Chiral (cyclopentadienone)iron complexes with a stereogenic plane as pre-catalysts for the asymmetric hydrogenation of polar double bonds

Article abstract of DOI:10.1016/j.tet.2019.01.057

In this paper, we describe a small library of easy-to-prepare chiral (cyclopentadienone)iron pre-catalysts for enantioselective C[dbnd]O and C[dbnd]N hydrogenations. Starting from readily accessible achiral materials, six chiral (cyclopentadienone)iron complexes (1a-f) possessing a stereogenic plane were synthesized in racemic form. Based on the screening of pre-catalysts (±)-1a-f in the hydrogenation of ketones and ketimines, we selected two complexes (1a and 1d) for resolution by semipreparative enantioselective HPLC. The absolute configuration of the separated enantiomers of 1a and 1d was assigned by XRD analysis (1a) and by comparison between experimental and DFT-calculated ECD and ORD spectra (1d). The enantiopure pre-catalysts (S)-1a and (R)-1d were tested in the asymmetric hydrogenation of several ketones and ketimines and showed good activity and modest enantioselectivity, the e.e. values ranging from very low to moderate (54%).

Full text of DOI:10.1016/j.tet.2019.01.057

Accepted Manuscript
Chiral (cyclopentadienone)iron complexes with a stereogenic plane as pre-catalysts
for the asymmetric hydrogenation of polar double bonds
Xishan Bai, Mattia Cettolin, Giulia Mazzoccanti, Marco Pierini, Umberto Piarulli,
Valentina Colombo, Alberto Dal Corso, Luca Pignataro, Cesare Gennari
PII:
S0040-4020(19)30096-1
https://doi.org/10.1016/j.tet.2019.01.057
TET 30109
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 14 December 2018
Revised Date: 21 January 2019
Accepted Date: 24 January 2019
Please cite this article as: Bai X, Cettolin M, Mazzoccanti G, Pierini M, Piarulli U, Colombo V, Corso
AD, Pignataro L, Gennari C, Chiral (cyclopentadienone)iron complexes with a stereogenic plane as
pre-catalysts for the asymmetric hydrogenation of polar double bonds, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.01.057.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Chiral (cyclopentadienone)iron complexes
with a stereogenic plane as pre-catalysts for
the asymmetric hydrogenation of polar
double bonds
Leave this area blank for abstract info.
X. Bai,a M. Cettolin,a G. Mazzoccanti,b M. Pierini,b U. Piarulli,c V. Colombo,a A. Dal Corso,a L. Pignataroa,*
and Cesare Gennaria,*
a Università degli Studi di Milano, Dipartimento di Chimica
b Sapienza Università di Roma, Dipartimento di Chimica e Tecnologie del Farmaco
c Università degli Studi dell’Insubria, Dipartimento di Scienza e Alta Tecnologia

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Chiral (cyclopentadienone)iron complexes with a stereogenic plane as pre-catalysts
for the asymmetric hydrogenation of polar double bonds
Xishan Baia, Mattia Cettolina , Giulia Mazzoccantib, Marco Pierini,b Umberto Piarulli,c
Valentina Colomboa, Alberto Dal Corsoa, Luca Pignataroa,* and Cesare Gennaria,*
a Università degli Studi di Milano, Dipartimento di Chimica, via C. Golgi, 19 – 20133 Milano, Italy
b Sapienza Università di Roma, Dipartimento di Chimica e Tecnologie del Farmaco, piazzale A. Moro, 5 – 00185 Roma, Italy
c Università degli Studi dell’Insubria, Dipartimento di Scienza e Alta Tecnologia, via Valleggio, 11 – 22100 Como, Italy
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
In this paper, we describe a small library of easy-to-prepare chiral (cyclopentadienone)iron pre-
catalysts for enantioselective C=O and C=N hydrogenations. Starting from readily accessible
achiral materials, six chiral (cyclopentadienone)iron complexes (1a-f) possessing a stereogenic
plane were synthesized in racemic form. Based on the screening of pre-catalysts (±)-1a-f in the
hydrogenation of ketones and ketimines, we selected two complexes (1a and 1d) for resolution
by semipreparative enantioselective HPLC. The absolute configuration of the separated
enantiomers of 1a and 1d was assigned by XRD analysis (1a) and by comparison between
experimental and DFT-calculated ECD and ORD spectra (1d). The enantiopure pre-catalysts
(S)-1a and (R)-1d were tested in the asymmetric hydrogenation of several ketones and ketimines
and showed good activity and modest enantioselectivity, the e.e. values ranging from very low
to moderate (54%).
Available online
Keywords:
Asymmetric hydrogenation
(Cyclopentadienone)iron complexes
Iron catalysis
Stereogenic plane
2009 Elsevier Ltd. All rights reserved
.
Polar double bonds
1. Introduction
hydrogen-borrowing reactions such as alcohol amination [8] and
others [8a,9].
In the search for sustainable catalytic methodologies,
replacement of precious metals with base metals is receiving
increasing attention by academic and industrial researchers.
However, as far as homogeneous catalysis is concerned, the
choice of the ligand is equally important as that of the metal.
Indeed, use of costly and sophisticated ligands may offset the
intrinsic advantage of employing
a
cheap metal.
(Cyclopentadienone)iron complexes 1 (Scheme 1) represent a
good balance between these two aspects because they combine
iron – i.e., the cheapest, most abundant and least toxic transition
metal [ 1 ]
– with simple ligands such as CO and
cyclopentadienones. The latter are readily prepared by
condensation of α-diketones with 1,3-disubstituted acetones or by
cyclative carbonylation/complexation of diynes (directly
affording the iron complexes) [2]. Additionally, unlike many
other iron complexes used in catalysis, compounds 1 are very
stable, which facilitates their purification (that can be performed
by chromatography) and use. Under suitable conditions (Scheme
1 A) they can be converted in situ into the activated forms act-1
and 2 [3], which promote several reactions involving hydrogen
transfer through the same pericyclic transition state (Scheme 1
B): i) reduction of polar double bonds by catalytic hydrogenation
[3d-g,4a,c-f,5] or catalytic transfer hydrogenation [3a,4a-b,6]; ii)
Oppenauer-type oxidation of alcohols [6b,e,7]; iii) redox-neutral
Scheme 1. A: in situ activation of (cyclopentadienone)iron complexes 1; B:
TS of the reactions involving transfer of hydrogen promoted by the active
complexes act-1 and 2.
Very
recently,
the
first
applications
of
(cyclopentadienone)iron complexes to reactions not involving
hydrogen transfer have also appeared in the literature [10].
