Iron(II)/(NH)2P2 Macrocycles: Modular, Highly Enantioselective Transfer Hydrogenation Catalysts

Article abstract of DOI:10.1021/acscatal.6b01872

A generalized protocol for the synthesis of chiral (NH)₂P₂ macrocycles allows changing the linker between the phosphines and gives access to a family of such ligands, as demonstrated for the propane-1,3-diyl analogue. The corresponding complexes based on earth-abundant and nontoxic iron were applied as catalysts in the asymmetric transfer hydrogenation of polar double bonds. Thanks to the ligand modularity and to the use of tunable isonitriles as ancillary ligands, the catalyst system can be individually optimized for each substrate to give high enantioselectivity (up to 99.9% conversion and 99.6% ee, TOF up to >3950 h^-1) for a broad scope of 26 substrates.

Full text of DOI:10.1021/acscatal.6b01872

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Article
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Iron(II)/(NH)P Macrocycles: Modular, Highly
Enantioselective Transfer Hydrogenation Catalysts
Raphael Bigler, Raffael Huber, Marco Stöckli, and Antonio Mezzetti
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01872 • Publication Date (Web): 23 Aug 2016
Downloaded from http://pubs.acs.org on August 27, 2016
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Iron(II)/(NH) P Macrocycles: Modular, Highly
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Enantioselective Transfer Hydrogenation Catalysts
Raphael Bigler, Raffael Huber, Marco Stöckli, and Antonio Mezzetti*
Department of Chemistry and Applied Biosciences, ETH Zürich, CH-8093 Zürich, Switzerland
ABSTRACT: A generalized protocol for the synthesis of chiral (NH) P macrocycles allows
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changing the linker between the phosphines and gives access to a family of such ligands, as
demonstrated for the propane-1,3-diyl analogue. The corresponding complexes based on earth-
abundant and nontoxic iron were applied as catalysts in the asymmetric transfer hydrogenation of
polar double bonds. Thanks to the ligand modularity and to the use of tunable isonitriles as
ancillary ligands, the catalyst system can be individually optimized for each substrate to give
–1
high enantioselectivity (up to 99.9% conversion and 99.6% ee, TOF up to >3 950 h ) for a broad
scope of 26 substrates.
KEYWORDS: alcohols, asymmetric catalysis, hydrogen transfer, iron, macrocyclic ligands
INTRODUCTION
The asymmetric reduction of prochiral ketones, imines, and olefins is the most important metal-
catalyzed enantioselective reaction in industry. However, the high cost of the involved transition
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metals, primarily ruthenium, rhodium, and iridium, together with that of the chiral ligands, has
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hampered the application of such precious metal-based catalysts. Thus, production processes
relying on asymmetric reduction are still scarce. Recently, cheap, non-toxic, and environmentally
benign iron catalysts have emerged as an attractive alternative to precious metals for the
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reduction of polar double bonds, i.e. ketones and imines (Chart 1).
[
Fe (CO)12] +
3
Ph
Ph BF4
N
NH HN
O
C
PCy2 BF4
H
CO
N
N Fe Br
OC
Fe
Cl
Me
PPh
PhP
P
Xyl
P
Xyl2
PPh2
2
Ph
NH HN
Morris
Gao
O
Ar
TMS
O
N
Ph
Ph
H
N
Fe
N
O
TMS
O
O
Fe CO
CO
O
Ph
P
H
OH
O
Ar
Gade
Beller
Chart 1. Iron-based Catalysts for Asymmetric Reduction
Most prominently, Morris has developed a series of highly active iron(II)/P(NH)NP and PNP
3
precatalysts, but the enantioselectivity is modest for most substrates. On the other side, the
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catalyst systems developed by Gao, Gade, and Beller are generally highly enantioselective, but
the turnover frequencies and numbers are low in most cases. Thus, the development of base
metal catalysts that are both highly active and enantioselective is still a formidable challenge.
Recently, we developed the macrocyclic iron(II) bis(isonitrile) complexes Λ-cis-β-
i
[
Fe(CNR) ((S ,S ,S ,S )-1a)](BF ) (R = CEt , 2a; R = N Pr , 2b), which are the first well-defined
2
P
P
C
C
4 2
3
2
–
1
iron-based precatalysts that combine high activity (TOF up to 6 650 h , TON up to 10 000) and
enantioselectivity (up to 99% ee) for a broad scope of aryl alkyl ketones under asymmetric
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transfer hydrogenation (ATH) conditions (Chart 2). In complexes 2a and 2b, the chiral informa-
tion stems from the C -symmetric tetradentate (NH) P macrocycle (S ,S ,S ,S )-1a. Sterically
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2
P
P
C
C
and electronically tunable isonitriles are required as ancillary ligand to stabilize the catalyst and
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b
to increase the enantioselectivity to >95% ee for most substrates. The scope of the ATH
reaction includes standard acetophenone derivatives, but also challenging or industrially relevant
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substrates such as tert-butyl phenyl ketone or 3,5-bis(trifluoromethyl)acetophenone are
efficiently reduced (99% conversion, 97% and 98% ee, respectively).
H
(BF4)2
N
(S)
(S)
Ph
P
N H
NH HN
Fe
P
C
C
N
(S) (S)
N
R
R
P
P
Ph
Ph
Ph
R = CEt3 (2a), N Pr (2b)
(
S ,S ,S ,S )-1a
i
P
P
C
C
2
Chart 2. Macrocyclic Iron(II)/(NH) P Complexes
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Although the enantioselectivity was high for most substrates, there is room for improvement
with some ketones, particularly acyl heterocycles (90–98% ee) and other substrates such as 3-tri-
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fluoromethylacetophenone (96% ee), an important intermediate in the synthesis of fungicides.
As further optimization of the ancillary isonitriles (C-isonitrile CNCEt in 2a and N-isonitrile
3
i
7b,11
CNN Pr in 2b, respectively) was not successful,
we decided to turn our attention to the
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macrocyclic (NH) P ligand 1a. A careful analysis of the crystal structures of the analogous bis-
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(
isonitrile) complexes 2c-2e bearing 1-adamantyl (2c), tert-butyl (2d), and phenyl isonitriles (2e)
as ancillary ligands shows that the five-membered P–Fe–P chelate ring is flexible and adopts
different half-chair conformations. Depending on the isonitrile ligand, the P–C–C–P torsion
angle involved in the ethane-1,2-diyl bridge changes from +20.7(5)° in 2d to –37.5(4)° in 2e.
7b
We speculated that a more rigid chelate ring may lead to higher enantioface discrimination, as
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the macrocycle might be less prone to rearrange to accommodate the substrate in the energeti-
cally disfavored transition state leading to the minor enantiomer of the secondary alcohol
product.
