Mechanistic investigations of the asymmetric hydrosilylation of ketimines with trichlorosilane reveals a dual activation model and an organocatalyst with enhanced efficiency

Article abstract of DOI:10.1039/c6ob02537d

Structural probes used to help elucidate mechanistic information of the organocatalyzed asymmetric ketimine hydrosilylation have revealed a new catalyst with unprecedented catalytic activity, maintaining adequate performance at 0.01 mol% loading. A new ‘dual activation’ model has been proposed that relies on the presence of both a Lewis basic and Br?nsted acidic site within the catalyst architecture.

Full text of DOI:10.1039/c6ob02537d

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: X. Li, A. Reeder, F.
Torri, H. Adams and S. Jones, Org. Biomol. Chem., 2017, DOI: 10.1039/C6OB02537D.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Organic & Biomolecular Chemistry
ARTICLE
Mechanistic investigations of the asymmetric hydrosilylation of
ketimines with trichlorosilane reveals a dual activation model and
an organocatalyst with enhanced efficiency
Received 00th January 20xx,
Accepted 00th January 20xx
X. Li,a A. T. Reeder,a F. Torri,a H. Adamsa and S. Jones*a.
DOI: 10.1039/x0xx00000x
Structural probes used to help elucidate mechanistic information of the organocatalyzed asymmetric ketimine
hydrosilylation have revealed a new catalyst with unprecedented catalytic activity, maintaining adequate performance at
0.01 mol% loading. A new ‘dual activation’ model has been proposed that relies on the presence of both a Lewis basic and
Brønsted acidic site within the catalyst architecture.
www.rsc.org/
ring system was first investigated. A series of N-substituted
Introduction
imidazoles and their corresponding dimethylamides were
prepared. 1-Methylimidazole
1
is commercially available,
The organocatalyzed asymmetric hydrosilylation of ketimines
provides an effective method to prepare chiral amines in good
yield and enantioselectivity. Since the first chiral Lewis-base
derived catalyst was reported in 2001,1 there have been many
variants of catalyst prepared and evaluated;2,3 selected
examples include formamides,4–7 sulfinimides,8,9 pyridines,10–12
and organophosphorus compounds.13–15 The main focus of
research from this group has been using an imidazole derived
catalyst that has been shown to function as efficiently as the
reported analogous picolinoyl series,16 in addition to being
amenable to reductive amination protocols.17 Despite it being
more than a decade since the first asymmetric catalysts for
this type of transformation were reported, mechanistic data
and insights have been sporadic, and only tentative models
have been put forward to explain the selectivity.18 The most
comprehensive study to date is that put forward by Malkov et
al.,19 crucially noting the dependence of adventitious Brønsted
acids to ensure the success of these reactions. Given the
scarcity of mechanistic detail for these catalytic processes, a
more in depth structural analysis of the imidazole catalyst
system developed in these laboratories has now been
conducted, providing new insights into the mechanism of this
process, and has delivered a new catalyst with even higher
activity.
whereas 1-tert-butylimidazole
2 was prepared by condensing a
mixture of glyoxal, aqueous formaldehyde, aqueous ammonia
and tert-butylamine.20 These were converted to the
dimethylamides
3 and 4 by deprotonation with n-BuLi and
quenching with dimethylcarbamoyl chloride (Scheme 1), and
evaluated in a benchmark HSiCl3 reduction of the N-PMP
acetophenone ketimine
5 under a standard set of reaction
conditions by removing aliquots and analyzing the conversion
1
by H NMR spectroscopy (Figure 1). N,N-Dimethyl benzamide
was included as a benchmark to compare the role of the
imidazole nitrogen atom.
Me2N
O
O
n-BuLi, THF, -78 oC
R
N
N
NMe2
R
N
N
then ClCONMe2
R = Me, 1
R = t-Bu, 2
R = Me, 3 36%
R= t-Bu, 4 43%
-Dimethyl
N,N
benzamide
PMP
10 mol% catalyst
2 equiv HSiCl3
PMP
Me
N
HN
Ph
Me
DCM, 0 oC
Ph
6
5
Scheme 1. Synthesis and evaluation of imidazole catalysts
benzamide.
