, the 2-PrOH was injected into the Schlenk flask, and then
the Schlenk flask was lowered into the oil bath. After the mixture was
stirred for 1 min, the KOtBu was injected into the Schlenk flask, then
immediately ketone substrate was injected into the Schlenk flask, and
the stop watch was started. At this stage, the concentrations were
calculated to be [acetophenone] = 0.312 M; [Mn complex] = 3.13 ×
10−4 M; [KOtBu] = 6.25 × 10−4 M [2-PrOH] = 13.1 M. After the
allotted reaction time, the reaction was removed from heat and
opened to air. A 0.1 mL aliquot was taken and added to a GC vial
containing di-tert-butylbenzene (0.019 mg, 0.1 mmol) in THF (0.9
mL).
General Procedure for the ATH of Ketones Using the
Optimized Conditions with No KOtBu Added (Figure 4). By the
Schlenk line, an oil bath was heated to 80 °C. Concurrently, in the
glovebox, Stock Solution 1 (SS1) containing manganese complexes
17, 18, or 19′ (0.025 mmol) was prepared with benzene (1 mL) and
quickly placed into a 1 mL syringe. A 10 mL Schlenk flask was
charged with 0.1 mL of SS1 and a magnetic stir bar. The solvent was
removed in vacuo to obtain 0.0025 mmol of manganese precatalyst in
the Schlenk flask. A syringe was filled with 2-PrOH (7.5 mL), and the
needle was stabbed into a rubber stopper. A second syringe was filled
with the ketone substrate (0.25 mmol), diluted with 2-PrOH (0.5
mL), and the needle was stabbed into the rubber stopper. Once the
temperature of the oil bath was stable, the Schlenk flask was brought
out of the glovebox and attached to the Schlenk line under argon. The
two syringes were taken out of the glovebox, the 2-PrOH was injected
into the Schlenk flask, and then the Schlenk flask was lowered into the
oil bath. After the mixture was stirred for 1 min, the ketone substrate
was injected into the Schlenk flask, and the stop watch was started. At
this stage, the concentrations were calculated to be [acetophenone] =
0.312 M; [Mn complex] = 3.13 × 10−4 M; [2-PrOH] = 13.1 M. After
the allotted reaction time, the reaction was removed from heat and
opened to air. A 0.1 mL sample was taken and added to a GC vial
containing di-tert-butylbenzene (0.019 mg, 0.1 mmol) in THF (0.9
mL).
AUTHOR INFORMATION
Corresponding Author
*E-mail: rmorris@chem.utoronto.ca.
ORCID
Robert H. Morris: 0000-0002-7574-9388
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
■
R.H.M. thanks NSERC for a Discovery Grant. NSERC is
thanked for a PGS D awarded to K.Z.D. The authors wish to
acknowledge the Canadian Foundation for Innovation, project
number 19119, and the Ontario Research Fund for funding of
the Centre for Spectroscopic Investigation of Complex
Organic Molecules and Polymers and Compute Canada and
Sharcnet for a resource allocation grant.
REFERENCES
■
(1) Dupau, P. Ruthenium-catalyzed Selective Hydrogenation for
Flavor and Fragrance Applications. Top. Organomet. Chem. 2011, 42,
47−64.
(2) De Vita, D.; Pandolfi, F.; Cirilli, R.; Scipione, L.; Di Santo, R.;
Friggeri, L.; Mori, M.; Fiorucci, D.; Maccari, G.; Arul Christopher, R.
S.; Zamperini, C.; Pau, V.; De Logu, A.; Tortorella, S.; Botta, M.
Discovery of in Vitro Antitubercular Agents Through in Silico Ligand-
based Approaches. Eur. J. Med. Chem. 2016, 121, 169−180.
(3) Hameed, P. S.; Chinnapattu, M.; Shanbag, G.; Manjrekar, P.;
Koushik, K.; Raichurkar, A.; Patil, V.; Jatheendranath, S.; Rudrapatna,
S. S.; Barde, S. P.; Rautela, N.; Awasthy, D.; Morayya, S.; Narayan, C.;
Kavanagh, S.; Saralaya, R.; Bharath, S.; Viswanath, P.; Mukherjee, K.;
Bandodkar, B.; Srivastava, A.; Panduga, V.; Reddy, J.; Prabhakar, K.
R.; Sinha, A.; Jimenez-Diaz, M. B.; Martinez, M. S.; Angulo-Barturen,
I.; Ferrer, S.; Sanz, L. M.; Gamo, F. J.; Duffy, S.; Avery, V. M.;
Magistrado, P. A.; Lukens, A. K.; Wirth, D. F.; Waterson, D.;
Balasubramanian, V.; Iyer, P. S.; Narayanan, S.; Hosagrahara, V.;
Sambandamurthy, V. K.; Ramachandran, S. Aminoazabenzimidazoles,
a Novel Class of Orally Active Antimalarial Agents. J. Med. Chem.