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H
N
(BF4)2
(S)
(S)
Ph
P
N H
NH HN
Fe
P
C
C
N
N
(S) (S)
R
R
P
P
Ph
Ph
Ph
3
a (R = CEt ) and
(SP,SP,SC,SC)-1b
3
i
3
b (R = N Pr )
2
O
O
O
O
O
O
O
(
R)
O O (R)
P
H
P
(
R)
P
Ph
Ph
(R ,R )-6
Ph
(
R )-5
P
P
P
Scheme 1. Retrosynthetic Analysis of Complexes 3a and 3b
A possible strategy to access more enantioselective catalysts might therefore rely on the
incorporation of a more rigid P–Fe–P chelate ring, and we planned to tackle this challenge by
introducing a propane-1,3-diyl (–(CH ) –) bridge between the phosphorus donors, as a six-
2
3
membered chelate ring is expected to be less flexible than the five-membered P–Fe–P chelate
ring in the ethane-1,2-diyl (–(CH ) –) linker of the bis(isonitrile) complexes 2. The synthesis of
2 2
the 15-membered ring analogue seemed feasible with our recently developed, versatile procedure
7c
for the synthesis of (NH) P macrocycles (Scheme 1). Instead of the methylation/oxidative
2
2
coupling sequence from (R )-5 that gives the ethane-1,2-diyl bridge in the parent ligand
P
(
S ,S ,S ,S )-1a (Chart 2), we planned to use an alkylative dimerization with 1,3-diiodopropane
P P C C
1
2
to afford the propane-1,3-diyl-bridged diphosphine oxide (R ,R )-6. Enantiomerically pure (R )-
P
P
P
5 was previously accessed from Han’s H-phosphinate (R )-4 in one step and is also accessible as
P
7c,13,14
the S enantiomer.
P
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Herein, we describe the synthesis of the 15-membered (NH) P macrocycle (S ,S ,S ,S )-1b
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2
P
P
C
C
containing a propane-1,3-diyl bridge and of the corresponding bis(isonitrile) iron(II) complexes
Fe(CNR) ((S ,S ,S ,S )-1b)](BF ) (3), which were assayed in the ATH of prochiral ketones and
[
2
P
P
C
C
4 2
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imines. The results described below highlight the versatility of the synthetic protocol for the
preparation of (NH) P macrocycles and the drastic effects of the bridge length between the
2
2
phosphorus donors on the catalysis outcome. Even more importantly, they open the way to the
development of a versatile family of ligands and catalysts.
RESULTS AND DISCUSSION
General Strategy. As outlined in Scheme 1, the synthesis of bis(isonitrile) iron(II) complexes 3
relies on the preparation of the (NH) P macrocycle (S ,S ,S ,S )-1b, which can be accessed by
2
2
P
P
C
C
macrocyclization of the dialdehyde (S ,S )-7 with (1S,2S)-cyclohexane-1,2-diamine followed by
P
P
reduction of the imine moieties. Dialdehyde (S ,S )-7 can be obtained by double stereoselective
P
P
phosphine oxide reduction and acetal cleavage from diphosphine oxide (R ,R )-6 (Scheme 2). As
P
P
mentioned above, the synthesis of the key intermediate (R ,R )-6 was planned by alkylative
P
P
dimerization of the previously described enantiomerically pure secondary phosphine oxide (R )-5
P
7c,12
with 1,3-diiodopropane.
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c
Synthesis of Dialdehyde (S ,S )-7. Following our previous report, the secondary phosphine
P
P
oxide (R )-5 was prepared as a single enantiomer (99% ee) by treatment of Han’s H-phosphinate
P
1
3a
(
R )-4 with an excess of (2-(1,3-dioxolan-2-yl)phenyl) lithium. To install the propane-1,3-diyl
P
bridge between the phosphorus atoms, (R )-5 was deprotonated with n-BuLi at –78 °C and
P
treated with 1,3-diiodopropane (Scheme 2). After warming to room temperature overnight and
purification by flash column chromatography, the desired diphosphine oxide (R ,R )-6 was
P
P
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isolated in 89% yield as a single diastereoisomer (d.r. > 95:5). In contrast, the analogous reaction
with 1,2-diiodoethane did not give the ethane-1,2-diyl-bridged analogue, which had to be
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prepared in a two-step procedure by methylation and oxidative coupling. The alkylative
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dimerization was also tested with 2,2-disubstituted 1,3-diiodopropanes CR (CH I) (R = Me, Bn,
2
2
2
fluorene-9,9-diyl). However, no conversion to the desired products was observed, which is
ascribed to the neo-pentyl position of the leaving groups in these electrophiles.
O
O
O(R)
O
Li
iPr
O
P
P
H
ref. 7c
(R)
+
O
H
O
Ph
Ph
Me
(
R )-4
P
(R )-5
P
8
9%, 99% ee
n-BuLi; then
THF
-78 °C to r.t.
I
I
i
1
) Ti(OPr) ,
4
H
H
O
O
O
1
) TMDS
O
O
O
1) PhMe, 60 °C
(
P
S) (S)
O O (R)
2) aq. HCl
2
(R)
P
P
P
) THF, r.t.
Ph
Ph
Ph
Ph
(
S ,S )-7
(R ,R )-6
P
P
P
P
88%, d.r. = 9.4:1
89%, d.r. > 95:5
Scheme 2. Synthesis of Dialdehyde (S ,S )-7
P
P
i
Treatment of (R ,R )-6 with Ti(O Pr) and 1,1,3,3-tetramethyldisiloxane (TMDS) in hot toluene
P
P
4
resulted in stereoselective reduction of the phosphine oxide moieties with retention of configura-
tion at phosphorus. After work-up, the acetal protecting groups of the crude diphosphine were
cleaved with aqueous hydrochloric acid. Purification by flash column chromatography afforded
the desired dialdehyde (S ,S )-7 in 88% yield and as a 9.4:1 mixture of the like and the meso
P
P
diastereoisomer. Overall, this synthetic route affords the propane-1,3-diyl-linked dialdehyde
S ,S )-7 in only four steps from Han’s H-phosphinate (R )-4 with an overall yield of 70%. As
(
P
P
P
removal of the minor meso diastereoisomer either by recrystallization or column chromatography
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was not possible, the dialdehyde (S ,S )-7 was used as a 9.4:1 mixture of diastereoisomers in the
P
P
macrocyclization experiments (vide infra).
Synthesis of (NH) P Macrocycle (S ,S ,S ,S )-1b. The reaction of dialdehyde (l)-7 with (l)-
2
2
P
P
C
C
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cyclohexane-1,2-diamine affords diastereomeric products and both enantiomers of the diamine
have therefore to be studied individually. As for the ethane-1,2-diyl-bridged derivative, the
macrocyclization experiments were carried out under high dilution conditions (0.01 M) to favor
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intra- over intermolecular imine formation in the second condensation step.
