Highly Enantioselective Transfer Hydrogenation of Polar Double Bonds by Macrocyclic Iron(II)/(NH)2P2 Catalysts

Article abstract of DOI:10.1021/acs.oprd.5b00391

We describe herein a new protocol for the synthesis of 2,2′-((1S,1′S)-ethane-1,2-diylbis(phenylphosphanediyl))dibenzaldehyde ((S_P,S_P)-5), which is the key intermediate in the synthesis of macrocyclic iron(II)/(NH)₂P₂ catalysts for the highly enantioselective transfer hydrogenation of polar double bonds. The dialdehyde (S_P,S_P)-5 was obtained as a single diastereoisomer and enantiomer from an optically pure H-phosphinate in 33% yield over five steps. It was further converted to afford multigram quantities of the macrocyclic iron(II)/(NH)₂P₂ complexes, which were tested in the asymmetric transfer hydrogenation of aryl alkyl ketones and imines in 2-propanol on a 100 mmol scale. Ten substrates, including challenging ones such as tert-butyl phenyl ketone and industrially relevant molecules such as 3,5-bis(trifluoromethyl)acetophenone, were reduced in high yield (89.0-99.7%), excellent enantioselectivity (95.8-99.4% ee), and with low catalyst loadings (S/C up to 10 000/1).

Full text of DOI:10.1021/acs.oprd.5b00391

Subscriber access provided by University of Pennsylvania Libraries
Full Paper
Highly Enantioselective Transfer Hydrogenation of Polar
2
2
Double Bonds by Macrocyclic Iron(II) / (NH)P Catalysts
Raphael Bigler, and Antonio Mezzetti
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.5b00391 • Publication Date (Web): 13 Jan 2016
Downloaded from http://pubs.acs.org on January 25, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Organic Process Research & Development is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Highly Enantioselective Transfer Hydrogenation of
Polar Double Bonds by Macrocyclic Iron(II) / (NH)2P2
Catalysts
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Raphael Bigler and Antonio Mezzetti*
Department of Chemistry and Applied Biosciences, ETH Zürich, CH-8093 Zürich, Switzerland
ACS Paragon Plus Environment
1

Organic Process Research & Development
Page 2 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Table of Contents Graphic
O
Ph OPN
Fe(II)-cat is:
2
H
N
2+
R'
or
R
Ph
P
N H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Fe
P
H
C
C
N
O
Fe(II)-cat
0.01 - 0.2 mol%)
N
R
R
H
(
Ph
H
H
O
Ph OPN
2
H
R'
H
-
100 mmol scale
- up to 99.4% ee
- up to 99.7% yield
or
R
ACS Paragon Plus Environment
2

Page 3 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Abstract
We describe herein a new protocol for the synthesis of 2,2’-((1S,1’S)-ethane-1,2-
diylbis(phenylphosphanediyl))dibenzaldehyde ((S ,S )-5), which is the key intermediate in the
P
P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
synthesis of macrocyclic iron(II) / (NH) P catalysts for the highly enantioselective transfer
2
2
hydrogenation of polar double bonds. The dialdehyde (S ,S )-5 was obtained as a single
P
P
diastereoisomer and enantiomer from an optically pure H-phosphinate in 33% yield over five
steps. It was further converted to afford multi-gram quantities of the macrocyclic iron(II) /
(NH) P complexes, which were tested in the asymmetric transfer hydrogenation of aryl alkyl
2
2
ketones and imines in 2-propanol on a 100 mmol scale. Ten substrates, including challenging
ones such as tert-butyl phenyl ketone and industrially relevant molecules such as 3,5-
bis(trifluoromethyl)acetophenone, were reduced in high yield (89.0 – 99.7%), excellent
enantioselectivity (95.8 – 99.4% ee), and with low catalyst loadings (S / C up to 10 000 / 1).
Keywords: iron – macrocycles – asymmetric catalysis – transfer hydrogenation – alcohols
ACS Paragon Plus Environment
3

Organic Process Research & Development
Page 4 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Introduction
Enantiomerically pure alcohols and amines bearing a stereogenic carbon atom in the α-position
are present in a variety of pharmaceuticals, agrochemicals as well as flavor and fragrance
compounds, and the most straightforward way to prepare them is the asymmetric hydrogenation
of prochiral ketones or imines, respectively. In academia, such asymmetric reductions are
ubiquitous and a variety of well-defined and highly enantioselective catalysts have been prepared
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
or are even commercially available. However, most of these catalysts are based on ruthenium,
iridium, or rhodium, and the high toxicity and costs of these late transition metals has been
2
hindering their implementation in industry. An intriguing alternative to these precious metal
catalysts is the use of cheap, abundant and environmentally benign early transition metals, and
3
iron is currently one of the most intensively investigated alternatives.
4
The iron-catalyzed asymmetric reduction of polar double bonds has been pioneered by Gao,
5
6
7
and was further developed by Morris, Beller and Gade. Currently, the most active iron-based
system for the asymmetric reduction of aryl alkyl ketones has been developed by Morris, whose
–1
third generation Fe(II) / PNNP catalyst achieves outstanding TOFs (up to 200 s ) and is most
efficient under asymmetric transfer hydrogenation (ATH) conditions using 2-propanol as solvent
1
2
5g
(
R = R = xylyl, X = Cl, Chart 1). This catalyst is highly active, but the enantioselectivity is
only moderate with most substrates (24 – >99% ee). Higher enantioselectivity was achieved by
1
2
introducing bulky alkyl phosphines (R = Ph, R = cyclohexyl, X = Br), but at the cost of
5i
significantly decreased activity.
ACS Paragon Plus Environment
4

Page 5 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Chart 1. State-of-the-art iron catalysts for the asymmetric reduction of polar bonds.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A highly enantioselective system (generally ≥95% ee) for the asymmetric direct hydrogenation
of ketones with H has been developed by Gao using a potentially hexadentate (NH) P
2
4
2
–
1
4d
macrocycle in combination with [Fe (CO) ], but its activity was modest (TOF up to 40 h ).
3
12
The same catalyst system is also active in the ATH of aryl alkyl ketones, where TOFs of up to
–1
4c
1 940 h were achieved without loss of enantioselectivity. The most selective catalyst
H
(
generally ≥98% ee) bearing a tridentate boxmi-Ph ligand was recently reported by Gade for the
hydrosilylation of ketones, but low temperature (gradient from -78 °C to r.t.) and high catalyst
7
,8
loadings (5 mol%) are necessary.
We recently prepared a series of complexes of the type [Fe(CNR) ((NH) P )] , in which a C -
2+
2
2
2
2
symmetric macrocycle ((NH) P ) carries the chiral information, and isonitriles act as sterically
2
2
9
-11
and electronically tunable ancillary ligands.
These complexes catalyze the ATH of aryl alkyl
ketones using 2-propanol as hydrogen donor with high enantioselectivity (generally >95% ee)
–1
and activity (TOF up to 1 960 h ). The macrocyclic complexes are the first iron-based, well-
ACS Paragon Plus Environment
5