2014, 57, 5702−5713.
(4) Smith, C. J.; Ali, A.; Hammond, M. L.; Li, H.; Lu, Z.;
Napolitano, J.; Taylor, G. E.; Thompson, C. F.; Anderson, M. S.;
Chen, Y.; Eveland, S. S.; Guo, Q.; Hyland, S. A.; Milot, D. P.;
Sparrow, C. P.; Wright, S. D.; Cumiskey, A.-M.; Latham, M.;
Peterson, L. B.; Rosa, R.; Pivnichny, J. V.; Tong, X.; Xu, S. S.; Sinclair,
P. J. Biphenyl-Substituted Oxazolidinones as Cholesteryl Ester
Transfer Protein Inhibitors: Modifications of the Oxazolidinone
Ring Leading to the Discovery of Anacetrapib. J. Med. Chem. 2011,
54, 4880−4895.
(5) Bhandari, K.; Srivastava, S.; Shanker, G.; Nath, C. Substituted
Propanolamines and Alkylamines Derived from Fluoxetine as Potent
Appetite Suppressants. Bioorg. Med. Chem. 2005, 13, 1739−1747.
(6) Kraft, S.; Ryan, K.; Kargbo, R. B. Recent Advances in
Asymmetric Hydrogenation of Tetrasubstituted Olefins. J. Am.
Chem. Soc. 2017, 139, 11630−11641.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.8b00625.
I
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
(7) Wills, M. Imino Transfer Hydrogenation Reductions. Top. Curr.
Chem. 2016, 374, 1−36.
(27) Naik, A.; Maji, T.; Reiser, O. Iron(II)-bis(isonitrile)
Complexes: Novel Catalysts in Asymmetric Transfer Hydrogenations
of Aromatic and Heteroaromatic Ketones. Chem. Commun. 2010, 46,
4475−4477.
(28) Mikhailine, A.; Lough, A. J.; Morris, R. H. Efficient Asymmetric
Transfer Hydrogenation of Ketones Catalyzed by an Iron Complex
Containing a P-N-N-P Tetradentate Ligand Formed by Template
Synthesis. J. Am. Chem. Soc. 2009, 131, 1394−1395.
(29) Ter Halle, R.; Breheret, A.; Schulz, E.; Pinel, C.; Lemaire, M.
Chiral Nitrogen-metal Complexes for the Asymmetric Reduction of
Ketones. Tetrahedron: Asymmetry 1997, 8, 2101−2108.
(30) Bruneau-Voisine, A.; Wang, D.; Dorcet, V.; Roisnel, T.; Darcel,
C.; Sortais, J.-B. Transfer Hydrogenation of Carbonyl Derivatives
Catalyzed by an Inexpensive Phosphine-Free Manganese Precatalyst.
Org. Lett. 2017, 19, 3656−3659.
(31) Zirakzadeh, A.; de Aguiar, S. R. M. M.; Stoeger, B.; Widhalm,
M.; Kirchner, K. Enantioselective Transfer Hydrogenation of Ketones
Catalyzed by a Manganese Complex Containing an Unsymmetrical
Chiral PNP′ Tridentate Ligand. ChemCatChem 2017, 9, 1744−1748.
(32) Elangovan, S.; Topf, C.; Fischer, S.; Jiao, H.; Spannenberg, A.;
Baumann, W.; Ludwig, R.; Junge, K.; Beller, M. Selective Catalytic
Hydrogenations of Nitriles, Ketones, and Aldehydes by Well-defined
Manganese Pincer Complexes. J. Am. Chem. Soc. 2016, 138, 8809−
8814.
(33) Elangovan, S.; Garbe, M.; Jiao, H.; Spannenberg, A.; Junge, K.;
Beller, M. Hydrogenation of Esters to Alcohols Catalyzed by Defined
Manganese Pincer Complexes. Angew. Chem., Int. Ed. 2016, 55,
15364−15368.
(34) Garbe, M.; Junge, K.; Walker, S.; Wei, Z.; Jiao, H.;
Spannenberg, A.; Bachmann, S.; Scalone, M.; Beller, M. Manganese-
(I)-catalyzed Enantioselective Hydrogenation of Ketones Using a
Defined Chiral PNP Pincer Ligand. Angew. Chem., Int. Ed. 2017, 56,
11237−11241.