3
1
1
The P{ H} NMR spectrum of the reaction solution indicates that the reaction of (S ,S )-7 with
P
P
(
1S,2S)-cyclohexane-1,2-diamine gives exclusively the desired N P macrocycle (Scheme 3). In
2 2
contrast to the P–(CH ) –P-linked N P macrocycle, the propane-1,3-diyl analogue does not
2 2
2 2
precipitate upon concentration. Therefore, the solvent was removed and the crude diimino N2P2
3
1
1
macrocycle (86% pure by P{ H} NMR spectroscopy) was directly reduced with LiAlH in
4
THF. After work-up, the desired (NH) P macrocycle (S ,S ,S ,S )-1b was obtained as a white
2
2
P
P
C
C
31
1
solid in good yield and with acceptable purity (83% pure by P{ H} NMR spectroscopy).
H
H
(
S)
(S)
(S)
(S)
O
O
H N
NH2
2
N
N
(
P
S) (S)
EtOH, r.t.
P
(S) (S)
P
P
Ph
Ph
Ph
Ph
(S ,S )-7
P
P
d.r. = 9.4:1
THF
°C to r.t.
LiAlH4
0
EtOH
r.t.
(
R)
(R)
H N
NH2
(S)
(S)
2
NH HN
(
P
S) (S)
complex mixture
P
Ph
Ph
(
S ,S ,S ,S )-1b
P
P
C
C
94% (83% pure)
Scheme 3. Reaction of (S ,S )-7 with (l)-Cyclohexane-1,2-diamine
P
P
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In contrast to the reaction with (1S,2S)-cyclohexane-1,2-diamine, the reaction solution of
(
S ,S )-7 with the R,R enantiomer showed several signals with similar intensity that were
P P
7
e
assigned to oligomeric products. Attempts to employ acid catalysts, metal templates in analogy
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f
to Morris, or more dilute conditions failed to give a macrocyclic product.
H
H
H
P
H
P
H N
2
N
NH
(S ,S )
N
(S ,S )
P P
P
P
2
H
C
H
(
S ,S )
(R ,R )
C
C
C
P
P
O
O
H
H
(S ,S )/(S ,S )
(S ,S )/(R ,R )
P P C C
P
P
C
C
matched
mismatched
Chart 3. Conformational Analysis of the Macrocyclization
The high diastereospecificity in the macrocyclization reaction of (S ,S )-7 with (l)-cyclohex-
P
P
ane-1,2-diamine resembles the situation with the ethane-1,2-diyl-bridged analogue, where the
selectivity was explained by conformational analysis of the N P macrocycle based on X-ray
2
2
7
e
data. The diastereospecificity is thus explained by conformational analysis of the intermediate
in which the first of the two imine bonds has already formed (Chart 3). This intermediate
preferably adopts a conformation in which the allylic 1,3-strain between the imine C-H bond and
the tertiary carbon atom of the diamine backbone is minimized. Also, the lone pairs of the adja-
cent P and N donors point in opposite directions to minimize electronic (and steric) repulsion.
With these restrictions, it is apparent that the intermediate is stereochemically prepared for the
second condensation step only in the case of the (S ,S )/(S ,S )-diastereoisomer. In the
P
P
C
C
(
S ,S )/(R ,R )-intermediate, the amine and the formyl group point in opposite directions, which
P P C C
explains the formation of oligomers for this combination.
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Bis(acetonitrile) Complex [Fe(MeCN) (1b)](BF ) (8b). The addition of an acetonitrile
2
4 2
solution of [Fe(OH ) ](BF ) to the (NH) P macrocycle (S ,S ,S ,S )-1b in CH Cl /MeCN at 55
2 6
4 2
2
2
P
P
C
C
2
2
3
1
1
°
C led to an immediate color change from light yellow to dark red (Scheme 4). The P{ H}
10
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR spectrum of the reaction mixture shows the presence of three different isomers in a
0.10:0.73:0.17 ratio. A singlet at δ 58.4 is assigned to the trans isomer trans-8b, whereas two
2
AX systems are attributed to the two cis-β complexes cis-β-8b (δ 49.8 and 57.0, J = 60.5 Hz)
P,P’
2
and cis-β’-8b (δ 41.6 and 58.9, J = 62.5 Hz). As for the ethane-1,2-diyl derivative 8a bearing
P,P’
7
b
macrocycle (S ,S ,S ,S )-1a, the addition of DBU to this initial mixture led to complete
P
P
C
C
isomerization to the thermodynamic product cis-β-8b, which was crystallized as a single isomer
in 56% yield on a 1.46 g scale.
(
S ,S ,S ,S )-1b
P P C C
[
Fe(OH ) ](BF )
MeCN/CH Cl , 55 °C
2
6
4 2
2
2
H
2
+
N
H
N
2
+
2+
H
H
Ph P
N H
N
Fe
N
Fe
P
N
P
N
P
N
N
Ph P
+
+
N H
Fe
P
N
N
Ph
cis-!-8b
Ph
Ph
Ph
trans-8b
cis-!'-8b
trans-8b:cis-!-8b:cis-!'-8b = 0.10:0.73:0.17
DBU (25 mol%) MeCN/CH Cl , 55 °C
2
2
H
N
(BF4)2
Ph
P
N H
Fe
P
N
N
Ph
cis-!-8b, single isomer
56%
Scheme 4. Synthesis of Bis(acetonitrile) Complex 8b
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Figure 1. ORTEP drawing of the complex cation of cis-β-8b (ellipsoids at 30% probability).
An X-ray study of cis-β-8b, crystallized from MeCN/Et O, confirmed the assignment by
2
3
1
1
P{ H} NMR spectroscopy (Figure 1). Despite the different ring size of the macrocyclic ligand,
the structure of the new P–(CH ) –P-linked bis(acetonitrile) complex [Fe(MeCN) ((S ,S ,S ,S )-
2
3
2
P
P
C
C
1
b)](BF ) (8b) is closely reminiscent of the ethane-1,2-diyl analogue [Fe(MeCN) ((S ,S ,S ,S )-
4 2 2 P P C C
7
e
1a)](BF ) (8a). As in 8a, both nitrogen stereocenters in 8b have the R absolute configuration,
4
2
N
and the diamine unit adopts the characteristic stepped conformation. However, the change of the
P–Fe–P chelate ring size causes subtle differences. Not surprisingly, the propane-1,3-diyl-
bridged bis(acetonitrile) complex 8b features significantly longer Fe–N and particularly Fe–P
bond distances, as well as a larger P–P bite angle as compared to the ethane-1,2-diyl analogue 8a
(Table 1, omitted bond angles differ by less than 2° in 8a and 8b). The smaller P(1)–Fe–N(3)
angle in 8b involving one MeCN ligand is a symptom of enhanced steric crowding with the
larger macrocycle 1b.