Organic Process Research & Development
Page 6 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
defined precatalysts that combine high activity with excellent enantioselectivity for a broad range
of ketones. Also, the substrate scope includes challenging ketones such as tert-butyl phenyl
1
2
ketone, as well as industrially relevant substrates such as 3,5-bis(trifluoromethyl)aceto-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
phenone. While these complexes are excellent precatalysts for ATH, their preparation is still
challenging as the synthesis of the key intermediate 2,2’-((1S,1’S)-ethane-1,2-diylbis(phenyl-
phosphanediyl))dibenzaldehyde ((S ,S )-5) is time-consuming, rather low-yielding (15% over 6
P
p
1
4
15
steps), and relies on the use of Jugé’s oxazaphospholidine borane, which is prepared using
controlled (–)-ephedrine.
Herein, we report a new synthetic approach to the key dialdehyde (S ,S )-5 that relies on Han’s
P
p
strategy for the synthesis of enantiomerically enriched secondary phosphine oxides starting from
1
6,17
optically pure, ambiphilic H-phosphinates.
This new protocol was used to prepare gram
quantities of the previously reported macrocyclic iron(II) / (NH) P complexes, which allowed us
2
2
to assay the corresponding bis(isonitrile) complexes in the ATH of ketones and imines on a 100
mmol scale. The results described below confirm the robustness of this new catalyst system and
demonstrates its scalability and synthetic utility.
Results and Discussion
General Strategy. The new retrosynthetic approach shown in Scheme 1 indicates that the key
dialdehyde (S ,S )-5 can be obtained by an oxidative coupling / stereoselective reduction /
P
P
deprotection sequence from enantiomerically pure (R)-(2-(1,3-dioxolan-2-yl)phenyl)(methyl)-
phenyl)phosphine oxide ((R )-3), which in turn is obtained by stereoretentive alkylation of the
(
P
corresponding secondary phosphine oxide (R )-2. For the preparation of enantiomerically pure
P
16,17
(RP)-2, we chose the method developed by Han,
which relies on the stereospecific
ACS Paragon Plus Environment
6

Page 7 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
substitution of secondary H-phosphinate (R )-1 with an appropriate organolithium or Grignard
P
reagent.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 1. Retrosynthetic Analysis of Dialdehyde (S ,S )-5
P
P
Following Han’s procedure, diastereomerically pure (R )-(1R,2S,5R)-2-isopropyl-5-methyl-
P
cyclohexyl phenylphosphinate ((R )-1) was prepared on a >60 g scale in a single step from
P
dichlorophenylphosphine and (–)-menthol, followed by quenching with water and selective
1
6
crystallization of one diastereoisomer at low temperature.
Synthesis of Dialdehyde (S ,S )-5. Adapting Han’s method for the preparation of
P
P
1
6a
enantiomerically enriched secondary phosphine oxides, the (–)-menthyl group in (R )-1 was
P
substituted by (2-(1,3-dioxolan-2-yl)phenyl)lithium (prepared from the corresponding aryl
t
bromide and BuLi) at low temperature to give (R )-2 as a single enantiomer and with inversion
P
1
8
of configuration at phosphorus (Scheme 2). Alkylation of the lithiated secondary phosphine
oxide with methyl iodide at low temperature afforded phosphine oxide (R )-3 in high yield and
P
good enantiospecificity (97% ee) with retention of configuration at phosphorus. On an 81 mmol
scale, (R )-3 was obtained in high yield (85% over two steps) and with good purity (>96% pure
P
ACS Paragon Plus Environment
7

Organic Process Research & Development
Page 8 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
31
1
by P{ H} NMR spectroscopy) by simple extraction, thus circumventing the need for flash
column chromatography.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. Synthesis of Dialdehyde (S ,S )-5
P
P
Oxidative coupling of (R )-3 using copper(II) chloride as oxidant after deprotonation of the
P
1
9
methyl group with lithium diisopropylamide afforded bisphosphine oxide (R ,R )-4 in 80%
P
P
yield on a 59 mmol scale and with a diastereomeric ratio of >10:1. The absolute configuration of
R ,R )-4 was determined to be (R ,R ) by X-ray diffractometry (Figure 1). Attempts to directly
(
P
P
P
P
couple deprotonated (R )-2 using 1,2-diiodoethane or 1,2-ditosylatoethane only resulted in
P
unidentified side products, and no (R ,R )-4 was isolated.
P
P
ACS Paragon Plus Environment
8

Page 9 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Figure 1. ORTEP drawing of (R ,R )-4 (with ellipsoids at 30% probability)
P
P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Having installed the skeleton of dialdehyde (S ,S )-5 in three steps from (R )-1, the last two
P
P
P
steps included the stereospecific reduction of the phosphine oxide to the free phosphine and the
deprotection of the aldehyde moiety. While several methods have been described for the
20
stereoselective reduction of tertiary phosphine oxides, the presence of the sensitive acetal
groups rendered this reaction a formidable task. Several standard reduction methods (i.e. HSiCl3 /
2
1
22
23
amine, PhSiH3, or (Et O)BF / NaBH ) gave either low yields or low stereospecificity.
3
4
4
i
Eventually, we found that the inexpensive combination of Ti(O Pr) and PMHS cleanly afforded
4
2
4
the desired phosphine with retention of configuration at phosphorus. The reduced diphosphine
was directly treated with aqueous hydrochloric acid to cleave the acetal groups and give the
crude diphosphine (S ,S )-5 as a ca. 6.4:1 mixture of diastereoisomers. Removal of the minor
P
P
1
4
isomer by crystallization from hot methanol as previously described afforded enantio- and
diastereomerically pure (S ,S )-5 in 49% yield based on (R ,R )-4 and 5.3 g of pure (S ,S )-5
P
P
P
P
P
P
were prepared in a single batch. The analytic and spectroscopic data of the resulting product
1
4
were identical to those of (S ,S )-5 obtained by the first route.
P
P
ACS Paragon Plus Environment
9

Organic Process Research & Development
Page 10 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Diphosphine (S ,S )-5 is routinely stored in a freezer under argon atmosphere, and no
P
P
decomposition is observed in the solid state over several months. Prolonged exposure of
solutions of (S ,S )-5 to air leads to oxidation of the phosphine. Concerning the configurational
P
P
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
stability at phosphorus, no epimerization was observed in the solid state and in solution at room
temperature. However, heating in solution, such as during recrystallization from methanol,
should be kept to a minimum to avoid the formation of the meso diastereoisomer.
Overall, the synthetic route described herein efficiently affords (S ,S )-5 in an overall yield of
P
P
33% over five steps with a single purification by flash column chromatography and one
recrystallization. Furthermore, as (+)-menthol is also commercially available (albeit at a slightly
higher price than the (–)-form), both enantiomers of like-5 can be accessed. Compared to the
14
previous synthesis, which afforded dialdehyde (S ,S )-5 in 15% overall yield after six steps, the
P
P
present synthetic strategy is shorter, higher yielding, cheaper, and significantly easier to perform
as the purifications are less cumbersome and all reaction can be performed on a >20 mmol scale.
Also, the substitution of (–)-ephedrine by (–)-menthol is a clear advantage, as access to the
former is restricted because of its role in the synthesis of methamphetamine.
Synthesis of Bis(isonitrile) Complexes. With gram quantities of (S ,S )-5 in hand, the
P
P
bis(isonitrile) iron(II) complexes 9a and 9b were prepared as previously described (Scheme 3,
9
,14
see Supporting Information for detailed experimental procedures).
In a first step, dialdehyde
(S ,S )-5 was treated with (1S,2S)-cyclohexane-1,2-diamine under high-dilution conditions (0.01
P
P
M in EtOH) to afford macrocycle (S ,S ,S ,S )-6, which precipitates from the solution upon
P
P
C
C
1
4
concentration and was isolated as a single diastereoisomer in 58% yield on a 10 mmol scale.
ACS Paragon Plus Environment
1
0