Despite the blossoming interest for these complexes, their use
in enantioselective catalysis is still very limited, with the notable
exception of the enantioselective C=N reductions reported by

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and discussion
Beller et al., in which an achiral type-2 complex (i.e., the air-
sensitive activated form) is combined with a chiral phosphoric
acid co-catalyst [3d-g]. Attempts to develop effective chiral type-
1 pre-catalysts met with only partial success, with poor or
moderate e.e.’s obtained in the reduction of ketones and
ketimines (Fig. 1). This is probably due to the difficulty to place
the stereogenic group(s) of the complexes sufficiently close to
the substrate in the pericyclic TS of reductions (see Scheme 1 B).
2.1. Synthesis of the racemic complexes and test of their
catalytic activity
In the ligand design, we decided to employ cyclopentadienone
ligands featuring the biggest possible difference, in steric and/or
stereoelectronic terms, between the substituents at C2 and C5.
Indeed, in the commonly accepted TS of the reductions promoted
by complexes 1 (Scheme 1 B), the 2,5-substituents are relatively
close to the approaching substrate.
We started with the preparation of complex (±)-1a – featuring
the same cyclopentadienone ligand as one of the Hayashi’s Ru-
complexes
–
by reacting Fe2(CO)9 with the known
cyclopentadienone 4 [14] (Scheme 2). The latter compound, in
turn, was readily synthesized by condensation of benzil with 1-
phenyl-2-butanone (3), prepared as described in the literature
[14,15].
Scheme 2. Synthesis of the racemic (cyclopentadienone)iron complex (±)-1a.
Next, starting from a common precursor (commercially
available 1,7-octadiyne), we synthesized five racemic
(cyclopentadienone)iron
substituents at C2 and C5 (Scheme 3). Following a literature
procedure [16], 1,7-octadiyne was treated with LiHMDS and
complexes
featuring
different
Fig. 1. Main strategies for synthesis of chiral (cyclopentadienone)iron
complexes. AH = asymmetric hydrogenation; ATH = asymmetric transfer
hydrogenation.
trimethylsilyl chloride to yield compound 5, bearing
a
trimethylsilyl (TMS) at one of its terminal alkyne groups. The
remaining C-terminus was functionalized in two different ways:
i) with a phenyl group (by Sonogashira coupling), yielding the
asymmetric diyne 6 [ 17 ]; ii) with a methyl group, giving
compound 7 [16]. The latter was either used directly for iron
complexation or de-silylated with K2CO3 to yield diyne 8 [18],
For the synthesis of chiral (cyclopentadienone)iron
complexes, two main strategies have been employed so far: the
first, developed by Berkessel and co-workers (Fig. 1 A), consists
in replacing a CO ligand of an achiral complex with a chiral
monodentate ligand [11]. The second, followed by Wills et al.
[6a,c,d,f], by Ward/Renaud et al. [12] and by our research group
[4a,e,f], involves the use of a chiral cyclopentadienone ligand
(Fig. 1 B) [13]. Attempts to merge these two approaches – i.e.,
whose terminal alkyne group was functionalized with
a
triethylsilyl (TES) or a triisopropylsilyl (TIPS) or a trityl group
yielding diynes 9, 10 and 11, respectively. Treatment of diynes 6-
7 and 9-11 with Fe2(CO)9 in toluene at 110 °C gave the racemic
complexes (±)-1b-f in yields ranging from 13% to 60%.
introducing
a
chiral monodentate ligand into
a
chiral
cyclopentadienone complex – did not lead to appreciable
improvements in terms of enantioselectivity [2a,6c]. Ward,
The catalytic activity of the newly synthesized complexes (±)-
1a-f, activated in situ with Me3NO, in the hydrogenation of polar
double bonds was tested using acetophenone (S1) and (E)-N-(4-
methoxyphenyl)-1-phenylethan-1-imine (S2) as model substrates
(Table 1). Pre-catalysts (±)-1a and (±)-1b gave high conversion
of S1 and S2 at both 5 mol% and 2 mol% loading (Table 1,
entries 1-4). Along the series (±)-1c → (±)-1f, conversions were
found to decrease with the increasing size of the “large”
substituent RL (Table 1, entries 5-12): while (±)-1c (RL = TMS)
and (±)-1d (RL = TES) gave full conversion of S1 and acceptable
conversions of S2 (entries 5-8), the activity of (±)-1e (RL = TIPS)
and (±)-1f (RL = CPh3) decreased dramatically (entries 9-12).
Complex 1d features the largest possible RL compatible with an
acceptable catalytic activity, and for this reason it was selected
for enantiomer separation. Moreover, it was decided to resolve
also complex 1a which, besides being the most active of the
Renaud
and
co-workers
developed
chiral
(cyclopentadienone)iron complexes bearing a biotin residue
which was exploited for
A third possible strategy, recently applied by Hayashi and co-
workers to the synthesis of chiral Shvo-type ruthenium
complexes [14], involves the use of achiral cyclopentadienones
bearing different substituents on the two sides of the C=O group
to synthesize chiral complexes possessing a stereogenic plane
(Fig. 1 C). This paper accounts for our efforts in this direction,
with the synthesis of six new chiral iron complexes, two of which
were resolved in the pure enantiomeric forms and tested in the
asymmetric hydrogenation (AH) of ketones and ketimines.

3
group, allows to establish a comparison with the corresponding
ruthenium complex developed by Hayashi and co-workers [14].
ACCEPTED MANUSCRIPT
Scheme 3. A: Synthesis of the asymmetric diynes 5-11; B: Synthesis of the racemic (cyclopentadienone)iron complexes (±)-1b-f.
Table 1
Test of the activity of the racemic complexes (±)-1a-f in C=O and C=N
hydrogenation.a
H2 (50 bar)
Preꢀcat. (x mol%)
Me3NO (2x mol%)
X
X
Ph
Ph
iPrOH, 80 °C, 22 h
S1 = O
P1 = OH
S2 = NꢀPMP
P2 = NHꢀPMP
Entry
1
Pre-cat.
Loading (mol%)
Conv. S1 (%)b
Conv. S2 (%)b
1a
2
5
2
5
2
5
2
5
2
5
2
5
> 99
> 99
> 99
> 99
> 99
> 99
> 99
> 99
73
> 99
2
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
> 99
89
> 99
69
82
4
3
4
5
6
7
8
92
8
9
10
11
76
62
12
18
0
12
1f
35
a
Reaction conditions: Pre-cat./Me3NO = 1:2, T = 80 °C, PH2 = 50 bar, 22 h.
C0,sub. = 0.5
M
.
b
Determined by 1H NMR.
2.2. Resolution of complexes 1a and 1d by semipreparative
enantioselective HPLC and determination of the absolute
configuration of the enantiomerically pure complexes
Fig. 2. Analytical separation of racemic mixtures (±)-1a (A) and (±)-1d (B)
by enantioselective HPLC. A) column: (R,R)-DACH-DNB 5 µm (250 mm ×
4.6 mm L. × I.D.); eluent: n-hexane/DCM 80:20 + 2% MeOH v/v; flow rate
1.0 mL/min at 25 °C. B) column: Chiralpak IC 5 µm (250 mm × 4.6 mm L.×
I.D.); eluent: n-hexane/IPA 95:5 v/v; flow rate 1.0 mL/min at 25 °C.