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Table 1. Selected Bond Lengths (Å) and Angles (°) in 8a and 8b
7
e
cis-β-8a
cis-β-8b
2.2187(12)
2.2193(11)
2.035(3)
Fe–P(1)
Fe–P(2)
Fe–N(1)
Fe–N(2)
Fe–N(3)
Fe–N(4)
2.1837(7)
2.1724 (6)
2.020(2)
2.039(2)
1.962(2)
1.927(2)
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2.048(4)
1.979(3)
1.932(3)
P(1)–Fe–P(2)
P(1)–Fe–N(1)
P(1)–Fe–N(2)
P(2)–Fe–N(1)
P(2)–Fe–N(2)
N(1)–Fe–N(2)
P(1)–Fe–N(3)
85.32(2)
94.93(6)
178.38(6)
94.36(7)
93.06(6)
85.26(8)
93.47(6)
92.92(4)
94.32(11)
176.16(11)
93.25(11)
90.75(11)
84.35(15)
89.39(11)
In contrast to bis(acetonitrile) complex 8a, where the five-membered P(1)–Fe–P(2) chelate
7
e
ring adopts a flexible half-chair conformation (Figure 2, left), the six-membered P(1)–Fe–P(2)
chelate ring in the propane-1,3-diyl-linked analogue 8b is in a chair conformation (Figure 2, right
and Table S3). The rigid chair conformation is held in place by the diamine unit, which directs
the benzylene linker between P(2) and N(2) to a pseudo-equatorial position and the benzylene
linker between P(1) and N(1) to a pseudo-axial position of the six-membered chelate ring. A ring
flip to the other chair conformation seems only possible with concomitant inversion of the N(2)
stereocenter. Also, twist-boat or boat conformations are strongly disfavored due to strong steric
repulsion with the ancillary acetonitrile ligand containing N(4) (not shown in Figure 2).
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e
Figure 2. Comparison of the macrocyclic ligands (S ,S ,S ,S )-1a in cis-β-8a (left) and
P
P
C
C
(
S ,S ,S ,S )-1b in cis-β-8b (right). Phenyl substituents and hydrogen atoms are omitted for
P P C C
clarity.
The iron(II) bis(acetonitrile) complexes are a convenient entry point to the coordination
7
a
7
chemistry of macrocyclic (NH) P ligands. In view of our previous work and the results
2
2
3
reported by Morris, we focused on the preparation of the bis(isonitrile) complexes [Fe(CNR) -
2
(
(
(S ,S ,S ,S )-1b)](BF ) (3) and of the bromocarbonyl species [FeBr(CO)((S ,S ,S ,S )-1b)]BPh
P
P
C
C
4 2
P
P
C
C
4
9).
Bis(isonitrile) Complexes [Fe(CNR) (1b)](BF ) (3a-3c). The bis(acetonitrile) complex 8b
2
4 2
i
undergoes quantitative substitution of the ancillary acetonitrile ligands by CNCEt and CNN Pr
3
2
within 24 h at 50 °C (Scheme 5). The corresponding bis(isonitrile) derivatives [Fe(CNR)2-
i
(
(S ,S ,S ,S )-1b)](BF ) (R = CEt , 3a; N Pr , 3b) were obtained as a single configurational
P
P
C
C
4 2
3
2
i
isomer in high yield. The C-isonitrile CNCEt and the N-isonitrile CNN Pr were the isonitriles of
3
2
choice as the use of these sterically demanding isonitriles has previously been shown to lead to a
7
b
vast increase in enantioselectivity for the ethane-1,2-diyl-bridged analogues 2 (vide supra).
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H
(
BF4)2
N
CNR
5 equiv)
(
Ph
P
N H
3a: R = CEt3 (95%)
3b: R = N Pr2 (96%)
3c: R = 1-Ad (67%)
8
b
Fe
P
i
C
C
N
R
2
CH Cl2
N
R
5
0 °C
Ph
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59
60
Scheme 5. Synthesis of Bis(isonitrile) Complexes 3a-3c
7b
As iron(II) bis(1-adamantyl isonitrile) (NH) P complexes are highly crystalline, the
2
2
corresponding derivative 3c (R = 1-Ad) was also prepared in order to gain structural information
by X-ray diffraction. Crystals of the bis(1-adamantyl isonitrile) complex 3c suitable for X-ray
analysis were obtained from CH Cl /hexane. In the crystal structure, the macrocyclic ligand
2
2
(S ,S ,S ,S )-1b adopts a cis-β structure, with the two ancillary isonitriles completing the
P
P
C
C
octahedral coordination sphere (Figure 3). The overall structure is closely related to the one of
the bis(acetonitrile) complex 8b (Table 2). As expected, the Fe–N(1) and Fe–P(2) distances in 3c
trans to the strong-field isonitrile ligands are slightly longer as compared to the bis(acetonitrile)
7f
complex 8b due to the strong trans influence exerted by isonitriles.
Figure 3. ORTEP drawing of the complex cation of cis-β-3c (ellipsoids at 30% probability).
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Table 2. Selected Bond Lengths (Å) and (Torsion) Angles (°) in 3c and 8b
cis-β-3c
2.2174(7)
2.2525(6)
2.063(2)
2.072(2)
1.898(2)
1.853(2)
cis-β-8b
2.2187(12)
2.2193(11)
2.035(3)
2.048(4)
–
Fe–P(1)
Fe–P(2)
Fe–N(1)
Fe–N(2)
Fe–C(36)
Fe–C(47)
0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
–
P(1)–Fe–P(2)
P(1)–Fe–N(1)
92.42(2)
92.14(6)
174.71(6)
90.13(7)
92.56(7)
92.94(6)
89.44(6)
177.32(7)
84.34(7)
82.82(8)
87.75(9)
174.66(9)
88.08(9)
92.55(9)
94.76(10)
92.92(4)
94.32(11)
176.16(11)
89.39(11)
87.87(11)
93.25(11)
90.75(11)
175.81(11)
91.17(11)
84.35(15)
90.06(14)
174.95(15)
87.01(15)
93.17(15)
85.42(14)
P(1)–Fe–N(2)
P(1)–Fe–C(36)/N(3)
P(1)–Fe–C(47)/N(4)
P(2)–Fe–N(1)
P(2)–Fe–N(2)
P(2)–Fe–C(36)/N(3)
P(2)–Fe–C(47)/N(4)
N(1)–Fe–N(2)
N(1)–Fe–C(36)/N(3)
N(1)–Fe–C(47)/N(4)
N(2)–Fe–C(36)/N(3)
N(2)–Fe–C(47)/N(4)
C(36)/N(3)–Fe–C(47)/N(4)
C(1)–C(2)–C(7)–P(1)
C(23)–C(28)–C(29)–N(2)
C(14)–P(1)–C(8)–C(9)
–0.9(3)
28.5(4)
116.1(2)
9.4(6)
43.3(6)
145.1(4)
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9
The macrocyclic (NH) P ligand (S ,S ,S ,S )-1b assumes very similar conformations in the
2
2
P
P
C
C
bis(acetonitrile) complex 8b and in the bis(isonitrile) complex 3c. In particular, the angles and
torsion angles in the six-membered P–Fe–P chelate ring in 8b and 3c differ by less than 2°. Only
three torsion angles deviate more than 10° in the two complexes, and the largest difference
affects the C(14)–P(1)–C(8)–C(9) angle, resulting from different orientations of the phenyl
substituent on P(1). In 3c, the phenyl group rotates by ca. 30° to accommodate the larger
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adamantyl substituent. Thus, the propane-1,3-diyl-linked macrocycle (S ,S ,S ,S )-1b is more
P
P
C
C
rigid than its (CH ) analogue (S ,S ,S ,S )-1a, in which the five-membered P–Fe–P chelate is
2
2
P
P
C
C
7b
flexible and can adopt different half-chair conformations as shown previously. Furthermore, the
bond angles involving the macrocycle are very similar in 3c and 8b, whereas those involving the
ancillary ligands (MeCN and CNAd) vary widely. This further suggests that macrocycle 1b
forms a rigid coordination pocket (Table 2).