Page 11 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Scheme 3. Synthesis of Bis(acetonitrile) Complex 8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The imine moieties in macrocycle (S ,S ,S ,S )-6 were cleanly reduced with lithium aluminum
P
P
C
C
hydride to afford the corresponding diamino macrocycle (S ,S ,S ,S )-7 in high yield and purity
P
P
C
C
9
after simple filtration through silica gel. Therefore, the reduced (NH) P macrocycle
2
2
(
S ,S ,S ,S )-7 was not further purified and treated directly with iron(II) tetrafluoroborate
P P C C
hexahydrate in MeCN / CH Cl at 55 °C in the presence of DBU (25 mol%). A catalytic amount
2
2
of DBU is necessary to isomerize the initial mixture of two Λ-cis-β isomers and a trans isomer to
the thermodynamic isomer Λ-cis-β-[Fe(MeCN) (7)](BF ) (8), which was obtained as a single
2
4 2
isomer after crystallization from MeCN / Et O (see Supporting Information for detailed
2
9
experimental procedures). The structure of the bis(acetonitrile) complex 8, including the
absolute configuration of the newly formed stereocenters on the nitrogen atoms, has previously
1
4
been determined by X-ray diffractometry. This procedure afforded 2.7 g of the bis(acetonitrile)
complex 8 as a monomeric, diamagnetic and stable solid in a single reaction highlighting the
scalability of this route to such macrocyclic iron(II) / (NH) P complexes.
2
2
ACS Paragon Plus Environment
1
1

Organic Process Research & Development
Page 12 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Scheme 4. Synthesis of Bis(isonitrile) Complexes 9a and 9b
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In the last step of the catalyst synthesis, the ancillary acetonitrile ligands in 8 were substituted
by bulky isonitriles (Scheme 4, see Supporting Information for detailed experimental
procedures). Quantitative substitution of the acetonitrile ligands by the isonitriles was observed
3
1
1
within 24 h at 50 °C (as readily monitored by P{ H} NMR spectroscopy), and the
i
bis(isonitrile) derivatives [Fe(CNR) (7)](BF ) (R = CEt , 9a; R = N Pr , 9b) were obtained as
2
4 2
3
2
single configurational isomers in high yield on a 1.0 g scale. The sterically demanding isonitriles
i
CNCEt and CNN Pr were used as the steric bulk significantly increases the enantioselectivity in
3
2
9
the ATH of ketones as previously described. As the isonitrile ligands are introduced in the last
step of the catalyst synthesis, the Fe(II) / (NH) P catalyst system is highly tunable (both
2
2
electronically and sterically) to give optimal results for specific substrates.
Bis(isonitrile) complexes 9a and 9b were routinely stored in a glove box and did not show any
sign of decomposition over several months. However, both 9a and 9b tolerate exposure to air
and moisture, at least for limited periods of time. In control experiments, exposure of these
ACS Paragon Plus Environment
1
2

Page 13 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
complexes to air both as a solid or in “wet” dichloromethane solutions over several days did not
1
result in any decomposition of the bis(isonitrile) iron(II) complexes as confirmed by H NMR
3
1
1
and P{ H} NMR spectroscopy.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ATH of Polar Bonds. We have previously reported the ATH of a series of prochiral ketones
and imines catalyzed by the macrocyclic bis(isonitrile) Fe(II) / (NH) P complexes 9a and 9b
2
2
9
with 2-propanol as hydrogen source. The corresponding alcohols and amines were obtained in
high yields (up to 99.9% GC yield) and excellent enantioselectivity (up to 99.3% ee) with
relatively low catalyst loading (generally 0.1 mol%) at slightly elevated temperatures (50 and 60
°
C for 9a and 9b, respectively). The substrate scope included standard aryl alkyl ketones, but
also challenging ones such as acyl pyridines, ortho-substituted acetophenones, and tert-butyl
phenyl ketone as well as industrially relevant ones such as 3,5-bis(trifluoromethyl)-
13
25
acetophenone and 3-trifluoromethylacetophenone. Overall, aryl alkyl ketones were reduced
with higher enantioselectivity (generally >95% ee) than dialkyl ketones (up to 24% ee), whereas
enones were hydrogenated to allylic alcohols with complete chemoselectivity but moderate
9
enantioselectivity (70% ee). As all reactions were run on relatively small scale (2.5 mmol), we
were interested in assaying bis(isonitrile) precatalysts 9a and 9b in the asymmetric transfer
hydrogenation of prochiral substrates on a larger scale (100 mmol) to highlight the synthetic
utility of the catalyst system.
As the ATH of aryl alkyl ketones using 2-propanol as hydrogen source is an equilibrium
reaction, and catalysts 9a and 9b are inactive in direct hydrogenation, we focus here on
substrates for which the equilibrium lies far to the side of the optically active alcohol. This is the
case for substrates bearing electron-poor or ortho-substituted aromatics or bulky alkyl groups
9
(
Chart 2). Nevertheless, the 2-propanol system is in principle not restricted to such substrates,
ACS Paragon Plus Environment
1
3

Organic Process Research & Development
Page 14 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and strategies to bias the equilibrium towards the formation of the optically active alcohol have
been developed. These strategies often rely on the constant removal of the by-product acetone
2
6
(
by distillation) or cycling of the reaction mixture (by complete removal of the solvent and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5h
resubjection to reaction conditions).
Chart 2. Substrates for ATH
For all substrates shown in Chart 2, the ATH reactions were first optimized on a 10 mmol scale
before scale-up to 100 mmol. Generally, it was found that an increase of the reaction temperature
from 50 to 60 °C for catalyst 9a (or from 60 °C to 75 °C for catalyst 9b) increased the activity of
the catalyst without erosion of enantioselectivity (Table 1). The optimization of the reaction
conditions for each substrate allowed to decrease the catalyst loadings as compared to the
reactions on a 2.5 mmol scale, in which 0.1 and 0.4 mol% was used for substrates 10a-10g and
9
10h-10j, respectively. A further advantage of the increased reaction temperature is the shift of
the reaction equilibrium to the product side, which increases the theoretical yield of the optically
active alcohol.
ACS Paragon Plus Environment
1
4