The racemic complexes (±)-1a and (±)-1d were resolved by
enantioselective HPLC. More in detail, the enantiomers of (±)-1a
were resolved on the (R,R)-DACH-DNB chiral stationary phase
(CSP) under normal phase conditions (mobile phase: n-
hexane/DCM 80:20 + 2% MeOH v/v), using both UV and ECD
detection (k’1 = 2.36; α = 1.27; T = 25 °C, see Fig. 2 A).
The separation was then scaled-up to semipreparative conditions,
with 60 replicate separations (2 mg of sample injected in each

4
Tetrahedron
run) carried out on a 1.0 cm internal diameter (R,R)-DACH-
ACCEPTED MANUSCRIPT
DNB column. This provided the two enantiomers with an overall
recovery of 80%. The e.e. values of the first and second eluted
enantiomer – determined by analytical HPLC with UV and ECD
detection at 300 nm – were 99% and 98%, respectively (see the
Supplementary data). As for complex (±)-1d, the enantiomers
were separated on a Chiralpak IC CSP column (mobile phase: n-
hexane/IPA 95:5 v/v), achieving an α value of 1.37 (k’1 = 2.84,
Figure 2 B). In the semipreparative scale-up stage, each
enantiomer (70 mg, process yield = 79%) was obtained with an
enantiomeric excess of 99%, measured by analytical HPLC with
UV and CD detection at 270 nm (see the Supplementary data).
After the successful resolution of complexes 1a and 1d, we set to
assign the absolute configuration (AC) of the separated
enantiomers [19]. In the absence of configurationally known
reference compounds which can be correlated to the chiral
analyte, X-ray diffraction (XRD) analysis represents the first-
choice method for AC assignment [20]. Suitable crystals of the
first-eluted enantiomer of complex 1a were obtained by vapor
diffusion of pentane into a DCM solution of the complex,
followed by cooling (-18 °C). Diffractometric analysis of a single
crystal showed that the absolute configuration of this enantiomer,
assigned according to the extended CIP rules [21], is S (Fig. 3,
additional details are reported in the Supplementary data).
As no crystals could be grown for the enantiomerically pure
forms of complex 1d, the AC was assigned by
a
spectroscopic/computational procedure [ 22 ]. The electronic
circular dichroism (ECD) and optical rotation dispersion (ORD)
spectra were registered for each of the separated enantiomers and
compared to the equivalent spectra simulated by DFT
calculations for the R enantiomer (see details in Section 4.8).
From inspection of the superimposed spectra (shown in Fig. 4), a
good matching was found between the spectra of the first-eluted
enantiomer and the calculated one. Thus, R configuration was
assigned to the first-eluted enantiomer of 1d, and S configuration
to the second eluted one.
Fig. 4. ECD and ORD experimental spectra of the resolved enantiomers of 1d
superimposed to the equivalent ones simulated through DFT calculations for
the R enantiomer.
Fig 3. X-Ray crystal structure of the first-eluted enantiomer (S) of complex 1a. Color codes: Fe, orange; O, red; C, gray; H, white. Selected bond distances: Fe-
C1B, 1.802(2); Fe-C1A, 1.804(2); Fe-C1C, 1.804(2); Fe-C4, 2.0721(16); Fe-C3, 2.0830(16); Fe-C5, 2.1222(18); Fe-C2, 2.1389(17).
2.3. Test of the enantiomerically pure complexes in the AH of
[Table 2, entries 3 and 4 with pre-catalyst (S)-1a]. Unfortunately,
only low enantioselectivity was obtained with substrates S1, S4,
S5 and S6 (Table 2, entries 1, 3-5), whereas 2,2,2-trifluoro-1-
phenylethan-1-one S3 was reduced with moderate e.e. values
(entry 2). Notably, the sense of stereoinduction was different
with the two pre-catalysts, consistent with the assigned opposite
configurations (see Section 2.2).
ketones and ketimines
The enantiomerically pure complexes (S)-1a and (R)-1d were
tested in the AH of several ketones, giving the results shown in
Table 2. The complexes confirmed to be quite active pre-
catalysts, giving always full conversion except in two cases

5
Table 2
Complexes (S)-1a and (R)-1d were screened also in the AH
AH of ketones promoted by the chiral pre-catalysts (S)-1a and (R)-1d.a
ACCEPTED MANUSCRIPT
of several N-PMP ketimines, showing again good activity:
conversions were high (> 90%) in most cases, and reasonable in
the remaining ones [Table 3, entry 3 with (R)-1d and entry 4].
Moderate e.e. values were achieved with the acetophenone- and
the propiophenone-derived imines S2 and S8 (Table 3, entries 1
and 3), (S)-1a being slightly more enantioselective than (R)-1d.
Imines S7 and S9 were hydrogenated with a low level of
stereoselectivity, somewhat higher with (S)-1a than with (R)-1d
(Table 3, entries 2 and 4). With all ketimines, the two pre-
catalysts showed opposite stereochemical preferences.
Me
H2 (50 bar)
Pre-Cat. (5 mol%)
Me3NO (10 mol%)
SiEt3
Ph
Ph
OC
O
O
O
OH
R2
Me
CO
Ph
Fe
Fe
R1
R2
R1
OC
OC
iPrOH, 80 °C, 22 h
CO
OC
(S)-1a
S
P
(R)-1d
Pre-catalyst (S)-1a
Conv. (%)b e.e. (%)b
Pre-catalyst (R)-1d
Entry Substrate
1c
Conv. (%)b e.e. (%)b
> 99 [99]d
> 99 [98]d
36 [33]d
3, R
45, R
9, S
> 99 [99]d
> 99 [98]d
9, R
3. Conclusion
The work described in this paper aims at developing easy-to-
prepare chiral (cyclopentadienone)iron pre-catalysts for
enantioselective reductions. Starting from readily accessible
achiral materials, six chiral (cyclopentadienone)iron complexes
(1a-f) possessing a stereogenic plane were synthesized in racemic
form. To enhance the enantiodiscrimination, pre-catalyst were
designed to maximize the difference – in terms of steric and
stereoelectronic properties – between the substituents at position
2 and 5 of the cyclopentadienone ring (which are close to the
substrate in the hydrogenation TS). Unfortunately, catalytic tests
carried out with the racemic complexes (±)-1a-f revealed that the
increasing the size of the ‘large’ substituent RL beyond a certain
extent leads to a drop of catalytic activity. The best compromise
between RL size and catalytic activity was reached with
complexes 1a and 1d, which were resolved by semipreparative
enantioselective HPLC. The absolute configuration of the two
enantiomeric forms of complex 1a was assigned on the basis of
XRD analysis of the first-eluted enantiomer (S). For complex 1d,
the assignment was made by comparing the ORD and ECD
spectra of the two enantiomers with the equivalent spectra
simulated by DFT calculations for the R enantiomer. The
enantiomerically pure complex (S)-1a promoted the AH of
ketones and ketimines with low to moderate enantioselectivity,
similar to that obtained with its ruthenium analog developed by
Hayashi and co-workers [14]. To our surprise, the larger RL
group present in pre-catalyst (R)-1d was not sufficient to enhance
the enantiocontrol. Overall, these results confirm that an effective
chiral (cyclopentadienone)iron pre-catalyst for enantioselctive
reduction still represents a distant goal. However, we believe that
the catalyst design adopted here, involving a short and
straightforward synthetic route starting from cheap precursors,
will provide useful directions for the future.