1–
4
and N,N-dimethyl
Results and discussion
The data obtained show slightly different reactivities between
and but this may be due to
The role of the Lewis basic amide in relation to the imidazole the N-Me and N-t-Bu catalysts
1
2
the N-Me catalyst not being completely soluble in DCM.
However, what is noticeable is the significant difference in
reaction rate between the two model dimethylamide catalysts;
the N-Me catalyst
3 showed a significant increase in relative
reaction rate compared to the parent imidazole, whilst the N-t-
Bu catalyst
4
reaction rate dropped. This leads to the relative
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 14
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
Journal Name
initial rate of the N-Me catalyst being of the order of 4 times coordinated catalyst were still present compared to the N-Me
faster than that of the N-t-Bu one. By comparison to the catalyst and this ratio did not change with time, or when a
3
imidazole catalysts, N,N-dimethyl benzamide was a very poor further equivalent of HSiCl3 was added. This suggests that
catalyst, barely operating above the background reaction rate coordination of this catalyst to HSiCl3 is more difficult than in
for these type of processes.
the case of the N-Me catalyst 3, and that steric effects of the
imidazole N-alkyl group play an important role in the activity of
such catalysts. In complete contrast, N,N-dimethyl benzamide,
showed no change in the carbonyl group signal, correlating
with its poor reactivity.
N-Me imidazole dimethylamide 3
N-t-Bu imidazole 2
100
80
60
40
20
0
For this series of compounds, it seems that the extent of
coordination of the HSiCl3 with the carbonyl group is a
reasonable measure of catalytic activity. The N-Me and N-t-Bu
catalysts are likely to incur different and significant energetic
penalties for the interaction of the amide N-methyl groups
with the imidazole alkyl substituent, in either case probably
ruling out a truly co-planar species 7a. This probably favours a
stable conformation that places the carbonyl group and
imidazole ring orthogonal to each other i.e. structure 7b in
N-t-Bu imidazole dimethylamide 4
N-Me imidazole 1
N,N-Dimethyl benzamide
Figure
2 (note that these are depicted as reactive
conformations, not active catalytic species that might be
protonated at the imidazole nitrogen atom, vide infra). The
increasing torsional angle then in-turn increases the distance
of the silicon and imidazole nitrogen atoms, reducing
reactivity, fitting well with observations with the N,N-dimethyl
benzamide system, lacking any cooperative effect of the
imidazole nitrogen atom.
0
100
200
300
400
Time / min
Figure 1. Relative reaction rates of imidazole catalysts
1
–
4
and N,N-dimethyl
benzamide. Reactions performed using 10 mol% catalyst, 2 equiv HSiCl3 in DCM
(1 mL mmol-1) at 0 oC. Conversion calculated from comparison of appropriate
integrals in 1H NMR spectrum of aliquots removed from reaction.
In order to probe this further, both dimethylamide catalysts
and were studied using in-situ infra-red experiments. The
absorption signal of the carbonyl group of N-Me catalyst in
3
Me
Me
4
Me
Me
N
Me
N
N
N
Me
N
3
N
R
R
DCM initially appeared at 1635 cm-1 and after addition of one
equivalent of HSiCl3, a new signal immediately appeared at
1668 cm-1, while the original signal at 1635 cm-1
simultaneously disappeared (Figure 3). Addition of further
equivalents of HSiCl3 led to no additional change other a
dilution effect (observed in the slight drop of the signal at 1668
cm-1 after 8 mins). This suggests that coordination of HSiCl3
with the amide is rapid and complete for this catalyst. In the
R
O
O
HSiCl3
O
Cl
Cl
Cl
Cl
Si
N
Si
N
N
H
Cl
H
Cl
7a
Cl
Cl
Cl
Me
N
H
Si
R
O
O
N
Me
Me
Me
Me
R
R
N
HSiCl3
N
N
N
N
O
Me
N
N
case of the N-t-Bu catalyst 4, the original signal of the carbonyl
HCl3Si
7b
group was at 1645 cm-1 with a smaller new signal appearing at
1671 cm-1 once treated with one equivalent of HSiCl3.