Page 15 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
a
Table 1. ATH of substrates 10a-10j
b
c
d
entry substrate catalyst
S / C / B
temperature (°C) time (h) yield (%) ee (%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
2
3
4
5
6
7
8
9
10a
10a
10b
10c
10d
10e
10f
10g
10h
10i
9a
9b
9a
9b
9b
9a
9a
9a
9b
9b
9a
10 000 / 1 / 25
5 000 / 1 / 20
2 500 / 1 / 15
2 500 / 1 / 15
2 500 / 1 / 15
1 500 / 1 / 10
5 000 / 1 / 20
10 000 / 1 / 25
2 500 / 1 / 15
500 / 1 / 10
60
75
60
75
75
60
60
60
75
75
75
2.0
3.0
2.5
2.0
1.5
1.0
1.5
1.5
5.0
5.0
5.0
91.8
90.7
98.8
99.3
99.3
99.7
98.6
96.3
97.8
99.4
97.6
99.4
97.1
99.1
e
e
97.1
89.0
97.6
97.3
97.7
95.8
1
0
1
f
f
1
10j
500 / 1 / 10
94.0
>99.9
a
b
Reaction conditions: 10 (100 mmol), 2-propanol (500 mL), sodium tert-butoxide as base. S /
c
C / B = substrate / catalyst / base. Yield of isolated product after flash column chromatography.
ee was determined by chiral GC or HPLC. Product purified by distillation. Product purified
by crystallization (initial ee was 98.4%).
d
e
f
Under optimized conditions, (R)-1-phenylethan-1-ol (11a) was obtained in 91.8% isolated
yield and with 96.3% ee by the ATH of acetophenone (10a) within 2.0 h by using 0.01 mol% of
i
the CNCEt derivative 9a as catalyst. Complex 9b, which bears the N-isonitrile CNN Pr , was
3
2
slightly less active and afforded alcohol 11a in 90.7% isolated yield and with 97.8% ee after 3.0
h with a catalyst loading of 0.02 mol%. For both ATH reactions, the enantioselectivity was
identical to that found previously in the hydrogenation with a catalyst loading of 0.1 mol% on a
2
.5 mmol scale. It should be noted that, although complexes 9a and 9b are stable towards air and
ACS Paragon Plus Environment
1
5

Organic Process Research & Development
Page 16 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
moisture, the ATH reaction solutions are air sensitive. Therefore, the ATH reactions were run
under argon atmosphere using degassed and distilled 2-propanol (see Supporting Information for
detailed experimental procedures).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The ortho-substituted ketones 10b-10d were reduced within 1.5 – 2.5 h using either catalyst 9a
or 9b with S / C / B = 2 500 / 1 / 15, and the optically active alcohols 11b-11d were obtained in
excellent isolated yields (98.8 – 99.3%) and with high enantiopurities (97.6 – 99.4% ee) after
flash column chromatography. Trifluoromethyl-substituted substrates 10e and 10f were readily
reduced with catalyst 9a, and the corresponding alcohols 11e and 11f, which are important
25
13
synthons for fungicides and NK1-antagonists, were obtained in high isolated yield and with
7.1% and 99.1% ee, respectively. Acyl-substituted heterocycles (i.e. acyl pyridines and
9
thiophenes) were also readily reduced with complex 9a on 2.5 mmol scale. As an example, we
tested the ATH of 2-acetylpyridine (10g, 100 mmol) using catalyst 9a (0.01 mol%). Full
conversion to (R)-1-(pyridin-2-yl)ethan-1-ol (11g) was observed within 1.5 h corresponding to
–
1
an average TOF of 6 650 h , and the pure product was obtained by distillation in 97.1% isolated
yield and with 97.3% ee.
The substrate scope is not restricted to aryl methyl ketones, though, and sterically demanding
alkyl groups are well tolerated. Although a moderate increase in the catalyst loading (0.04 – 0.2
mol%) is necessary to obtain high conversion, the catalyst loadings are still significantly lower
than in the small-scale reactions with the same substrates, where 0.4 mol% of catalyst was used.
Cyclohexyl phenyl ketone 10h was hydrogenated by catalyst 9b (0.04 mol%) in 89.0% isolated
yield and with an impressive 97.7% ee, which shows that the macrocyclic iron(II) / (NH)2P
2
complexes 9 readily differentiate between an alkyl and an aryl group of similar size (Cy vs. Ph).
Accordingly, the reduction with catalysts 9 occurs from the si-side of the substrate independently
ACS Paragon Plus Environment
1
6

Page 17 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
from electronic and steric changes. Along these lines, the very bulky tert-butyl phenyl ketone
1
2
1
0i, which is one of the most challenging substrates for asymmetric hydrogenation, was
reduced to give the corresponding alcohol 11i in 97.6% yield and with high enantioselectivity
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(
95.8% ee) using catalyst 9b.
Finally, activated imines are also efficiently hydrogenated using bis(isonitrile) complex 9a.
Thus, phosphinyl imine 10j was reduced using catalyst 9a (0.2 mol%) to give 11j with 98.4% ee.
As purification of the reduced product by flash column chromatography is difficult due to its
high polarity, the crude was crystallized directly from 2-propanol to afford pure 11j in 94.0%
isolated yield as essentially a single enantiomer (>99.9% ee). The phosphinyl group is readily
2
7
cleaved by ethanolic hydrochloric acid affording chiral amines without loss of enantiopurity,
which makes phosphinyl imines efficient precursors to enantiopure primary amines.
In summary, the ATH of prochiral ketones and imines with the macrocyclic bis(isonitrile)
iron(II) complexes 9a and 9b is highly efficient and selective. A representative set of aryl alkyl
ketones and an activated imine was reduced with low catalyst loadings (0.01 – 0.2 mol%) within
short reaction times (1.0 – 5.0 h) on a 100 mmol scale, which highlights the robustness and
synthetic utility of the iron(II) / (NH) P catalyst system.
2
2
Comparison with Other Iron-based Catalysts. To gain a full overview on the recent
advances in iron-catalyzed asymmetric reductions, we give here a survey of representative iron-
based catalysts in the asymmetric reduction of acetophenone 10a (as standard substrate) in terms
of activity, enantioselectivity, and catalyst loading (Table 2). In an analogous comparison,
Morris has shown that their second-generation catalyst C is considerably more active than most
5
e
platinum-metal-based ATH catalysts. As can be seen from Table 2, only few iron catalysts
combine high enantioselectivity (>95% ee) with good activity, though. Also taking into account
ACS Paragon Plus Environment
1
7

Organic Process Research & Development
Page 18 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
catalyst loading and reaction temperature, the data in Table 2 show that Morris’ third generation
complex D is by far the most active ATH catalyst, as it achieves 82% conversion within 3 min at
5
g
room temperature with 0.016 mol% of catalyst. For comparison, catalysts 9a and 9b require
0 – 75 °C and 2 – 3 h to reach 92 % conversion. However, D is considerably less enantioselec-
tive (90% ee) than 9a and 9b (96 and 98% ee, respectively), and the more selective analogue E
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
5i
(
98% ee) has a similar activity as 9a and 9b. Furthermore, in terms of substrate scope, Morris'
third-generation catalysts give high enantioselectivity (>95% ee) only with a few substrates (10f
5
g-i
for D; 10a, 10f, and α-chloroacetophenone for E).
Besides 9a and 9b, Gao’s catalyst F is the only system that combines good enantioselectivity
4
c
and high activity for a broad scope of substrates. Like 9a and 9b, F is based on macrocyclic
ligands, albeit with a much larger ring size, but is considerably less active than 9a and 9b under
ATH conditions at the same temperature. An advantage of F is that it is effective under direct
hydrogenation conditions with 50 bar of H , which is particularly interesting as the ATH
2
4
d
equilibrium is avoided.
ACS Paragon Plus Environment
1
8