2c
3c
41, S
> 99 [99]d 9, R
> 99 [99]d 18, R
4c
5e
73 [72]d
13, S
14, S
> 99 [85]d
> 99 [99]d
18, S
a
Reaction conditions: Substrate/Me3NO/Pre-cat. = 100:10:5, T = 80 °C, PH2
50 bar, 22 h. C0,sub. = 0.5
Determined by GC analysis with a chiral capillary column.
Absolute configuration of the product assigned by comparing the order of
elution with literature data (see the experimental section).
Isolated yield.
=
M
.
b
c
d
e
Absolute configuration of the product assigned by comparing the sign of
optical rotation with literature data (see the experimental section).
Table 3
AH of ketimines promoted by the chiral pre-catalysts (S)-1a and (R)-1d.a
Me
H2 (50 bar)
Pre-Cat. (5 mol%)
Me3NO (10 mol%)
SiEt3
Ph
Ph
OC
R3
R2
R3
R2
O
O
N
HN
R1
Me
CO
Ph
Fe
Fe
R1
OC
OC
iPrOH, 80 °C, 22 h
CO
OC
(S)-1a
S
P
(R)-1d
Pre-catalyst (S)-1a
Pre-catalyst (R)-1d
Entry
1d
Substrate
Conv. (%)b e.e. (%)c Conv. (%)b e.e. (%)c
> 99 [98]e
97 [91]e
40, R
29, R
96 [96]e
91 [78]e
39, S
6, S
4. Experimental Section
2f
4.1. General information
All reactions were carried out in flame-dried glassware with
magnetic stirring under inert atmosphere (nitrogen or argon),
unless otherwise stated. Solvents for reactions were distilled over
the following drying agents and transferred under nitrogen: THF
(Na), toluene (Na). Dry N,N-dimethylformamide (DMF, over
molecular sieves in bottles with crown cap) was purchased from
Sigma Aldrich and stored under nitrogen. All reagents were used
without purification. Known compounds 3 [15], 4 [14], 5 [16], 6
[17], 7 [16] and 8 [18] were prepared following slightly modified
literature procedures (see the Supplementary data). Imines S2
and S7-S9 were prepared as previously described [4a,b].
3f
4f
> 99 [76]e
76 [57]e
54, R
18, S
65 [41]e
73 [48]e
40, S
6, R
a
Reaction conditions: Substrate/Me3NO/Pre-cat. = 100:10:5, T = 80 °C, PH2
=
50 bar, 22 h. C0,sub. = 0.5
M.
Determined by 1H NMR.
b
c
d
Determined by enantioselective HPLC.
Absolute configuration of the product assigned by comparing the sign of
optical rotation with literature data (see the experimental section).
Isolated yield.
Absolute configuration assigned by comparing the order of elution with
literature data (see the experimental section).
Reactions
were
monitored
by analytical
thin-layer
chromatography (TLC) using silica gel 60 F254 pre-coated glass
plates (0.25 mm thickness). Visualization was accomplished by
irradiation with a UV lamp and/or staining with a potassium
permanganate alkaline solution. Flash Column Chromatography
e
f

6
Tetrahedron
(FCC) was performed using silica gel (60 Å, particle size 40-64
842.7, 806.1, 736.7, 726.1 cm-1; MS (ESI +) m/z 257.51 [M +
+
ꢀm) as stationary phase, following the proceduAreCbyCSEtilPl aTndEcDo- MANUSCRIPT
Na] (calcd. for C15H26SiNa: 257.17); elemental analysis (%): C
workers [23]. Optical rotations were measured with a Jasco-P-
75.60, H 11.01, (calcd. for C15H26Si: C 76.84, H 11.18).
2000 digital polarimeter at 20 or 22 °C, and concentrations (c)
are given in g / 100 mL. H-NMR spectra were recorded on a
1
4.3. Triisopropyl(nona-1,7-diyn-1-yl)silane (10)
spectrometer operating at 400.13 MHz. Proton chemical shifts
are reported in ppm (δ) with the solvent reference relative to
tetramethylsilane (TMS) employed as the internal standard
(CDCl3, δ = 7.26 ppm; CD2Cl2 δ = 5.32 ppm). The following
abbreviations are used to describe spin multiplicity: s = singlet, d
= doublet, t = triplet, q = quartet, m = multiplet. 13C-NMR spectra
were recorded on a 400 MHz spectrometer operating at 100.56
MHz, with complete proton decoupling. Carbon chemical shifts
are reported in ppm (δ) relative to TMS with the respective
solvent resonance as the internal standard (CDCl3 δ = 77.16 ppm;
CD2Cl2 δ = 54.00 ppm). The coupling constant values are given
in Hz. Infrared spectra were recorded on a standard FT/IR
spectrometer. Melting points were recorded with a standard
melting-point apparatus. High resolution mass spectra (HRMS)
were performed on a ESI QTof SYNAPT G2 Si mass
spectrometer (Waters), available at the UNITECH-COSPECT
laboratories (Università degli Studi di Milano). Elemental
analyses were performed on a Perkin Elmer Series II CHNS/O
Analyzer 2000. X-ray intensity data were collected with a Bruker
AXS APEXII CCD area detector by using graphite
monochromated Mo-Kα radiation.