Bromocarbonyl Complex [FeBr(CO)(1b)]BPh (9). Besides bis(isonitrile) complexes 3, we
4
targeted the bromocarbonyl complex [FeBr(CO)((S ,S ,S ,S )-1b)]BPh (9), as related iron(II)/
P
P
C
C
4
–
1
P(NH)NP complexes are highly active ATH catalysts and achieve TOFs up to 200 s (see Chart
3
1). In analogy to Morris’ system, the bromocarbonyl complex 9 was prepared from the
bis(acetonitrile) complex 8b and KBr (2 equiv) in acetone under a CO atmosphere. The reaction
3
1
1
2
afforded a single new species as indicated by P{ H} NMR spectroscopy (δ 21.3 and 39.0, J
P,P’
=
69.6 Hz), which was isolated as the tetraphenylborate salt [FeBr(CO)(S ,S ,S ,S )-1b)]BPh (9)
P
P
C
C
4
(
Scheme 6).
2
13
1
The large difference in the J coupling of the phosphines to CO in the C{ H} NMR spec-
P,C
2
trum (δ 216.0 (dd, J = 52.7, 25.4 Hz) suggests a cis-β isomer with CO trans to phosphorus
P,C
7
e
and bromide trans to amine, as previously observed for related species. For the other cis-β
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isomer with CO trans to amine and bromide trans to phosphorus (and also for trans isomers),
2
similar J coupling constants are expected as both phosphines are cis to CO (and not one trans
P,C
and one cis as in 9). Unfortunately, as all attempts to obtain suitable crystals failed, this assign-
0
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9
0
ment is not confirmed by X-ray crystallography.
KBr
2 equiv)
CO
H
N
BPh4
(
(2.25 atm)
Ph
P
N H
8
b
Fe
P
acetone, r.t.
then NaBPh4
Br
C
O
(1 equiv)
Ph
9
5
9% (single isomer)
Scheme 6. Synthesis of Bromocarbonyl Complex 9
Asymmetric Transfer Hydrogenation. The newly prepared complexes containing the
propane-1,3-diyl-bridged macrocycle 1b, that is, the bis(acetonitrile) derivative 8b, the bis-
i
(
isonitrile) analogue 3a-3c (R = CEt , 3a; N Pr , 3b; 1-Ad, 3c), and the bromocarbonyl complex
3
2
9
, were tested as catalysts in the ATH of acetophenone (10a) as standard substrate (Table 3). The
t
i
ATH reactions were performed in the presence of NaO Bu (S/C/B = 400/1/10) in PrOH (0.2 M
in substrate) at 40 °C, and the reactions were followed by GC. For the sake of comparison, 10a
was hydrogenated under these conditions with the previously reported ethane-1,2-diyl bis(iso-
i
7b
nitrile) catalysts [Fe(CNR) ((S ,S ,S ,S )-1a)](BF ) (R = CEt , 2a; R = N Pr , 2b).
2
P
P
C
C
4 2
3
2
The screening showed that the bis(acetonitrile) complex 8b achieves only 1% conversion to 1-
phenylethan-1-ol after 1 h (entry 1) and is hence essentially inactive as ATH catalyst. This is in
7
d
line with previous results showing that Fe(II) bis(acetonitrile) complexes are poor catalysts,
possibly because acetonitrile does not efficiently stabilize low-valent iron(II) intermediates. The
catalyst activity increases on going from bis(acetonitrile) (8b) to bromocarbonyl (9) and even
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more to the bis(isonitrile) motive (3a). This suggests that π-accepting ligands increase the
catalyst activity, but is in contrast with Morris' finding that the bromocarbonyl complexes are the
3
k
most active iron-based ATH catalysts.
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The enantioselectivity increases along with the steric bulk of the ancillary ligands from bromo-
i
carbonyl 9 (86% ee, 5 min, entry 2) to 3a (R = CEt , 98% ee, 5 min, entry 3) and 3b (R = N Pr ,
3
2
9
9% ee, 1 h, entry 4). However, the activity of the latter is considerably lower than that of the
less bulky CNCEt analogue 3a. Accordingly, the bis(1-adamantyl isonitrile) complex 3c is the
3
–
1
most active catalyst (average TOF was 3 700 h after 5 min). However, it gives only 92% ee
after 5 min (entry 5), and the enantioselectivity declines during the reaction (81% ee after 1 h) as
the equilibrium position is approached. Therefore, catalysts 3a and 3b were chosen for the
screening of the substrate scope (see below).
a
Table 3. Catalyst Screening in the ATH of Acetophenone (10a)
O
Fe(II)-catalyst (0.25 mol%)
NaO Bu, PrOH, 40 °C
OH
t
i
S / C / B = 400 / 1 / 10
(0.2 M in substrate)
1
0a
11a
entry
catalyst
after 5 min
after 60 min
1%
14% 86% ee 77% 84% ee
1
2
3
4
5
6
7
8b
9
<1%
–
–
3a (R = CEt ) 50% 98% ee 92% 98% ee
3
i
3b (R = N Pr ) 4%
–
33% 99% ee
2
3c (R = 1-Ad) 78% 92% ee 93% 81% ee
2a (R = CEt ) 17% 97% ee 91% 96% ee
3
i
2b (R = N Pr ) 8% 98% ee 47% 98% ee
2
a
i
Reactions were performed on a 1.0 mmol scale in PrOH (0.2 M in substrate). Conversions
and ee values were determined by GC.