Page 19 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Table 2. Comparison of iron-based catalyst for the reduction of acetophenone 10a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
catalyst
reaction type
S / C
T (°C)
yield
(%)
time
ee
(%)
ref
9
a, base
b, base
ATH
ATH
10 000
5 000
100
60
75
92
91
93
95
94
82
71
89
98
99
100
94
98
99
2 h
3 h
96
98
84
29
90
90
98
97
96
80
50
98
83
54
this work
9
this work
A, base
B, base
C, base
D, base
E, base
F, base
F, base
ATH
75
15 h
24 min
7 min
3 min
2 h
10
5b
5e
5g
5i
ATH
400
22
ATH
1 000
6 121
6 121
2 000
500
28
ATH
28
ATH
28
ATH
75
2 h
4c
4d
5j
AH (50 bar)
AH (5 bar)
AH (30 bar)
45
12 h
30 min
18 h
6 h
b
G , base
1 000
50
50
c
H
70
28
7
I
AHS ((EtO)
2
MeSiH)
43
-78 to r.t.
25
d
J
AHS (Ph SiH )
100
3 h
29
30
2
2
e
K
AHS (PhSiH3)
333
23
1 h
a
ATH: asymmetric transfer hydrogenation (with 2-propanol); AH: asymmetric hydrogenation
with H under specified pressure); AHS: asymmetric hydrosilylation (with specified silane).
Catalyst activated with LiAlH and AmylOH. Catalyst activated with Me NO. Catalyst
activated with NaBHEt . Catalyst activated with B(C F ) .
b
(
2
t
c
d
4
3
e
3
6 5 3
ACS Paragon Plus Environment
1
9

Organic Process Research & Development
Page 20 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Together with Gao's system F, Morris’ PNP complex G is the only highly active catalyst for
AH of ketones even at low hydrogen pressure (5 bar), but its enantioselectivity is modest so far
5
j
(
up to 85% ee). Table 2 also shows that asymmetric hydrosilylation with iron catalysts is not
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7,29,30
competitive with ATH or AH today.
Overall, we believe that the macrocyclic bis(isonitrile)
catalysts 9a and 9b are valuable alternatives to the best iron catalyst systems for ATH,
particularly as they are broadly applicable and predictably reduce aryl alkyl ketones with high
enantioselectivity and activity throughout.
Conclusion
A new synthetic route to macrocyclic iron(II) / (NH) P complexes is reported, which affords
2
2
the key synthon (S ,S )-5 in 33% yield over 5 steps. This new synthetic protocol is shorter,
P
P
14
higher yielding and easier to perform compared to the previous route and multigram quantities
of the dialdehyde (S ,S )-5 were prepared in a single batch. Furthermore, the substitution of (–)-
P
P
ephedrine by (–)-menthol as the chiral auxiliary renders this approach more suitable because (–)-
ephedrine is controlled, while menthol is commercially available in the (+)- and (–)-form, thus
guaranteeing access to both enantiomers of like-5 (and therefore also to the catalysts 9a and 9b in
both enantiomeric forms).
The results reported herein show that the bis(isonitrile) complexes 9a and 9b bearing C-
i
isonitrile CNCEt and N-isonitrile CNN Pr , respectively, are highly effective and enantioselec-
3
2
tive catalysts for the ATH of prochiral substrates on a 100 mmol scale. A representative set of
aryl alkyl ketones 10a-10i and imine 10j was hydrogenated in high isolated yield (89.0 – 99.7%),
with excellent enantioselectivity (95.8 – 99.4% ee) and low catalyst loadings (0.01 – 0.2 mol%),
which highlights the robustness and synthetic utility of the iron(II) / (NH) P system.
2
2
ACS Paragon Plus Environment
2
0

Page 21 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Furthermore, the application of chiral iron complexes to asymmetric reductions on synthetically
useful scale shows that the highly desired substitution of precious metal catalyst by cheap and
non-toxic 3d metals is feasible.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General Procedures. Reactions with air- or moisture-sensitive materials were carried out
under an argon atmosphere using Schlenk techniques. All solvents were distilled from an
appropriate drying agent under argon prior to use (Et O and THF from Na / benzophenone;
2
hexane from Na / benzophenone / tetraglyme; EtOH from Na / ethyl phthalate; CH Cl , MeCN,
2
2
1
13
MeOH and 2-propanol from CaH ). H and C positive chemical shifts in ppm are downfield
2
3
1
1
from tetramethylsilane. P{ H} NMR spectra are referenced to external 85% H PO . For
3
4
13
31
1
31
1
complexes, C{ P, H} were measured with P (and H) decoupling to improve the S / N ratio.
Mass spectra were measured by the MS service of the Laboratory of Organic Chemistry (ETH
Zürich). Elemental analyses were carried out by the Laboratory of Microelemental Analysis
(
ETH Zürich). Detailed experimental procedures for the preparation of all compounds, and NMR
spectra thereof, are given in the Supporting Information.
R)-(2-(1,3-Dioxolan-2-yl)phenyl)phenylphosphine Oxide, (R )-2. A pentane solution of
(
P
tert-butyllithium (200 mL, 1.9 M, 380 mmol, 4.2 equiv) was added to 2-(2-bromophenyl)-1,3-
dioxolane (28.4 mL, 190 mmol, 2.1 equiv) in Et O (570 mL) at -78 °C over 0.5 h. After stirring
2
the resulting solution at 0 °C for 1.5 h, (R )-1 (25.4 g, 90 mmol) in Et O (110 mL) was added at -
P
2
7
8 °C over 0.5 h, after which the solution was warmed to room temperature overnight. A
saturated aqueous NH Cl solution (400 mL) was added thereto, and the organic solvent was
4
removed under reduced pressure. The aqueous phase was washed four times with hexane (4 ×
ACS Paragon Plus Environment
2
1