nBuLi (1.6
M in hexanes, 2.29 mL, 3.661 mmol) was added
dropwise to a stirred solution of diyne 8 (400 mg, 3.328 mmol) in
THF (22 mL) at -78 °C. After stirring for 1 hour at -78 °C, TIPS-
Cl (770 mg, 3.9936 mmol) was added and the mixture was stirred
at -78 °C for 1 h before being allowed to warm to room
temperature overnight. The reaction was quenched using
saturated sat. aq. NH4Cl (25 mL) and extracted with Et2O (3 × 25
mL). The combined organic extracts were dried over MgSO4 and
the solvent was removed in vacuo. The residue was purified by
flash column chromatograph (98:2 hexane/AcOEt) to afford the
1
pure product as a light yellow oil. Yield: 1.167 g (95%). H-
NMR (400MHz, CDCl3): 2.28-2.24 (m, 2H), 2.15-2.13 (m, 2H),
1.76 (t, J = 2.60 Hz 3H), 1.62-1.60 (m, 4H), 1.07-1.02 (m, 21H);
13C-NMR (100 MHz, CDCl3): 108.89, 80.41, 78.92, 75.75, 28.13,
28.06, 19.53, 18.75, 18.34, 11.45, 3.55; IR (film): ν = 3584.1,
2942.8, 2892.7, 2865.7, 2724.0, 2171.5, 1639.2, 1462.7, 1383.7,
1366.3, 1326.8, 1242.9, 1071.3, 1016.3, 995.1, 919.9, 883.2,
702.0, 676.9, 660.5, 621.0 cm-1; elemental analysis (%): C 71.21,
H 11.05, (calcd. for C18H32Si: C 78.18, H 11.66).
4.4. Deca-2,8-diyne-1,1,1-triyltribenzene (11)
4.2. Complex (±)-1a
In a Schlenk tube at 0 °C, a solution of ethylmagnesium bromide
(2
M in THF, 4.1 mL, 8.33 mmol) was added dropwise to a stirred
In a Schlenk tube fitted with a Teflon-topped screw cap,
Fe2(CO)9 (1.1284 g, 3.102 mmol) was added to a stirred solution
of cyclopentadienone 3 (500 mg, 1.551 mmol) in toluene (10
mL). The reaction mixture was heated to 110°C and stirred for 16
hours. The reaction mixture was cooled down to room
temperature and filtered through Celite (rinsing with AcOEt).
After removal of the solvent, the residue was purified by flash
column chromatograph (9:1 hexane/AcOEt) to afford the product
as a light yellow solid. Yield: 628 mg (88%). M.p. = 199.1 °C;
1H-NMR (400 MHz, CD2Cl2) δ 7.52-7.49 (m, 2H), 7.41-7.33 (m,
5H), 7.28-7.23 (m, 4H), 7.16-7.15 (m, 4H), 1.94(s, 3H); 13C-
NMR (100 MHz, CD2Cl2) δ209.52, 171.68, 132.28, 132.02,
131.93, 130.96, 130.66, 130.49, 129.39, 129.18, 128.79, 128.55,
128.49, 128.44, 128.33, 105.35, 104.93, 83.63, 80.60, 10.81; IR
(film): ν = 3058.6, 2922.6, 2855.1, 2062.5, 1991.1, 1641.1,
1577.5, 1499.4, 1445.4, 1390.4, 1171.5, 1073.2, 1029.8, 1003.8,
927.6, 853.3, 769.5, 757.9, 853.3, 76935, 757.9, 736.7, 698.1,
666.3, 645.1, 613.3 cm-1; HRMS (ESI+): m/z 463.0631 [M+H]+
(calcd. for C32H27FeO4: 463.0633).
solution of compound 8 (1g, 8.33 mmol) and THF (11 mL). The
resulting mixture was heated to reflux and stirred for 1 h. After
cooling down to room temperature, trityl chloride (2.322 g, 8.33
mmol) was added. The resulting mixture was heated to reflux and
stirred overnight. After cooling down to room temperature, the
reaction was quenched with sat. aq. NH4Cl (15 mL), and the
obtained aqueous phase was extracted with AcOEt (3 × 30 mL).
The organic layer was washed with water (25 mL) and brine (25
mL), dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography on silica gel
(9:1 hexane/AcOEt) to give the product as a white solid. Yield:
1
1.61 g (53%). M.p. = 85.2 °C; H-NMR (400MHz, CD2Cl2):
7.31-7.25 (m, 15H), 2.41 (t, J = 6.72 Hz, 2H), 2.20-2.15 (m, 2H),
1.77 (t, J = 2.56 Hz, 3H), 1.72-1.63 (m, 4H); 13C-NMR
(100MHz, CD2Cl2): 146.48, 129.65, 128.44, 127.21, 86.73,
86.17, 79.25, 76.07, 56.17, 28.94, 28.59, 19.10, 18.78, 3.73; IR
(film): ν = 3584.1, 3083.6, 3058.6, 3021.9, 2939.0, 2859.0,
1951.6, 1595.8, 1489.7, 1445.4, 1328.7, 1182.2, 1077.1, 1032.7,
1001.8, 891.0, 746.3, 689.1, 638.3, 618.1 cm-1; MS (ESI +) m/z
363.52 [M + H]+ (calcd. for C28H26: 363.52); elemental analysis
(%): C 92.77, H 7.22, (calcd. for C28H26: C 92.77, H 7.23).
Triethyl(nona-1,7-diyn-1-yl)silane (9)
nBuLi (1.6
M in hexanes, 2.29 mL, 3.661 mmol) was added
4.5. General procedure for the synthesis of complexes (±)-1b-f
dropwise to a stirred solution of diyne 8 (400 mg, 3.328 mmol) in
THF (22 mL) at -78 °C. After stirring for 1 hour at -78 °C, TES-
Cl (601.9 mg, 3.9936 mmol) was added and the mixture was
stirred at -78 °C for 1 h before being allowed to warm to room
temperature overnight. The reaction was quenched using
saturated sat. aq. NH4Cl (25 mL) and extracted with Et2O (3 × 25
mL). The combined organic extracts were dried over MgSO4 and
the solvent was removed in vacuo. The residue was purified by
flash column chromatograph (98:2 hexane/AcOEt) to afford the
In a Schlenk tube fitted with a Teflon-topped screw cap,
distilled toluene (6 mL) was added to a mixture of the diyne
(0.853 mmol) and Fe2(CO)9 (621 mg, 1.706 mmol). The mixture
was heated to 110 °C and stirred overnight. After cooling down
to room temperature, the products were purified by column
chromatography (4:1 hexane/AcOEt) to afford the pure iron
complexes.
1
4.5.1. Complex (±)-1b
pure product as a light yellow oil. Yield: 733 mg (94%). H-
NMR (400 MHz, CDCl3): 2.25 (t, J = 6.80 Hz, 2H), 2.15-2.12
(m, 2H), 1.76 (t, J = 2.56 Hz, 3H), 1.61-1.57 (m, 4H), 0.97 (t, J =
7.96 Hz, 9H), 0.59 (q, J1 = 7.84 Hz, J2 = 15.80 Hz, 6H); 13C-
NMR (100 MHz, CDCl3): 108.38, 81.80, 78.92, 75.77, 28.18,
27.99, 19.57, 18.37, 7.58, 4.69, 3.55; IR (film): ν = 3585.0,
2953.5, 2916.8, 2874.4, 2733.6, 2172.4, 1655.6, 1458.9, 1414.5,
1377.9, 1326.8, 1260.3, 1236.2, 1096.3, 1017.3, 973.9, 930.5,
Prepared from diyne 6 according to the General procedure.