(35) Perez, M.; Elangovan, S.; Spannenberg, A.; Junge, K.; Beller, M.
Molecularly Defined Manganese Pincer Complexes for Selective
Transfer Hydrogenation of Ketones. ChemSusChem 2017, 10, 83−86.
(36) van Putten, R.; Uslamin, E. A.; Garbe, M.; Liu, C.; Gonzalez-
de-Castro, A.; Lutz, M.; Junge, K.; Hensen, E. J. M.; Beller, M.; Lefort,
L.; Pidko, E. A. Non-pincer-type Manganese Complexes as Efficient
Catalysts for the Hydrogenation of Esters. Angew. Chem., Int. Ed.
2017, 56, 7531−7534.
(37) Widegren, M. B.; Harkness, G. J.; Slawin, A. M. Z.; Cordes, D.
B.; Clarke, M. L. A Highly Active Manganese Catalyst for
Enantioselective Ketone and Ester Hydrogenation. Angew. Chem.,
Int. Ed. 2017, 56, 5825−5828.
(8) Stefane, B.; Pozgan, F. Metal-catalysed Transfer Hydrogenation
of Ketones. Top. Curr. Chem. 2016, 374, 1−67.
(9) Margarita, C.; Andersson, P. G. Evolution and Prospects of the
Asymmetric Hydrogenation of Unfunctionalized Olefins. J. Am. Chem.
Soc. 2017, 139, 1346−1356.
(10) Foubelo, F.; Najera, C.; Yus, M. Catalytic Asymmetric Transfer
Hydrogenation of Ketones: Recent Advances. Tetrahedron: Asymmetry
2015, 26, 769−790.
(11) Mikhailine, A. A.; Maishan, M. I.; Lough, A. J.; Morris, R. H.
The Mechanism of Efficient Asymmetric Transfer Hydrogenation of
Acetophenone Using an Iron(II) Complex Containing an (S,S)-
Ph2PCH2CHNCHPhCHPhNCHCH2PPh2 Ligand: Partial Li-
gand Reduction Is the Key. J. Am. Chem. Soc. 2012, 134, 12266−
12280.
(12) Zuo, W.; Lough, A. J.; Li, Y. F.; Morris, R. H. Amine(imine)-
diphosphine Iron Catalysts for Asymmetric Transfer Hydrogenation
of Ketones and Imines. Science 2013, 342, 1080−1083.
(13) Demmans, K. Z.; Ko, O. W. K.; Morris, R. H. Aqueous Biphasic
Iron-catalyzed Asymmetric Transfer Hydrogenation of Aromatic
Ketones. RSC Adv. 2016, 6, 88580−88587.
(14) Demmans, K. Z.; Seo, C. S. G.; Lough, A. J.; Morris, R. H.
From Imine to Amine: An Unexpected Left Turn. Cis-β iron(II)
PNNP′ Precatalysts for the Asymmetric Transfer Hydrogenation of
Acetophenone. Chem. Sci. 2017, 8, 6531−6541.
(15) Bigler, R.; Huber, R.; Stockli, M.; Mezzetti, A. Iron(II)/
(NH)2P2 Macrocycles: Modular, Highly Enantioselective Transfer
Hydrogenation Catalysts. ACS Catal. 2016, 6, 6455−6464.
(16) Bigler, R.; Huber, R.; Mezzetti, A. Iron Chemistry Made Easy:
Chiral N2P2 Ligands for Asymmetric Catalysis. Synlett 2016, 27, 831−
847.
(17) Mikhailine, A. A.; Kim, E.; Dingels, C.; Lough, A. J.; Morris, R.
H. Template Syntheses of Iron(II) Complexes Containing Chiral P-
N-N-P and P-N-N Ligands. Inorg. Chem. 2008, 47, 6587−6589.
(18) Smith, S. A. M.; Morris, R. H. An Unsymmetrical Iron Catalyst
for the Asymmetric Transfer Hydrogenation of Ketones. Synthesis
2015, 47, 1775−1779.
(19) Sues, P. E.; Lough, A. J.; Morris, R. H. Stereoelectronic Factors
in Iron Catalysis: Synthesis and Characterization of Aryl-substituted
Iron(II) Carbonyl P-N-N-P Complexes and Their Use in the
Asymmetric Transfer Hydrogenation of Ketones. Organometallics
2011, 30, 4418−4431.
(20) Smith, S. A. M.; Prokopchuk, D. E.; Morris, R. H. Asymmetric
Transfer Hydrogenation of Ketones Using New Iron(II) (P-NH-N-
P′) Catalysts: Changing the Steric and Electronic Properties at
Phosphorus P′. Isr. J. Chem. 2017, 57, 1204−1215.