Organic Process Research & Development
Page 22 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
00 mL) and extracted four times with CHCl (4 × 400 mL). The combined CHCl phases were
3
3
dried over MgSO , and the solvent was removed under reduced pressure to afford the product as
4
3
1
1
1
a slightly yellowish oil (>99% pure by P{ H} NMR). Yield: 22.1 g (89%). H NMR (300 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
3
4
CDCl ): δ 8.34 (d, J = 502.2 Hz, 1H, P-H), 7.86 (ddd, J = 15.2 Hz, J
= 7.5 Hz, J
=
3
P,H
P,H
H,H’
H,H’
3
4
1.5 Hz, 1H, Ar-H), 7.73 – 7.63 (m, 3H, Ar-H), 7.58 (tt, JH,H’ = 7.6 Hz, J
= 1.6 Hz, 1H, Ar-
H,H’
H), 7.55 – 7.42 (m, 4H, Ar-H), 6.05 (s, 1H, CH(OCH ) ), 4.00 – 3.89 (m, 4H, CH(OCHH) ).
2
2
2
3
1
1
31
1
P{ H} NMR (122 MHz, CDCl ): δ 19.0 (s). P NMR (122 MHz, CDCl ): δ 19.0 (ddt, J =
P,H
3
3
3
13
1
2
502.2 Hz, J = 15.2, 14.9 Hz). C{ H} NMR (75 MHz, CDCl ): δ 140.8 (d, J = 7.5 Hz,
P,H
3
P,C
2
4
1
arom.), 132.9 (d, J = 10.5 Hz, arom.), 132.5 (d, J = 2.7 Hz, arom.), 132.4 (d, J = 102.7
P,C
P,C
P,C
4
2
1
Hz, arom.), 132.2 (d, J = 2.9 Hz, arom.), 130.8 (d, J = 11.4 Hz, arom.), 129.9 (d, J =
P,C
P,C
P,C
3
3
96.1 Hz, arom.), 129.3 (d, J = 12.4 Hz, arom.), 128.7 (d, J = 12.9 Hz, arom.), 127.3 (d,
P,C
P,C
3
3
JP,C = 9.7 Hz, arom.), 101.6 (d, JP,C = 4.4 Hz, CH(OCH ) ), 65.1 (CH(OCH ) ), 65.0
2 2
2 2
–1
(CH(OCH ) ). IR (liquid film, cm ): 3058 (C-H), 2955 (C-H), 2892 (C-H), 2334 (P=O), 1645,
2 2
1
1
591, 1573, 1483, 1474, 1438, 1398, 1347, 1311, 1293, 1177, 1134, 1113, 1096, 1065, 1038,
+
023. HRMS (ESI): calcd for C H O P m/z = 275.0832, found m/z = 275.0837 [M + H] .
1
5
16
3
HPLC: Chiralpak IB-3 (hexane/2-PrOH = 80:20, flow rate 1.0 mL/min, λ = 230 nm), retention
2
0
times t (minor) = 13.5 min, t (major) = 19.1 min; 99% ee. [α] : +40.5 (c 1.0, CH Cl ).
R
R
D
2
2
(
R)-(2-(1,3-Dioxolan-2-yl)phenyl)(methyl)(phenyl)phosphine Oxide, (R )-3. A hexane
P
solution of n-butyllithium (50.4 mL, 1.6 M, 81 mmol, 1.0 equiv) was added to (R )-2 (22.1 g, 81
P
mmol) in THF (410 mL) at -78 °C and stirred for 0.5 h. Iodomethane (5.5 mL, 89 mmol, 1.1
equiv) in THF (46 mL) was added over 1.0 h, and the solution was warmed to room temperature
over 3 h. The solvent was removed under reduced pressure, water (250 mL) was added to the
residue, and the aqueous phase was extracted three times with CHCl (3 × 250 mL). The
3
ACS Paragon Plus Environment
2
2

Page 23 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
combined organic phases were dried over MgSO , and the solvent was removed under reduced
4
3
1
1
pressure to afford the product as a clear oil that solidified upon standing (>96% pure by P{ H}
1
NMR). Yield: 22.0 g (95%). H NMR (300 MHz, CDCl ): δ 7.83 – 7.78 (m, 1H, Ar-H), 7.75 –
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7
.66 (m, 2H, Ar-H), 7.62 – 7.37 (m, 6H, Ar-H), 6.41 (s, 1H, CH(OCH ) ), 4.09 – 3.85 (m, 4H,
2 2
2
31
1
CH(OCHH) ), 2.11 (d, J = 13.3 Hz, 3H, CH ). P{ H} NMR (122 MHz, CDCl ): δ 27.0 (s).
2
P,H
3
3
3
1
2
3
13
1
P NMR (122 MHz, CDCl ): δ 27.0 (qd, J = 13.3 Hz, J = 11.6 Hz). C{ H} NMR (75
3
P,H
P,H
2
1
MHz, CDCl ): δ 141.7 (d, J = 7.3 Hz, arom.), 134.8 (d, J = 101.8 Hz, arom.), 132.5 (d,
3
P,C
P,C
1
4
2
JP,C = 89.6 Hz, arom.), 132.1 (d, J = 2.8 Hz, arom.), 132.0 (d, J = 10.8 Hz, arom.), 131.8
P,C
P,C
4
3
3
(d, J = 2.7 Hz, arom.), 130.7 (d, J = 9.8 Hz, arom.), 128.9 (d, J = 7.3 Hz, arom.), 128.7
P,C
P,C
P,C
2
3
3
(d, J
= 12.0 Hz, arom.), 127.5 (d, JP,C = 9.5 Hz, arom.), 100.2 (d, J
= 4.4 Hz,
P,C
P,C
1
CH(OCH ) ), 65.4 (2C, CH(OCH ) ), 18.2 (d, J = 74.2 Hz, PCH ). Melting Point: 108 °C. IR
2
2
2 2
P,C
3
–1
(liquid film, cm ): 3058 (C-H), 2956 (C-H), 2887 (C-H), 2216 (P=O), 1643, 1591, 1572, 1473,
1
2
437, 1395, 1296, 1177, 1132, 1113, 1091, 1060, 1025. HRMS (ESI): calcd for C H O P m/z =
16 18 3
+
89.0988, found m/z = 289.0985 [M + H] . HPLC: Chiralpak ID-3 (hexane/2-PrOH = 90:10,
flow rate 1.0 mL/min, λ = 210 nm), retention times t (major) = 75.0 min, t (minor) = 82.3 min;
R
R
2
0
97% ee. [α] : –16.9 (c 1.0, CH Cl ). Anal. Calcd for C H O P: C, 66.66; H, 5.94. Found: C,
D
2
2
16 17
3
6
6.48; H, 6.04.
(1R,1’R)-Ethane-1,2-diylbis((2-(1,3-dioxolan-2-yl)phenyl)(phenyl)phosphine
Oxide,
(R ,R )-4. A hexane solution of n-butyllithium (51.6 mL, 1.6 M, 82.6 mmol, 1.4 equiv) was
P
P
added to diisopropylamine (12.4 mL, 88.5 mmol, 1.5 equiv) in THF (48 mL) at 0 °C. After
stirring for 0.5 h, this solution was added to (R )-3 (17.0 g, 59.0 mmol) in THF (220 mL) at -78
P
°
C over 0.25 h under stirring. After 5 min, copper(II) chloride (13.5 g, 100 mmol, 1.7 equiv) was
added, and the solution was warmed to room temperature overnight. The solvent was removed
ACS Paragon Plus Environment
2
3