Noticeably, in this case significant amounts of the un-
R = Me, -Bu
t
Figure 2. Reactive conformations of catalysts 3 & 4.
Figure 3. From left to right; in-situ IR data of N-Me catalyst 3 treated with HSiCl3 as a function of time; in-situ IR data of catalyst N-t-Bu 4 treated with HSiCl3 as a
function of time; in-situ IR data of N,N-dimethyl benzamide treated with HSiCl3 as a function of time.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 3 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Organic & Biomolecular Chemistry
ARTICLE
t-Bu
Ph
Ph
O
O
N
O
-BuLi
(COCl)2, DMF
n
KOH
13, NEt3
2
then
DCM, rt to reflux
N
R
OH
DCM, rt
OH
~90%
R
Cl
N
OEt
ClC(O)OEt
37%
O
8
9 - 11
R
KOH
57%
14 25%; 15 54%
16 26%; 17 - prepared as
Ph
in reference 16
Me
Ph
N
H
O
N
R =
Me
t-Bu
Me
N
OH
N
N
N
13
OMe
N
12
N
N
Me
9, 14
10, 15
11, 16
17
Scheme 2. Synthesis of catalysts 14–17.
Naturally, these catalyst fragments lack the prolinol moiety catalyst 4, perhaps unsurprisingly the N-t-Bu catalyst 16 was
that might have synergistic effects when considering the whole essentially inactive, the 15% conversion being typical of the
catalyst system. Thus any speculation about mechanism for background reaction rate for this process. None of these
these simple amides might not directly translate to more surpassed the performance of the previously reported catalyst
complex systems. Thus, in order to further probe such 17. This compares well with the findings with the simple,
interactions, a series of chiral heterocyclic catalysts were achiral catalysts
3 and 4, whereby torsional freedom around
investigated containing a prolinol derived backbone that were the imidazole – carbonyl bond to appropriately locate the
prepared starting from their parent carboxylic acids. Thus, 1- imidazole nitrogen atom is critical for high catalytic activity.
methylimidazole-4-carboxylic acid
9 is commercially available, The previously reported development of the imidazole catalyst
and 1-methylpyrrole-2-carboxylic acid 10 was obtained by 17 clearly demonstrated some key requirements in order to
hydrolysis of the methyl ester 12 with aqueous potassium obtain both high yields and selectivity.16 Most critical for
hydroxide. 1-t-Butylimidazole-4-carboxylic acid 11 was obtaining high selectivities was use of a gem-diaryl group. This
accessed by deprotonation of 1-t-butylimidazole
then quenching with ethyl chloroformate to give the ester
followed by basic hydrolysis. These three heterocyclic environment that facilitates the required facial differentiation
carboxylic acids 11 were transformed into the respective of the planar ketimine.
acid chlorides with oxalyl chloride, followed by immediate
coupling with α,α-diphenylprolinol 13 giving catalysts 14 16
2
with n-BuLi most likely relays stereochemical information from the
8,
adjacent proline stereogenic center to create chiral
a
9–
Ph
Ph
OH
Ph
Ph
OH
Ph
–
,
Ph
OH
with previously reported catalyst 17 being prepared by a
similar method as previously described (Scheme 2).16
N
N
N
Me
t-Bu
O
O
O
N
N
All of these new catalysts were then evaluated under the
standard set of reaction conditions (Scheme 1, Figure 4). The
isomeric imidazole 14 was active but led to poor selectivity
N
Me
N
N
14
15
16
100% conv.
-31% ee
19% conv.
0% ee
15% conv.
0% ee
delivering the opposite enantiomer of product amine
6 to that
normally observed. Given the torsional freedom that this
isomeric system has compared to the parent imidazole catalyst
17, it is likely that an alternative reactive conformation may be
accessible in this case, perhaps even a co-planar species
analogous to 7a, resulting in a competitive pathway with a
different stereochemical bias. The N-Me pyrrole catalyst 15
was essentially inactive which is interesting as it indicates that
the amide functionality alone is not sufficient to promote this
reaction. Based on the kinetic data for the dimethylamide
Ph
Ph
N
OH
Me
O
N
100% conv.