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Compared with their ethane-1,2-diyl analogues 2a and 2b, the propane-1,3-diyl-bridged
catalysts 3a and 3b reduce acetophenone with higher enantioselectivity under identical reaction
conditions (98 and 99% ee vs. 96 and 98% ee, respectively) (entries 3, 4, 6, and 7). Interestingly,
the propane-1,3-diyl-based C-isonitrile complex 3a is also more active than 2a and 2b, which
shows that the increased macrocycle size and hence enhanced steric crowding at the metal are
not necessarily detrimental to activity.
0
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Before investigating the substrate scope, the reactions conditions with catalysts 3a and 3b were
further optimized. Catalyst loadings of 0.1 and 0.02 mol% (instead of 0.25 mol%) left the
enantioselectivity of acetophenone reduction unchanged, even though higher reaction tempera-
tures and longer times were used to achieve high conversions (Table 4). This emphasizes the
robustness of the macrocyclic iron(II)/(NH) P catalyst system and is in line with the successful
2
2
7
c
scale-up studies performed for the ethane-1,2-diyl-bridged analogues 2a and 2b.
a
Table 4. Effect of Catalyst Loading on the ATH of Acetophenone (10a)
entry catalyst
10a
S / C / B
400/1/10
T
t
conv. ee
(mol%) (mmol)
(°C) (h) (%) (%)
1
2
3
4
5
6
3a (0.25)
3a (0.1)
1.0
40 1.0
92
93
91
33
93
93
98
98
98
99
99
99
2.5 1 000/1/10 50 0.5
5.0 5 000/1/20 60 1.5
3a (0.02)
3b (0.25)
3b (0.1)
3b (0.02)
1.0
400/1/10
40 1.0
2.5 1 000/1/10 60 1.5
5.0 5 000/1/20 75 1.5
a
t
Reaction solutions were 0.2 M in substrates, NaO Bu was used as base, conversions and ee
values were determined by GC.
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Substrate Scope. A broad set of substrates bearing polar double bonds (Chart 4) was reduced
with the propane-1,3-diyl-linked catalysts 3a and 3b under the conditions of entries 2 and 5 in
Table 4 (0.1 mol% of catalyst, 50 and 60 °C, respectively), which allows full comparison with
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7
b
catalysts 2a and 2b (see below and Chart S2).
O
[Fe(CNR)
2
((S
P
,S
P
,S
C
,S
C
)-1b)](BF
4
)
2
(0.1 mol%)
OH
R''
i
3
a (R = CEt ), 50 °C or 3b (R = N Pr ), 60 °C
3
2
R''
t
i
R'
NaO Bu, PrOH (0.2 M), S / C / B = 1000 / 1 / 10 R'
10
OH
11
OH
Me
OH
Me
Me OH
Me
OH
Me
OH
Me
Me
MeO
Me
Me
MeO
11a
11b
11c
11d
11e
11f
3
3
a (0.5 h): 93%, 98% ee 3a (0.5 h): 86%, 96% ee 3a (0.5 h): 90%, 98% ee 3a (5.0 h): 81%, 97% ee 3a (0.5 h): 72%, 96% ee 3a (0.5 h): 92%, 97% ee
b (1.5 h): 91%, 99% ee 3b (1.0 h): 87%, 98% ee 3b (1.5 h): 91%, 98% ee 3b (5.0 h): 65%, 99% ee 3b (1.5 h): 71%, 97% ee 3b (1.0 h): 92%, 98% ee
OMe OH
Me
OH
OH
Me
Cl
OH
Me
OH
Me
Cl
Me
Cl
11g
11h
11i
11j
11k
3a (5.0 h): 82%, 98% ee
3a (0.5 h): 97%, 96% ee
3b (1.0 h): 97%, 97% ee
3a (0.25 h): 97%, 97% ee
3b (1.0 h): 98%, 97% ee
3a (5.0 h): 97%, 97% ee
3b (5.0 h): 77%, 97% ee
3a (0.5 h): 93%, 93% ee
3b (1.0 h): 92%, 98% ee
3
b (5.0 h): 44%, 92% ee
OH
OH
Me
OH
OH
OH
F C
3
Me
F C
3
Me
Me
N
Me
N
CF3
11l
11m
11n
11o
11p
3
a (4.0 h): 96%, 98% ee
3a (0.5 h): 99%, 98% ee 3a (0.5 h): >99.5%, 99% ee 3a (0.25 h): >99.5%, 96% ee 3a (0.5 h): 99%, 97% ee
3b (5.0 h): 90%, 99% ee
3b (2.0 h): 99%, 98% ee
3b (5.0 h): 61%, 84% ee
3b (5.0 h): 60%, 95% ee
3b (2.0 h): 99%, 93% ee
OH
OH
OH
OH
OH
N
S
i
Me
Me
S
Et
Pr
Me
11q
11r
11s
11t
11ub
3
a (0.5 h): >99.5%, 98% ee
3a (0.5 h): 81%, 98% ee
3b (1.0 h): 83%, 97% ee
3a (0.25 h): 66%, 97% ee
3b (1.0 h): 71%, 96% ee
3a (0.5 h): 94%, 99% ee
3b (1.5 h): 94%, 99% ee
3a (3.0 h): 98%, 99% ee
3b (1.5 h): 98%, 99% ee
3
b (1.5 h): 99%, 87% ee
OH
OH
tBu
OH
Me
HNPOPh2
Me
OH
Cy
iPr
Me
1v b
11wb
11xb
11yc
11zb,d
1
3a (4.0 h): 98%, 99% ee
b (1.0 h): 97%, >99.5% ee
3a (5.0 h): 42%, 98% ee
3b (5.0 h): 65%, 99% ee
3a (5.0 h): 93%, 9% ee
3b (2.5 h): 98%, 5% ee
3a (0.25 h): 82%, 68% ee
3b (1.0 h): 81%, 69% ee
3a (5.0 h): 86%, 99% ee
3b (5.0 h): 81%, 79% ee
3
a
i
Reactions were performed on a 2.5 mmol scale in PrOH (0.2 M). Conversion and enantio-
meric excess were determined by GC or HPLC. Reaction performed on a 0.625 mmol scale
with S/C/B = 250/1/10 at 75 °C. Complete chemoselectivity for the allylic alcohol observed
b
c
d
(
saturated products <1%). Isolated yield.
a
Chart 4. ATH of Substrates Containing Polar Double Bonds with Catalysts 3a and 3b
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The reactions with chloro-, methyl-, or methoxy-substituted aryl methyl ketones (10b-10j) and
with acetonaphthones (10k and 10l) showed that para- and meta-substitution is well tolerated.