Organic Process Research & Development
Page 24 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
under reduced pressure, CHCl (1000 mL) was added, and the organic phase was washed three
3
times with an aqueous 10% NH solution (3 × 300 mL) and once with water (300 mL). Each
3
aqueous phase was extracted twice with CHCl (2 × 100 mL). The combined organic phases
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
were dried over MgSO , and the solvent was removed under reduced pressure. Flash column
4
chromatography on silica gel (gradient CH Cl to MeOH : CH Cl = 7 : 93) afforded the product
2
2
2
2
1
3
as an off-white solid. Yield: 13.5 g (80%). H NMR (300 MHz, CDCl ): δ 7.78 (d, J
= 7.5
3
H,H’
Hz, 2H, Ar-H), 7.72 – 7.62 (m, 4H, Ar-H), 7.61 – 7.35 (m, 12H, Ar-H), 6.45 (s, 2H,
3
1
1
CH(OCH ) ), 4.01 – 3.79 (m, 8H, CH(OCHH) ), 2.90 – 2.48 (m, 4H, PCHH). P{ H} NMR
2
2
2
13
1
2
(
122 MHz, CDCl ): δ 35.6 (s). C{ H} NMR (75 MHz, CDCl ): δ 142.4 (t, J = 3.5 Hz,
3 3 P,C
arom.), 133.2 (m, arom.), 132.23 (m, arom.), 132.17 (t, JP,C = 5.4 Hz, arom.), 132.0 (m, arom.),
1
131.0 (t, JP,C = 4.8 Hz, arom.), 130.6 (t, J = 47.3 Hz, arom.), 129.0 (t, JP,C = 5.8 Hz, arom.),
P,C
3
1
28.7 (t, JP,C = 5.9 Hz, arom.), 127.7 (t, JP,C = 4.8 Hz, arom.), 100.2 (t, J = 2.0 Hz,
P,C
1
CH(OCH ) ), 65.33 (CH(OCH ) ), 65.30 (CH(OCH ) ), 18.2 (t, J = 33.8 Hz, PCH ). Melting
2 2
2 2
2 2
P,C
2
–
1
Point: 146 °C. IR (liquid film, cm ): 3058 (C-H), 3023 (C-H), 2955 (C-H), 2887 (C-H), 2227
P=O), 1725, 1638, 1596, 1572, 1492, 1473, 1437, 1412, 1396, 1349, 1333, 1312, 1285, 1171,
1132, 1112, 1092, 1061, 1027. HRMS (ESI): calcd for C H O P m/z = 575.1747, found m/z =
(
32
33
6 2
+
20
5
75.1744 [M + H] . [α] : –5.6 (c 1.0, CH Cl ). Anal. Calcd for C H O P : C, 66.90; H, 5.61.
D 2 2 32 32 6 2
Found: C, 66.87; H, 5.59.
2,2’-((1S,1’S)-Ethane-1,2-diylbis(phenylphosphanediyl))dibenzaldehyde, (S ,S )-5. Tita-
P
P
nium(IV) iso-propoxide (42.8 mL, 141 mmol, 6.0 equiv) was added dropwise to (R ,R )-4 (13.5
P
P
g, 23.5 mmol) in THF (470 mL) at 60 °C over 0.25 h and stirred for 0.25 h. PMHS (70.2 mL,
average M = 1700 – 3200, 50 equiv) was added dropwise over 0.75 h, and the solution was
n
stirred overnight at 60 °C. The volatiles were removed under reduced pressure, hexane (350 mL)
ACS Paragon Plus Environment
2
4

Page 25 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
was added, and the suspension was stirred at 50 °C for 0.5 h before cooling to -78 °C. The
precipitate was filtered over Celite, washed twice with hexane (2 × 15 mL), and dissolved in
THF (430 mL). The resulting solution was filtered and 5% aqueous HCl (215 mL) was added
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
thereto. After stirring for 5 h at room temperature, a saturated aqueous NaHCO solution (400
3
mL) was added, and the organic solvent was removed under reduced pressure. The aqueous
phase was extracted three times with CH Cl (3 × 400 mL), the combined organic phases were
2
2
dried over MgSO , and the solvent was removed under reduced pressure. Filtration through silica
4
gel (EtOAc : hexane = 1 : 3) and crystallization from hot MeOH afforded the product as a yellow
1
4
solid. Yield: 5.28 g (49%). H NMR (300 MHz, CD Cl ): δ 10.55 (t, J = 2.7 Hz, 2H, O=CH),
2
2
P,H
7
.94 – 7.85 (m, 2H, Ar-H), 7.55 – 7.45 (m, 4H, Ar-H), 7.37 – 7.25 (m, 12H, Ar-H), 2.29 – 2.01
3
1
1
(m, 4H, PCHH). P{ H} NMR (122 MHz, CD Cl ): δ –22.0 (s, (S ,S )-5), –22.2 (s, (R ,S )-5);
2
2
P
P
P
P
13
1
dr > 99 : 1. C{ H} NMR (75 MHz, CD Cl ): δ 192.4 (m, CHO), 142.6 (m, arom.), 139.5 (m,
2
2
arom.), 137.9 (m, arom.), 134.1 (arom.), 133.7 (m, arom.), 132.5 (arom.), 131.3 (arom.), 129.6
(
arom.), 129.4 (arom.), 129.2 (m, arom.), 24.2 (m, PCH ). Melting Point: 128 °C. IR (liquid film,
2
–1
cm ): 3054 (C-H), 2823 (C-H), 2739 (C-H), 1693 (C=O), 1584, 1561, 1482, 1461, 1433, 1422,
1386, 1294, 1258, 1197, 1163, 1117, 1094. HRMS (ESI): calcd for C H NaO P m/z =
2
8
24
2 2
+
20
4
77.1144, found m/z = 477.1135 [M + Na] . [α] : +35.6 (c 1.0, CH Cl ). Anal. Calcd for
D 2 2
C H O P : C, 74.00; H, 5.32. Found: C, 73.73; H, 5.30. Analytical data are in agreement with
28
24
2 2
1
4
literature data. For the determination of the enantiomeric purity, the product was converted to
14
(((1S,1’S)-ethane-1,2-diylbis(phenylphosphanediyl))bis(2,1-phenylene))dimethanol diborane.
HPLC: Chiralpak IC-3 (hexane/2-PrOH, 80:20, flow rate 1.0 mL/min, λ = 230 nm), retention
times t ((R ,R )) = 7.9 min, t ((R ,S )) = 8.9 min, t ((S ,S )) = 11.0 min; >99% ee.
R
P
P
R
P
P
R
P
P
ACS Paragon Plus Environment
2
5

Organic Process Research & Development
Page 26 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Representative ATH Reaction: (+)-(R)-1-Phenylethan-1-ol, 11a. 2-Propanol (500 mL) was
added to 9a (10.2 mg, 10.0 μmol, 0.01 mol%) and sodium tert-butoxide (24.0 mg, 250 μmol,
0
.25 mol%) and the yellow solution was stirred for 10 min at 60 °C. Acetophenone (10a) (11.7
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mL, 100 mmol) was added to the resulting homogeneous solution, and the reaction progress was
monitored by gas chromatography. After 2.0 h, the solvent was removed under reduced pressure.
Flash column chromatography on silica gel (gradient Et O : pentane = 1 : 9 to 3 : 2) afforded the
2
1
product as a clear liquid. Yield: 11.22 g (91.8%). H NMR (300 MHz, CDCl ): δ 7.45 – 7.27 (m,
3
3
3
5H, Ar-H), 4.92 (d, J
= 6.4 Hz, 1H, CHOH), 2.10 (br s, 1H, OH), 1.53 (d, J
= 6.4 Hz,
H,H’
H,H’
13
1
1
H, CH ). C{ H} NMR (75 MHz, CDCl ): δ 145.9 (arom.), 128.6 (arom.), 127.5 (arom.), 125.5
3 3
–
1
(
arom.), 70.5 (CHOH), 25.3 (CH ). IR (liquid film, cm ): 3338 (O-H), 3085 (C-H), 3062 (C-H),
3
3029 (C-H), 2972 (C-H), 2926 (C-H), 2872 (C-H), 1602, 1493, 1450, 1407, 1368, 1327, 1283,
261, 1203, 1177, 1156, 1098, 1075, 1028, 1009. HRMS (EI): calcd for C H O m/z = 122.0727,
1
8
10
+
found m/z = 122.0727 [M] . GC: β-DEX column, 100 °C isotherm, retention times t (major) =
R
2
0
2
2.2 min, t (minor) = 24.1 min; 96.3% ee. [α] : +61.3 (c 1.0, CHCl ). Analytical data are in
R D 3
9
agreement with literature data.
ASSOCIATED CONTENT
Supporting Information. Detailed experimental procedures and characterization of all
products.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: mezzetti@inorg.chem.ethz.ch
ACS Paragon Plus Environment
2
6