90% ee
17
N
From previous work
Figure 4. Evaluation of prolinol catalysts 14–17 according to Scheme 1.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Organic & Biomolecular Chemistry
ARTICLE
Evaluation in asymmetricreduction of N-PMP-ketimine 5 (Scheme 1)
Me
Ph
Ph
OH
H
N
O
Me
Me
OH
H
N
Me
Me
N
OH
N
OEt
N
(i) Mg, MeI
OMe
Me
Me
20
Me
N
N
H
O
O
O
N
N
N
(ii) KOH, EtOH
H2O
O
OH
NaH
toluene
EtO
O
N
N
N
18
19
17
22
21
72%
39%
84% conv.
47% ee
100% conv.
46% ee
100% conv.
90% ee
This work
From previous work
as shown in Scheme 1.
Figure 5. Synthesis of catalyst 21 and comparison of activity with previous catalysts in the reduction of N-PMP ketimine
5
In order to investigate this further, the gem-dimethyl catalyst 25 but led to poor selectivity compared to the parent catalyst
21 was prepared by coupling (S)-α,α-dimethylprolinol 19 23, inferring the need for a hydrogen bond to effectively
(obtained from reaction of ester 18 with an excess of MeMgI, coordinate with the ketimine substrate, leading to the
followed by hydrolysis) with ethyl N-methyl imidazole-1- commonly accepted model shown.12 In order to compare this
carboxylate 20 and evaluated in the benchmark reduction of effect in the imidazole series, removal of the hydrogen bond
the N-PMP-ketimine of acetophenone
5 (Figure 5, Scheme 1). acceptor was achieved by methylation of catalyst 17 with
Noticeably, although the conversion to product was sodium hydride and methyl iodide giving the O-Me catalyst 26
approximately the same as other catalysts previously in 56% yield (Scheme 3). For comparison purposes,
prepared, the enantioselectivity was lower than that of the Matsumura’s picolinic acid derived catalyst 23 was prepared
gem-diaryl catalyst 17, and similar to the catalyst 22 without from commercially available 2-picolinic acid by treating with
the gem-dimethyl group. Thus, the role of this component may oxalyl chloride, then reaction with α,α-diphenylprolinol 13
not simply be steric, an effect that has been previously This was also O-methylated in analogous fashion to give
documented for gem-diaryl groups.21
catalyst 27 in 83% yield. These catalysts were then evaluated
In the final stages of catalyst evaluation, the role of the in the benchmark reduction of the N-PMP ketimine , each
.
5
hydroxyl group was examined. Matsumura’s work had being challenged at low catalyst loadings to better determine
previously shown that the deoxy-picoline derivative 24 efficacy (Table 1). Commercially available Sigamide® 28 was
catalyzed the asymmetric hydrosilylation of N-phenyl ketimine also included to provide
a
frame of reference.
N
N
Ph
Ph
H3C
N
O
Ph
10 mol% catalyst
1.5 equiv HSiCl3
Ph
H
O
N
HN
HO
23
H
O
73% ee (S)-enantiomer
DCM, 0 oC
Ph
Me
Cl
Cl
N
Ph
Me
Si
Cl
25
N
N
N
Ph
Ph
Matsumura'smodel
O
24
H
13% ee ( )-enantiomer
R
Ph
Ph
Ph
Ph
Ph
OMe
t-Bu
O
Ph
OH
(COCl)2
NaH
N
N
NaH
MeI
OMe
Me
N
O
N
17
OH
MeI
Me
then 13
O
23
O
O
N
N
H
t-Bu
N
56%
83%
66%
O
i-Pr
N
N
N
27
28
26
Scheme 3. Matsumura’s picolinoyl catalysts 23
&
24 and selectivity model, synthesis of O-methyl catalysts 26
&
27, and structure of Sigamide® 28.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 4
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 5 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Organic & Biomolecular Chemistry
ARTICLE
similar trend was observed with the picoline catalysts 23 and
27 although not at the same performance level as the
imidazole ones (entries 7-10). Under the conditions used,
Sigamide® 28 did not perform as well as the other catalysts
(entry 11).