Yield: 216 mg (60%). M.p. = 117.8 °C; H-NMR (400 MHz,
1
CD2Cl2): 7.65-7.62 (m, 2H), 7.38-7.31 (m, 3H), 2.71-2.68 (m,
2H), 2.65-2.55 (m, 2H), 1.91-1.84 (m, 4H), 0.32 (s, 9H); 13C-
NMR (100 MHz, CD2Cl2): 209.86, 175.84, 132.51, 130.19,
128.76, 128.20, 107.37, 106.12, 85.16, 68.79, 60.05, 24.87,
24.85, 22.88, 22.82, 0.01; IR (film): ν = 2949.6, 2852.2, 2057.7,

7
1998.9, 1632.5, 1501.3, 1442.5, 1403.0, 1247.7, 1181.2, 1152.3,
(process yield 80%). The enantiomeric excess, the UV, and
-1
1017.3, 892.0, 838.9, 757.9, 695.2, 617.1 cmA; CHRCMESP(TESEI+D): MANUSCRIPT
ECD at 300 nm were determined by analytical HPLC with use of
a Regis (R,R)-DACH-DNB column (250 mm × 4.6 mm L. × I.D.)
under the same conditions employed for semipreparative HPLC,
excepting the flow rate (1.0 mL/min). Concerning the racemic
(±)-1d, the enantiomers were resolved by using a Chiralpak IC
column (250 mm × 10 mm L. × I.D.) in semipreparative HPLC
conditions, mobile phase consisted in a mixture of n-hexane/IPA
95:5 v/v (flow rate 5.0 mL/min and Tcol. = 25 °C). The racemic
(±)-1d was dissolved in the mobile phase (c = 60 mg/mL); each
injection was 100 µL (process yield 79%). The enantiomeric
excess, the UV, and ECD at 270 nm were determined by
analytical HPLC with use of a Chiralpak IC column (250 mm ×
4.6 mm L. × I.D.) with a flow rate of 1.0 mL/min. The ECD
spectra of chromatographically resolved (R)-1d and (S)-1d were
recorded with the circular dichroism detector Jasco J710 CD
m/z 423.0708 [M+H]+ (calcd. for C32H27FeO4: 423.0715).
4.5.2. Complex (±)-1c
Prepared from diyne 7 according to the General procedure.
1
Yield: 61.4 mg (25%). M.p. = 74.4 °C; H-NMR (400 MHz,
CD2Cl2): 2.57-2.43 (m, 4H), 1.84-1.81 (m, 4H), 1.68 (s, 3H), 0.26
(s, 9H); 13C-NMR (100 MHz, CD2Cl2): 210.10, 176.89, 107.04,
81.98, 68.47, 24.81, 23.07, 22.59, 22.43, 8.87, 0.04; IR (film): ν
= 2950.6, 2056.7, 1996.0, 1635.3, 1447.3, 1247.7, 1087.7, 845.6,
761.7, 698.1, 654.7, 618.1 cm-1; HRMS (ESI+): m/z 361.0552
[M+H]+ (calcd. for C32H27FeO4: 361.0559).
4.5.3. Complex (±)-1d
Prepared from diyne 9 according to the General procedure.
1
spectrometer, using 2.1 × 10-5
M solutions in CHCl3.
Yield: 90.7 mg (25%). M.p. = 58.5 °C; H-NMR (400 MHz,
CD2Cl2): 2.52-2.47 (m, 4H), 1.84-1.79 (m, 4H), 1.64 (s, 3H), 1.01
(t, J = 7.84 Hz, 9H), 0.88-0.81 (m, 6H); 13C-NMR (100 MHz,
CD2Cl2): 210.10, 176.82, 107.28, 107.17, 82.08, 67.19, 25.36,
23.15, 22.54, 22.43, 8.91, 7.91, 4.36; IR (film): ν = 2951.5,
2874.4, 2056.7, 1996.0, 1979.6, 1636.3, 1446.4, 1293.0, 1240.0,
1143.6, 1004.7, 784.9, 732.8, 699.1, 617.1 cm-1; HRMS (ESI+):
calcd. for C19H27FeO4Si [M+H], found. HRMS (ESI+): m/z
403.1018 [M+H]+ (calcd. for C32H27FeO4: 403.1028).
4.6.1. Complex (S)-1a
[α]D22 = -20.82 (c = 0.061 in CHCl3).
4.6.2. Complex (R)-1d
[α]D20 = -16.22 (c = 0.018 in CHCl3).
4.5.4. Complex (±)-1e
Prepared from diyne 10 according to the General procedure.
Yield: 49.3 mg (13%). M.p. = 86.4 °C; H-NMR (400 MHz,
4.7. Single crystal XRD analysis of compound (S)-1a
1
X-ray quality sample was selected at the optical microscope,
resulting in pale-yellow prisms with dimensions of about 0.15 ×
0.10 × 0.10 mm. A crystal of (S)-1a, deriving from the first
fraction obtained by enantiomer resolution by enantioselective
HPLC, was mounted on a Bruker AXS APEXII CCD area-
detector diffractometer, at room temperature, for the unit cell
determination and data collection. Graphite-monochromatized
MoKα (λ = 0.71073 Å) radiation was used with the generator
working at 50 kV and 30 mA. Orientation matrixes were initially
obtained from least-squares refinement on ca. 300 reflections
measured in three different ω regions, in the range 0° < θ < 23°;
cell parameters were optimized on the position, determined after
integration, of ca. 7000 reflections. The intensity data were
retrieved in the full sphere, within the θ limits reported in the
crystal data section, from 1080 frames collected with a
sample−detector distance fixed at 5.0 cm (50 s frame−1; ω scan
method, ꢁω = 0.5°). An empirical absorption correction was
applied (SADABS) [24]. Crystal structure was solved by direct
methods using SHELXT2017 and refined with SHELXL-2017/1
[25] within the Wingx suite of programs [26]. Hydrogen atoms
were riding on their carbon atoms. Anisotropic temperature
factors were assigned to all non-hydrogen atoms. Crystal data
collection and refinement parameters are listed in the
Supplementary data and in the cif files. An ORTEP [27] view of
the molecules with the full numbering scheme is given in Fig. S1
and S2. Selected distances of bond lengths (Å) and angles (°) are
given in Table S1, while atomic coordinates and displacement
parameters are listed in the corresponding cif file.