(21) De Luca, L.; Mezzetti, A. Base-Free Asymmetric Transfer
Hydrogenation of 1,2-Di- and Monoketones Catalyzed by a (NH)2P2-
Macrocyclic Iron(II) Hydride. Angew. Chem., Int. Ed. 2017, 56,
11949−11953.
(22) Mezzetti, A. Iron Complexes with Chiral N/P Macrocycles as
Catalysts for Asymmetric Transfer Hydrogenation. Isr. J. Chem. 2017,
57, 1090−1105.
(23) Magubane, M. N.; Alam, M. G.; Ojwach, S. O.; Munro, O. Q.
Orientation Towards Asymmetric Transfer Hydrogenation of Ketones
Catalyzed by (Pyrazolyl)ethyl)pyridine Fe(II) and Ni(II) Complexes.
J. Mol. Struct. 2017, 1135, 197−201.
(24) Bigler, R.; Mezzetti, A. Highly Enantioselective Transfer
Hydrogenation of Polar Double Bonds by Macrocyclic Iron(II)/
(NH)2P2 Catalysts. Org. Process Res. Dev. 2016, 20, 253−261.
(25) Sues, P. E.; Demmans, K. Z.; Morris, R. H. Rational
Development of Iron Catalysts for Asymmetric Transfer Hydro-
genation. Dalton Trans. 2014, 43, 7650−7667.
(26) Mikhailine, A. A.; Maishan, M. I.; Morris, R. H. Asymmetric
Transfer Hydrogenation of Ketimines Using Well-defined Iron(II)-
based Precatalysts Containing a PNNP Ligand. Org. Lett. 2012, 14,
4638−4641.
(38) Wang, D.; Bruneau-Voisine, A.; Sortais, J.-B. Practical
(Asymmetric) Transfer Hydrogenation of Ketones Catalyzed by
Manganese with (Chiral) Diamines Ligands. Catal. Commun. 2018,
105, 31−36.
(39) Espinosa-Jalapa, N. A.; Nerush, A.; Shimon, L. J. W.; Leitus, G.;
Avram, L.; Ben-David, Y.; Milstein, D. Manganese-catalyzed Hydro-
genation of Esters to Alcohols. Chem. - Eur. J. 2017, 23, 5934−5938.
(40) Espinosa-Jalapa, N. A.; Kumar, A.; Leitus, G.; Diskin-Posner,
Y.; Milstein, D. Synthesis of Cyclic Imides by Acceptorless
Dehydrogenative Coupling of Diols and Amines Catalyzed by a
Manganese Pincer Complex. J. Am. Chem. Soc. 2017, 139, 11722−
11725.
(41) Nguyen, D. H.; Trivelli, X.; Capet, F.; Paul, J.-F.; Dumeignil, F.;
Gauvin, R. M. Manganese Pincer Complexes for the Base-free,
Acceptorless Dehydrogenative Coupling of Alcohols to Esters:
Development, Scope, and Understanding. ACS Catal. 2017, 7,
2022−2032.
(42) Mukherjee, A.; Nerush, A.; Leitus, G.; Shimon, L. J. W.; Ben
David, Y.; Espinosa Jalapa, N. A.; Milstein, D. Manganese-catalyzed
Environmentally Benign Dehydrogenative Coupling of Alcohols and
Amines to Form Aldimines and H2: A Catalytic and Mechanistic
Study. J. Am. Chem. Soc. 2016, 138, 4298−4301.
(43) Haack, K.-J.; Hashiguchi, S.; Fujii, A.; Ikariya, T.; Noyori, R.
The Catalyst Precursor, Catalyst and Intermediate in the RuII-
J
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX

Organometallics
Article
promoted Asymmetric Hydrogen Transfer Between Alcohols and
Ketones. Angew. Chem., Int. Ed. Engl. 1997, 36, 285−288.
(44) Castellanos-Blanco, N.; Arevalo, A.; Garcia, J. J. Nickel-
catalyzed Transfer Hydrogenation of Ketones Using Ethanol as a
Solvent and a Hydrogen Donor. Dalton Trans. 2016, 45, 13604−
13614.
(45) Guo, R.; Chen, X.; Elpelt, C.; Song, D.; Morris, R. H.
Applications of Ruthenium Hydride Borohydride Complexes
Containing Phosphinite and Diamine Ligands to Asymmetric
Catalytic Reactions. Org. Lett. 2005, 7, 1757−1759.
K
DOI: 10.1021/acs.organomet.8b00625
Organometallics XXXX, XXX, XXX−XXX