Table 1. Evaluation of catalysts 17, 23, 26–28 according to the reaction shown in
Scheme 1.a
Entry Catalyst
Catalyst loading
(mol %)
Conversion
(%)b
ee (%)c
ACEd
The enhanced catalytic activity of catalyst 26 was exemplified
with a small representative selection of ketimines 29–33, with
1
17
26
1
100
88
90
87
80
91
89
84
79
56
62
NDe
80
56
2
0.1
0.01
1
481
3018
58
3
60
conversion and enantioselectivities of the product amines 34
–
4
100
100
96
38 comparable to those obtained at higher loading using
catalyst 17 (Scheme 4, Table 2). Given the structural similarity
of these catalysts it is not surprising that the
stereodifferentiating elements result in comparable
selectivities and further exemplification and optimisation of
reaction parameters was not carried out.
5
0.1
0.01
1
538
4881
50
6
7
23
27
100
100
95
8
1
34
9
0.1
0.01
1
359
10
11
25
28
60
31
R2
R2
Catalyst 17 or 26
N
HN
R1
34-38
a
HSiCl3 (2 equiv)
Reactions conducted with N-PMP-ketimine 5 (1 mmol), HSiCl3 (2 mmol) at the
specified catalyst loading in DCM (0.5 mL) at 0 oC for 4 h, followed by aqueous
R1
29-33
Scheme 4. Substrate scope with catalysts 17 and 26.
b
DCM, 0 °C, 4 h
workup; Conversion calculated by comparison of the value of the integrals for
c
the product to residual ketimine and ketone (from hydrolysis); Determined by
chiral phase HPLC analysis; d See reference 22; e Not determined.
Imidazole derived catalyst 17 performed as expected, its
reactivity dropping off slightly with reduced loading, but still
acting in a reasonably stereoselective manner (Table 1, entries
1-3). However, completely unexpectedly, methylated
imidazole catalyst 26 showed superior activity and selectivity
at even as low as 0.01 mol% loading (entries 4-6). Calculation
and comparison of the Asymmetric Catalytic Efficiency (ACE)22
factor at each of the catalyst loadings highlights the
exceptional activity of methoxy catalyst 26 at low catalyst
loading (Table 1, compare entries 3 & 6). Given the accepted
hypothesis of the importance of the hydrogen bond, this is a
remarkable and unprecedented result. Interestingly, a broadly
The remarkable and unexpected catalyst activity, presumably
due to the absence of the hydrogen bond, warranted further
investigation. The difference in hydroxy and methoxy catalysts
1
17 and 26 is first evident from their H NMR spectra. Hydroxy
catalyst 17 has a very broad and almost uninterpretable
spectrum in CDCl3 at room temperature and is best recorded in
o
DMSO at 100 C in order to obtain the best resolution signals,
presumably due to the presence of an internal hydrogen bond,
although this is not evident in the single crystal X-ray crystal
structure (see electronic supplementary information). In
contrast, methoxy catalyst 26 provides a much better resolved
Table 2. Substrate scope of catalysts 17 and 26 according to the reaction shown in Scheme 4 a
Entry
Catalyst (loading / mol %)
R1
R2
imine
amine
Conversion (%)b
ee (%)c
1
2
26 (0.1)
17 (1)
Ph
4-FC6H4
29
29
30
30
31
31
32
32
33
33
34
34
35
35
36
36
37
37
38
38
95
96
97
81
98
85
77
61
99
86
86
87
84
85
84
86
80
79
92
86
Ph
4-FC6H4
3
26 (0.1)
17 (1)d
26 (0.1)
17 (1)d
26 (0.1)
17 (1)e
26 (0.1)
17 (1)d
4-MeOC6H4
4-MeOC6H4
4-NO2C6H4
4-NO2C6H4
2-Thienyl
2-Thienyl
β-Naphthyl
β-Naphthyl
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4
5
6
7
8
9
10
a
b
Reactions conducted with ketimine (1 mmol), HSiCl3 (2 mmol) at the specified catalyst loading in DCM (0.5 mL) at 0 oC for 4 h, followed by aqueous workup;
Conversion calculated by comparison of the value of the integrals for the product to residual ketimine and ketone (from hydrolysis); c Determined by chiral phase HPLC
analysis; d Literature values, see reference 16; e Using reductive amination protocol, see reference 17.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 6 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Organic & Biomolecular Chemistry
ARTICLE
spectrum at room temperature in CDCl3, existing as two
rotameric forms in a 4.5:1 ratio.