Page 27 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We thank the Swiss National Science Foundation for financial support to Raphael Bigler (grant
no. 200020_146881) and Raffael Huber for single-crystal X-ray analyses.
REFERENCES
(
1) For selected articles, see: (a) The Handbook of Homogeneous Hydrogenation; de Vries,
J. G.; Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007. (b) Ikariya, T. Top.
Organomet. Chem. 2011, 37, 31. (c) Gladiali, S.; Alberico, E. Chem. Soc. Rev. 2006, 35,
2
26. (d) Wang, C.; Wu, X.; Xiao, J. Chem. Asian. J. 2008, 3, 1750. (e) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (f) Diéguez, M.; Pàmies, O.; Claver, C.
Top. Organomet. Chem. 2011, 34, 11. (g) Saidi, O.; Williams, J. M. J. Top. Organomet.
Chem. 2011, 34, 77. (h) Malacea, R.; Poli, R.; Manoury, E. Coord. Chem. Rev. 2010,
2
54, 729. (i) Etayo, P.; Vidal-Ferran, A. Chem. Soc. Rev. 2013, 42, 728.
(2) For selected articles, see: (a) Blaser, H.-U.; Pugin, B.; Spindler, F. Top. Organomet.
Chem. 2012, 42, 65. (b) Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16,
1
156. (c) Ager, D. J.; de Vries, A. H. M.; de Vries, J. G. Chem. Soc. Rev. 2012, 41, 3340.
(d) Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H. Adv. Synth. Catal.
011, 353, 1825.
2
(3) For selected articles: (a) Darcel, C.; Sortais, J.-B. Top. Organomet. Chem. 2015, 50, 173.
(b) Nakazawa, H.; Itazaki, M. Top. Organomet. Chem. 2011, 33, 27. (c) Darwish, M.;
ACS Paragon Plus Environment
2
7

Organic Process Research & Development
Page 28 of 31
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Wills, M. Catal. Sci. Technol. 2012, 2, 243. (d) Le Bailly, B. A. F.; Thomas, S. P. RSC
Adv. 2011, 1, 1435. (e) Chakraborty, S.; Guan, H. Dalton Trans. 2010, 39, 7427.
(f) Morris, R. H. Chem. Soc. Rev. 2009, 38, 2282. (g) Junge, K.; Schröder, K.; Beller, M.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Chem. Commun. 2011, 47, 4849. (h) Bauer, I.; Knölker, H.-J. Chem. Rev. 2015, 115,
3170. (i) Misal Castro, L. C.; Li, H.; Sortais, J.-B.; Darcel, C. Green. Chem. 2015, 17,
2
283.
(
4) (a) Li, Y.-Y.; Yu, S.-L.; Shen, W.-Y.; Gao, J.-X. Acc. Chem. Res. 2015, 48, 2587. (b)
Chen, J.-S.; Chen, L.-L.; Xing, Y.; Chen, G.; Shen, W.-Y.; Dong, Z.-R.; Li, Y.-Y.; Gao,
J.-X. Acta Chim. Sin. 2004, 62, 1745. (c) Yu, S.; Shen, W.; Li, Y.; Dong, Z.; Xu, Y.; Li,
Q.; Zhang, J.; Gao, J. Adv. Synth. Catal. 2012, 354, 818. (d) Li, Y.; Yu, S.; Wu, X.; Xiao,
J.; Shen, W.; Dong, Z.; Gao, J. J. Am. Chem. Soc. 2014, 136, 4031.
(
5) For selected articles, see: (a) Morris, R. H. Acc. Chem. Res. 2015, 48, 1494. (b) Sui-Seng,
C.; Freutel, F.; Lough, A. J.; Morris, R. H. Angew. Chem. Int. Ed. 2008, 47, 940. (c)
Mikhailine, A.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2009, 131, 1394. (d)
Lagaditis, P. O.; Lough, A. J.; Morris, R. H. J. Am. Chem. Soc. 2011, 133, 9662. (e)
Sues, P. E.; Lough, A. J.; Morris, R. H. Organometallics 2011, 30, 4418. (f) Mikhailine,
A. A.; Maishan, M. I.; Morris, R. H. Org. Lett. 2012, 14, 4638. (g) Zuo, W.; Lough, A.
J.; Li, Y. F.; Morris, R. H. Science 2013, 342, 1080. (h) Zuo, W.; Morris, R. H. Nat.
Protoc. 2015, 10, 241. (i) Smith, S. A. M.; Morris, R. H. Synthesis 2015, 47, 1775. (j)
Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H.
J. Am. Chem. Soc. 2014, 136, 1367.
ACS Paragon Plus Environment
2
8

Page 29 of 31
Organic Process Research & Development
1
2
3
4
5
6
7
8
9
(
6) (a) Shaikh, N. S.; Enthaler, S.; Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47,
2
497. (b) Zhou, S.; Fleischer, S.; Junge, K.; Das, S.; Addis, D.; Beller, M. Angew. Chem.
Int. Ed. 2010, 49, 8121. (c) Zhou, S.; Fleischer, S.; Junge, K.; Beller, M. Angew. Chem.
Int. Ed. 2011, 50, 5120. (d) Fleischer, S.; Zhou, S.; Werkmeister, S.; Junge, K.; Beller,
M. Chem. Eur. J. 2013, 19, 4997. (e) Lu, L.-Q.; Li, Y.; Junge, K.; Beller, M. J. Am.
Chem. Soc. 2015, 137, 2763.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(7) Bleith, T.; Wadepohl, H.; Gade, L. H. J. Am. Chem. Soc. 2015, 137, 2456.
(8) For a related Fe(II) / tetraphenyl-carbpi system, see: Langlotz, B. K.; Wadepohl, H.;
Gade, L. H. Angew. Chem. Int. Ed. 2008, 47, 4670.
(
(
(
9) Bigler, R.; Huber, R.; Mezzetti, A. Angew. Chem. Int. Ed. 2015, 54, 5171.
10) For a related Fe(II) / N P system, see: Bigler, R.; Mezzetti, A. Org. Lett. 2014, 16, 6460.
2
2
11) For an account on macrocyclic Fe(II) complexes, see: Bigler, R.; Huber, R.; Mezzetti, A.
Synlett 2016, 27, in press.
(
12) (a) Clarke, M. L. Synlett 2014, 25, 1371. (b) Noyori, R.; Ohkuma, T. Angew. Chem. Int.
Ed. 2001, 40, 40. (c) Dong, Z.-R.; Li, Y.-Y.; Chen, J.-S.; Li, B.-Z.; Xing, Y.; Gao, J.-X.
Org. Lett. 2005, 7, 1043. (d) Ohkuma, T.; Sandoval, C. A.; Srinivasan, R.; Lin, Q.; Wei,
Y.; Muñiz, K.; Noyori, R. J. Am. Chem. Soc. 2005, 127, 8288. (e) Clarke, M. L.; Díaz-
Valenzuela, M. B.; Slawin, A. M. Z. Organometallics 2007, 26, 16.
(13) Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.; Candelario, A.; Huffman, M.
A.; Zhao, M. M.; Li, J.; Craig, B.; Song, Z. J.; Tschaen, D. M.; Hansen, K.; Devine, P.
ACS Paragon Plus Environment
2
9