The corresponding optically active alcohols were obtained with excellent enantioselectivity (93–
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–
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8% ee, ≥97% ee for the more selective catalyst) within 0.5–1.5 h (TOF = 470 to 3 890 h ). In
stark contrast, the hydrogenation of ortho-substituted substrates 10d, 10g, 10j, and 10l was still
highly enantioselective (92–99% ee, ≥97% ee for the more selective catalyst), but the reactions
were much slower and only moderate conversions (44–97%) were obtained after 4.0–5.0 h (TOF
–
1
= 90 to 240 h ). A similar trend has been observed with the P–(CH ) –P-based complexes 2a and
2
2
7b
2
b, but catalysts 3a and 3b are much more sensitive to steric effects as discussed below.
Overall, electronic effects were less pronounced for catalysts 3, and both electron-rich and
electron-poor ketones were reduced with excellent enantioselectivity.
The industrially relevant trifluoromethylated ketones 10m and 10n were rapidly hydrogenated
by the CNCEt derivative 3a. The corresponding alcohols 11m and 11n, which are important
3
10
9
building blocks for fungicides and NK antagonists, were obtained in quantitative yield within
1
–
1
0
.5 h and with 98% and 99% ee, respectively. In both cases, average TOFs of >1 950 h were
measured. The results differ strongly from the ones obtained with N-isonitrile catalyst 3b, which
only performed poorly with these substrates, and show again the pivotal role played by the
tuning of the isonitrile ligand.
Complex 3a was also the catalyst of choice for the ATH of acyl-substituted heterocycles (10o-
1
0s). Acyl pyridines 10o-10q were reduced in quantitative yield and with 96–98% ee within
0.25–0.5 h with no sign of catalyst poisoning by the pyridine substrate. The highest activity was
–1
achieved in the case of 4-acetylpyridine (10o), for which the average TOF was >3 950 h . Acyl
thiophenes 10r and 10s were also reduced by 3a within 0.25–0.5 h with 98 and 97% ee,
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respectively, but the conversions were significantly lower than for acyl pyridines (83 and 71%
for acyl thiophenes 10r and 10s, respectively). The electron-rich thiophene moiety, which shifts
the ATH equilibrium toward the ketone, probably account for the low conversions, rather than
catalyst decomposition or poisoning by the thiophene group. Again, the N-isonitrile catalyst 3b
was inferior to C-isonitrile catalyst 3a for these acyl heterocycles.
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Phenyl alkyl ketones bearing larger alkyl groups (10t-10w) were also tested. Catalyst 3a was
superior in the reduction of propiophenone (10t) to (R)-1-phenylpropan-1-ol (94% conversion,
99% ee after 0.5 h), whereas the N-isonitrile catalyst 3b gave better results for substrates bearing
secondary and tertiary alkyl groups (10u-10w). The catalyst loading (0.4 mol%) and reaction
temperature (75 °C) were slightly increased with these substrates to ensure rapid conversion to
the optically active alcohols. Under these optimized conditions, iso-propyl phenyl ketone (10u)
and cyclohexyl phenyl ketone (10v) were reduced by N-isonitrile catalyst 3b in 98% yield and
with outstanding ≥99% ee within 1.0–1.5 h.
The enantioselectivity was also high in the case of tert-butyl phenyl ketone (10w, 99% ee), but
the reaction was sluggish and only 65% conversion was achieved after 5.0 h. Again, this finding
shows that the propane-1,3-diyl-bridged complexes 3a and 3b are rather sensitive toward
sterically demanding substrates.
A dialkyl ketone such as 10x was reduced with poor enantioselectivity with either catalyst (9%
7
b
and 5% ee for 3a and 3b respectively). Thus, similarly to their (CH ) -linked analogues 2, the
2
2
bis(isonitrile) catalysts 3 readily differentiate between an aromatic and an aliphatic substituent,
but not between two alkyl substituents of different size. On these lines, enone 10y was reduced
with modest enantioselectivity (68% and 69% for 3a and 3b, respectively), which further
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indicates that an aryl group conjugated with the polar double bond is essential for good
enantiodiscrimination.
Finally, the C-isonitrile catalyst 3a efficiently hydrogenates the phosphinyl imine 10z, and the
reduced product 11z was isolated in 86% yield and with 99% ee after flash column chromato-
graphy. Phosphinyl imines are efficient precursors to enantiopure primary amines as the phos-
phinyl group in 11z is readily cleaved by ethanolic hydrochloric acid without loss of configura-
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tion at the adjacent stereocenter.
Substrate Scope: Discussion. A previous comparison with state-of-the-art iron-based
7c
4
catalysts has shown that the ethane-1,2-diyl analogues 2a and 2b and Gao’s system (see Chart
1
) are the only ones that combine high activity with excellent enantioselectivity for a broad scope
of substrates. However, rational modification of the latter catalyst is difficult, as it is prepared in
situ and is poorly defined. Also, poisoning experiments and the observation of a long activation
rd
period suggest the involvement of iron nanoparticles. Morris' 3 generation P(NH)NP catalysts
are the most active in the series, but their enantioselectivity exceeds 95% ee only with a few
3
k,m
substrates (10a, 10n and α-chloroacetophenone). Therefore, the propane-1,3-diyl-bridged
complexes 3a and 3b are benchmarked here with the ethane-1,2-diyl analogues 2a and 2b (for a
full comparison see Chart S2).
The propane-1,3-diyl-linked complexes 3a and 3b hydrogenate meta- and para-substituted
acetophenones (10b, 10c, 10d, 10e, 10f, 10h, 10i, 10k, and 10m) to the corresponding alcohols
with higher activity and enantioselectivity than their (CH ) -bridged analogues 2a and 2b.
2
2
Overall, 3a and 3b achieve 93–98% ee (≥97% ee for the more selective catalyst), while catalysts
7b
2
give 91–98% ee (≥94% ee for the more selective catalyst). The differences seem negligible in
‡
percentage, but the absolute increase in ΔΔG is considerable, also taking into account that 2 and
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differ only for a single methylene unit in the macrocyclic ligand. However, the ethane-1,2-diyl-
bridged catalysts 2a and 2b are significantly more active than 3a and 3b in the hydrogenation of
the sterically demanding, ortho-substituted acetophenones (10d, 10g, 10j, and 10l).
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We tentatively invoke steric and conformational effects of the macrocyclic ligand to explain
the higher enantioselectivity and increased sensitivity to steric effects of catalysts 3 as compared
to 2. In fact, the larger P–Fe–P bite angle (and possibly the longer Fe–ligand bonds) of 1b as
compared to 1a increases the steric bulk of the macrocycle, and the decreased flexibility of the
P–Fe–P chelate ring in the (CH ) -linked catalysts 3 reinforces this effect by preventing the P–
2
3
Fe–P chelate to move out of the trajectory of the incoming acetophenone. Overall, this leads to
increased enantioselectivity, but also to increased activation energy with sterically demanding
substrates.