CD2Cl2): 2.60-2.52 (m, 4H), 1.88-1.78 (m, 4H), 1.64 (s, 3H),
1.49-1.41 (m, 3H), 1.16 (t, J = 7.88 Hz, 18H); 13C-NMR (100
MHz, CD2Cl2): 210.12, 176.55, 107.96, 106.46, 81.60, 69.92,
26.28, 23.43, 22.42, 22.40, 19.85, 19.82, 18.99, 13.10, 8.96; IR
(film): ν = 2945.7, 2865.7, 2057.7, 1997.9, 1980.5, 1632.5,
1446.4, 1385.6, 1365.4, 1289.2, 1254.5, 1139.7, 1070.3, 1021.1,
881.3, 729.0, 687.5, 665.3, 618.1 cm-1; HRMS (ESI+): HRMS
(ESI+): m/z 445.1493 [M+H]+ (calcd. for C32H27FeO4: 445.1498).
4.5.5. Complex (±)-1f
Prepared from diyne 11 according to the General procedure.
1
Yield: 149.3 mg (33%). M.p. = 90.8 °C; H-NMR (400 MHz,
CD2Cl2): 7.25-7.16 (m, 15H), 2.60-2.51 (m, 2H), 1.81-1.70 (m,
2H), 1.63 (s, 3H), 1.56-1.46 (m, 2H), 1.30-1.19 (m, 2H); 13C-
NMR (100 MHz, CD2Cl2): 210.39, 174.29, 146.61, 131.80,
127.83, 127.10, 104.03, 101.74, 95.58, 78.84, 60.61, 24.21,
23.75, 22.67, 21.86, 8.94; IR (film): ν = 3057.6, 2932.2, 2054.8,
1994.0, 1647.9, 1491.7, 1445.4, 1034.6, 854.3, 755.0, 736.7,
699.1, 613.3 cm-1; HRMS (ESI+): m/z 531.1254 [M+H]+ (calcd.
for C32H27FeO4: 531.1259).
4.6. Resolution of complexes 1a and 1d by chiral semipreparative
HPLC and ECD spectra registration
The analytical liquid chromatography was performed on an
HPLC equipped with a Rheodyne model 7725i 20 ꢀL loop
injector, a PU-1580-CO2 and PU-980 Jasco HPLC pumps, a UV
detector Jasco-975, and a circular dichroism detector Jasco 995-
CD. Chromatographic data were collected and processed using
Borwin software (Jasco Europe, Italy). The semipreparative
CCDC number 1885148 contains the full supplementary
crystallographic data for this work. The latter can be obtained
free of charge from the Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
liquid chromatography was performed on
a
Waters
chromatograph (WatersAssociates) equipped with a 200 µL loop
injector, a UV SpectroMonitor 4100 spectrophotometer, and a
refractive index detector. Racemic complex (±)-1a were resolved
by semipreparative HPLC, using a (R,R)-DACH-DNB column
(250 mm × 10 mm L. × I.D.), a mixture of n-hexane/DCM 80:20
+ 2% MeOH v/v was employed as eluent (flow rate 4.0 mL/min
and Tcol. = 25 °C). The sample of (±)-1a was dissolved in the
mobile phase (c = 20 mg/mL); each injection was 100 µL
Crystal data for compound name: C27H18FeO4, fw = 462.26 g mol-
1, orthorhombic P212121 (No. 19), a = 9.1937(5), b = 12.5845(6)
and c = 19.2348(10) Å; V = 2225.4(2) Å3; Z = 4; Mo-Kα λ =
0.71073 Å; T (K) 293(2); ρcalc = 1.38 g cm-3, ꢀ(Mo-Kα) = 0.708
mm-1; θ range 1.934-31.685 °; Limiting indices -13≤ h ≤13, -18≤
k ≤18, -28≤ l ≤27; data (unique), 6992 (6191); restraints, 0;
parameters, 289; Goodness-of-Fit on F2, 1.015; R1 and wR2

8
Tetrahedron
(I>2σ(I)), 0.0279 and 0.0676; R1 and wR2 (all data), 0.0349 and
2,2,2-Trifluoro-1-phenylethan-1-ol (P3) [14]
Conversion was determined by 1H NMR, the product was
purified by flash chromatography (hexane/ethyl acetate = 9/1)
and then analyzed by enantioselective HPLC [14].
HPLC conditions of e.e. determination: column: Chiralcel OD-H,
0.8 mL/min, 95:5 hexane/iPrOH, λ = 210 nm, tS = 12.7 min, tR =
21.5 min.
ACCEPTED MANUSCRIPT
0.071; Flack parameter, 0.003(3); Largest Diff. Peak and Hole (e
Å–3), 0.261 and -0.212.
4.8 Simulation of ORD and CD spectra for the (R) enantiomer of
1d.
The chiroptical properties of the enantiomers of 1d were
estimated by molecular modelling calculations performed in two
steps. In the first step the structure of the (R)-1d enantiomer was
optimized at the B3LYP/6-31G* level of theory using the
computer program SPARTAN 10v1.1.0 (Wavefunction Inc.,
18401 Von Karman Avenue, Suite 370, Irvine, CA 92612, USA).
In the second step, by resorting to the Amsterdam Density
Functional (ADF) package v. 2007.01, the optimized structure of
(R)-1d was subjected to assessment of chiroptical properties,
represented by the Optical Rotatory Dispersion (ORD) and the
Electronic Circular Dichroism (ECD) spectra. Optical Rotation
values [α]n at four different wavelengths n, in the range 320-589
nm, were assessed using the BLYP method, employing the QZ4P
large core basis set, as implemented in ADF. Always starting
from the same optimized (R)-1d geometry, and again resorting to
the ADF program, further calculations were also performed in
order to simulate the relevant ECD spectrum. To this end, the set
options were: single point calculation at the BLYP level of
theory, employing the QZ4P large core basis set; 40 singlet and
triplet excitations; diagonalization method: Davidson; velocity
representation; scaling factor 1.00; peak width 31.0. It was found
that, from comparison with the relevant experimental ECD and
ORD spectra, the first-eluted enantiomer of 1d under the
CSP/mobile phase conditions explored in the study had the R
configuration. As a consequence, S configuration was assigned to
the second-eluted enantiomer.
GC conditions for determining conversion and e.e. were also
established. Capillary column: MEGA-DEX DAC Beta, diacetyl-
tert-butylsilyl-β-cyclodextrin, 0.25 ꢀm; diameter = 0.25 mm;
length = 25 m; carrier: hydrogen; inlet pressure: 1 bar; oven
temperature: 100 °C for 20 min: tsubstrate = 1.38 min; tS = 8.97 min,
tR = 10.23 min;
1-Phenylpropan-1-ol (P4)
Conversion and e.e. were determined by chiral GC [4e,f].
Capillary column: MEGA-DEX DAC Beta, diacetyl-tert-
butylsilyl-β-cyclodextrin, 0.25 ꢀm; diameter = 0.25 mm; length =
25 m; carrier: hydrogen; inlet pressure: 1 bar; oven temperature:
120 °C for 15 min: tsubstrate = 2.91 min; tR = 3.45 min; tS = 3.58
min.
1-(Naphthalen-2-yl)ethan-1-one (P5)
Conversion and e.e. were determined by chiral GC [4e,f].
Capillary column: MEGA-DEX DAC Beta, diacetyl-tert-
butylsilyl-β-cyclodextrin, 0.25 ꢀm; diameter = 0.25 mm; length =
25 m; carrier: hydrogen; inlet pressure: 1 bar; oven temperature:
150 °C for 20 min: tsubstrate = 9.23 min; tR = 14.89 min; tS = 16.07
min.
3,4-Dihydronaphthalen-2(1H)-one (P6)
Conversion and e.e. were determined by chiral GC. Capillary
column: MEGA-DEX DAC Beta, diacetyl-tert-butylsilyl-β-
cyclodextrin, 0.25 ꢀm; diameter = 0.25 mm; length = 25 m;
carrier: hydrogen; inlet pressure: 1 bar; oven temperature: 110 °C
for 40 min: tR = 18.74 min; tS = 19.43 min; tsubstrate = 26.03 min.
Absolute configurations were assigned by comparing the sign of
4.9. General Procedure for the AH of ketones and ketimines
Under argon atmosphere, the pre-catalyst was dispensed as
DCM solution into oven-dried glass tubes fitted in an aluminum
block inside a Schlenk tube. After removing DCM under vacuum,
23
optical rotation with literature data ([α]D = -51.4, c 0.70 in
CHCl3, 82% e.e., S) [28].
a 0.2
M solution of Me3NO in iPrOH (0.1 mL, 0.002 mmol) was
dispensed. The resulting mixture was stirred at room temperature
for 20 min, during which a deep orange color gradually
developed. iPrOH (0.3 mL) and the substrate (0.2 mmol) were
added in each vial. Each vial was capped with a Teflon septum
pierced by a needle, the block was transferred into the autoclave,
and stirring was started. After purging four times with hydrogen,
the reaction was pressurized at 50 bar and heating was started
(80 °C). The reactions were stirred for 22 h under hydrogen
pressure at 80 °C. After cooling down to room temperature, the
mixtures were filtered through a short part of celite and then
analyzed for conversion and e.e. determination. When needed,
product purification was carried out by flash column
chromatography (hexane/AcOEt eluent mixtures).
4.9.2. Analysis of ketimine AH products
1
Conversions were determined by H NMR analysis of the
crude reaction mixtures. After purification by flash
chromatography (hexane/ethyl acetate/triethylamine, 89.6/10/0.4),
the enantiomeric excesses were determined by HPLC analysis
with a chiral column.
4-Methoxy-N-(1-phenylethyl)aniline (P2) [4b]
Column: Chiralpak AD-H, 0.8 mL/min, 97:3 hexane/iPrOH, λ
= 210 nm, tR = 11.79 min, tS = 13.40 min. Absolute configuration
was determined by comparison of the sign of optical rotation
15
with literature data ([α]D = +8.5, c 0.9 in CHCl3, 98% e.e., R)
[29].
4.9.1. Analysis of ketone AH products
4-Methoxy-N-(1-(naphthalen-2-yl)ethyl)aniline (P7) [4b]
Column: Chiralcel OD-H, 0.5 mL/min, 9:1 hexane/iPrOH, λ =
210 nm, tR = 15.70 min, tS = 17.73 min. Absolute configuration
was determined by comparing the elution order with previous
data obtained with the same column [29a].
The reaction mixtures were analyzed either by GC with a
chiral column or by 1H NMR / enantioselective HPLC to measure
conversion and enantiomeric excess. Absolute configurations
were determined by comparing the elution order with previous
data obtained with the same column, unless otherwise stated.
4-Methoxy-N-(1-phenylpropyl)aniline (P8) [4b]
1-Phenylethanol (P1)
Column: Chiralcel OD-H, 0.8 mL/min, 98:2 hexane/iPrOH, λ =
210 nm, tR = 10.66 min, tS = 11.90 min. Absolute configuration
was determined by comparing the elution order with previous
data obtained with the same column [29a].
Conversion and e.e. were determined by chiral GC [4e,f].
Capillary column: MEGA-DEX DAC Beta, diacetyl-tert-
butylsilyl-β-cyclodextrin, 0.25 ꢀm; diameter = 0.25 mm; length =
25 m; carrier: hydrogen; inlet pressure: 1 bar; oven temperature:
95 °C for 20 min: tsubstrate = 4.76 min; tR = 10.36 min; tS = 12.39
min.
4-Methoxy-N-(octan-2-yl)aniline (P9) [4b]
Column: Phenomenex Cellulose 3 (5 ꢀm), 0.5 mL/min, 100:1
hexane/iPrOH, λ = 210 nm, tR = 14.93 min, tS = 15.57 min.

9
Absolute configuration was determined by comparing the elution
order with previous data obtained with the same column [29a].
ACCEPTED MANUSCRIPT
(e) P. Gajewski, M. Renom-Carrasco, S. Vailati Facchini, L.
Pignataro, L. Lefort, J.G. de Vries, R. Ferraccioli, U. Piarulli, C.
Gennari, Eur. J. Org. Chem. (2015) 5526-5536;
Acknowledgments
(f) P. Gajewski, M. Renom-Carrasco, S. Vailati Facchini, L.
Pignataro, L. Lefort, J.G. de Vries, R. Ferraccioli, A. Forni, U.
Piarulli, C. Gennari, Eur. J. Org. Chem. (2015) 1887-1893.
[5] (a) A. Lator, S. Gaillard, A. Poater, J.-L. Renaud, Chem. Eur. J. 24
(2018) 5770-5774;
X. Bai thanks the China Scholarship Council for a PhD
fellowship (CSC No. 201608410107). L. Pignataro thanks the
Dipartimento di Chimica, Università degli Studi di Milano, for
financial support (Piano di Sostegno alla Ricerca 2015–2017).
We thank Prof. F. Gasparrini of “Sapienza” Università di Roma
for inspiring discussions and Mr. Andrea Dell’Acqua for
experimental assistance.
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Supplementary material
(e) D. S. Mérel, M. Elie, J.-F. Lohier, S. Gaillard, J.-L. Renaud,
ChemCatChem 5 (2013) 2939-2945;
(f) S. Fleischer, S. Zhou, K. Junge, M. Beller, Angew. Chem. Int.
Ed. 52 (2013) 5120-5124;
Supplementary data associated with this article can be found,
in the online version, at …….
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10
Tetrahedron
ACCEPTED MANUSCRIPT
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