The above hypothesis is corroborated by the results obtained for phenyl alkyl ketones 10t-10w,
which are reduced with higher enantioselectivity (98–99.6% ee) by the propane-1,3-diyl-linked
complexes 3a and 3b than by the (CH ) analogues 2 (86–98% ee). Phenyl alkyl ketones with
2
2
primary or secondary alkyl groups are hydrogenated rapidly, but a strong decrease in activity is
observed for tert-butyl phenyl ketone (10w, 65% conversion after 5 h with catalyst 3b). How-
ever, 10w is efficiently reduced to the corresponding secondary alcohol (R)-11w in quantitative
7
b
yield and with 97% ee within 4.0 h by the (CH ) analogue 2b.
2 2
For the acyl heterocycles 10o-10s, the propane-1,3-diyl-based C-isonitrile complex 3a is the
catalyst of choice and achieves 96–98% ee (vs. 92–98% ee for the better performing of the
ethane-1,2-diyl analogues 2a and 2b). Furthermore, 3a was by far the most active catalyst for all
–1
heterocyclic substrates (the TOF was up to >3 950 h for 10o). With most substrates, changing
i
from C-isonitrile CNCEt to N-isonitrile CNN Pr affects the enantioselectivity marginally
3
2
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(
usually within 5%). However, the C-isonitrile complex 3a hydrogenates 2-acetylpyridine (10q)
with impressive 98% ee, whereas the N-isonitrile derivative 3b gives only 87% ee. A similar
difference was also observed for 3,5-bis(trifluoromethyl)acetophenone (10n, 99% and 84% ee
for 3a and 3b, respectively) and for the phosphinyl imine 10z (99% and 79% ee for 3a and 3b,
respectively), but its origin is currently unclear.
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In summary, complexes 2 and 3 are complementary to a certain extent. The propane-1,3-diyl-
bridged complexes 3a and 3b efficiently reduce sterically less demanding substrates such as
para- and meta-substituted aryl alkyl ketones, acyl heterocycles, and aryl alkyl ketones with
primary or secondary alkyl groups. High enantioselectivity (≥96% ee) is obtained with the more
selective catalyst. Sterically more demanding substrates that are hydrogenated by 3 with low
activity are efficiently reduced by the ethane-1,2-diyl analogues 2a and 2b (≥97% ee for the
7
b
more selective catalyst), which are less sensitive to steric bulk. In the light of these considera-
tions, the importance of catalyst modularity is obvious.
Complex Design. In this section, we highlight the possible sites for catalyst tuning and
optimization for the iron(II)/(NH) P bis(isonitrile) complexes. As shown above, the strategy
2
2
based on Han’s H-phosphinate (R )-4 allows to easily change from an ethane-1,2-diyl to a
P
propane-1,3-diyl bridge (Chart 5, blue). However, this modification is not necessarily restricted
to a three-carbon bridge, as different backbones, e.g. longer ones, seem feasible.
Chart 5. Possible Catalyst Modifications
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We have shown previously that the diamine can be changed from (1S,2S)-diaminocyclohex-
ane1-2-diamine to (1R,2R)-diphenylethane-1,2-diamine in the matched macrocyclization step
7
e
7d
(
Chart 5, green). Furthermore, the diimino macrocycles can be reduced to the diamino ana-
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7
b
logues, whose complexes are three orders of magnitude more active as ATH catalysts (Chart 5,
red). Finally, the R group of the CNR isonitrile ligands, which are introduced in the last step of
the catalyst preparation, can be widely varied, as a plethora of isonitriles are commercially
7
b-d
7b,c
available or can be prepared in few steps (Chart 5, violet). The present and previous
examples underscore the success of this strategy and show that, with these handles, the macro-
cyclic iron(II)/(NH) P catalysts build a flexible platform that allows facile optimization for
2
2
individual substrates.
7
b,c
So far, we have explored the effect of tuning the CNR ligands, of changing imine to
7
b,d
amine, and of adding a methylene group to the bridge between the phosphines (this paper), but
further sites of the catalysts can be addressed. Thus, our group is currently exploring the effect of
changing the aryl substituents on the phosphorus donors (i.e. the exo-aryl substituent and the
benzylene linker to nitrogen) extending the protocol described herein to different H-phosphin-
1
4
ates. To get insight into the catalytically active species and develop a stereochemical model for
the reaction, we are also preparing hydride complexes with the (NH) P macrocycles, but their
2
2
formulation and stereochemistry are still under investigation.
CONCLUSION AND OUTLOOK
In this work, we have presented the synthesis of the propane-1,3-diyl-bridged (NH) P macro-
2
2
cycle (S ,S ,S ,S )-1b in 6 steps and high yield from Han’s H-phosphinate (R )-4. As (S )-4 is
P
P
C
C
P
P
also available by using (+)- instead of (–)-menthol, both enantiomers of the macrocycle (and,
consequently, of the iron(II) catalysts) are accessible, ultimately guaranteeing access to both
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enantiomers of the catalysis products. The new protocol based on menthol guarantees the
availability of the (NH) P macrocycles on a multigram scale, as well as the tuning of the diphos-
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The addition of a single methylene unit into the macrocycle strongly affects the outcome of
catalysis, as catalysts of type 3 are significantly more active and enantioselective with most sub-
strates than their previously reported ethane-1,2-diyl analogues 2. Thus, this study shows that
minute, facile changes in catalyst design alter the catalyst performance considerably, which can
be rationalized by careful analysis of X-ray structural data. This opens the way to effective
individual optimization of each substrate, also in combination with the tuning of the isonitrile
7
b,c
ligand, as demonstrated in this paper and before. Therefore, the present class of macrocyclic
iron(II) complexes truly constitutes a family of catalysts that can be easily prepared, structurally
characterized, and systematically modified. These properties are the sine qua non for rational
catalyst design, in combination with mechanistic understanding and a stereochemical model for
enantioselection, which are among our next goals.
Independently from future developments, the propane-1,3-diyl-bridged catalysts 3a and 3b
described herein, as well as the previously reported ethane-1,2-diyl-based analogues 2a and 2b,
form a toolbox for the efficient and highly enantioselective transfer hydrogenation of aryl alkyl
ketones and bring the development of cost-efficient base metals catalyst for such reactions closer
at hand.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: mezzetti@inorg.chem.ethz.ch
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Notes
The authors declare no competing financial interest.
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Supporting Information Available: Detailed experimental procedures and characterization of
all products (PDF), crystallographic information file for complexes 3c and 8b (CIF). This
material is available free of charge via the Internet at http://pubs.acs.org.
ACKNOWLEDGMENT
We thank the Swiss National Science Foundation for financial support (grant no.
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00020_146881).
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