100
80
60
40
20
In an attempt to elucidate the mechanism further, the
relationship of product ee and catalyst ee was examined using
the N-PMP-ketimine substrate
5 and hydroxy catalyst 17.
Plotting this gave a linear relationship (Figure 6), indicating
that one molecule of catalyst was involved in formation of the
catalytically active species. Furthermore, the ee of the product
remained constant over the duration of the experiment.
Since the critical unusual feature that was observed in this
catalyst screen related to the hydroxyl group, further efforts
1
were made to examine the chemistry around this centre by H
0
0
20
40
60
80
100
Catalyst ee / %
NMR and 29Si NMR experiments. The reduction of N-PMP
ketimine
5 was performed with HSiCl3 (2 equiv) in CDCl3 with 1
Figure 6. Plot of product 5 ee vs catalyst ee 17.
mol% imidazole catalyst 17
.
Figure 7. In situ 1H and 29Si NMR spectra of reaction products as depicted in Scheme 1 with catalyst 17.
Figure 8. 1H and 29Si NMR spectra of catalyst 17 and excess HSiCl3.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 6
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 7 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Organic & Biomolecular Chemistry
ARTICLE
1
After 4 h, H NMR and 29Si NMR spectroscopy indicated that asymmetric hydrosilylation reaction, and returned unchanged
the main species resulting from the reduction were N-SiCl2H catalyst after work-up. In contrast, no new signals were
amine 39
(
δH 5.55 ppm and δSi -9.7 ppm) and silicon observed in the 29Si NMR spectrum of the methoxy catalyst 26
tetrachloride (δSi -18.9 ppm) (Figure 7). The identity of the when treated with trichlorosilane, which was corroborated by
former species was confirmed by independent synthesis by the presence of only a very small signal at δH 5.27 ppm in the
addition of trichlorosilane to
methylbenzylamine , and the latter by comparison with a observed (Figure 9). However, significant chemical shift
reference sample. It is noticeable that the silicon tetrachloride changes were observed in the imidazole and methine protons,
results from the reaction and is not present in the HSiCl3. in addition to those signals corresponding to the pyrrolidine
a
sample of N-PMP-
α
-
1H NMR spectrum where evidence of a Si-H signal might be
6
When hydroxy catalyst 17 was treated with an excess of ring. As in the case of the hydroxyl-catalyst 17, these changes
1
trichlorosilane, new signals were observed in the H NMR (δH may have resulted from protonation of the imidazole, in this
4.99 ppm) and 29Si NMR (δSi -33.2 ppm) spectra. These signals case from adventitious HCl usually found in HSiCl3.
are consistent with an oxosilane species formed by silylating The presence of HCl and protonation of the catalysts appeared
the hydroxyl group of catalyst 17, confirmed by comparison of to be a key factor in their activity, and related studies have
1
the H and 29Si chemical shifts of the related EtOSiCl2H in the also shown that additives such as water (to form HCl in situ),
literature, including JSi-H coupling of 29Si satellite signals in the acetic acid, and benzoic acid can improve the catalytic
1H NMR spectrum (Figure 8).23 Importantly, the 29Si NMR activity.6,7,9,24,25 As previously indicated, HCl is most likely also
spectrum only provided evidence for a tetra-coordinate silicon present in commercial HSiCl3, and to confirm the effect of this,
atom. The 1H NMR spectrum also shows a significant downfield a series of reactions were performed under diluted conditions
chemical shift of the methine proton adjacent to the amide in order to slow them down sufficiently to observe positive or
nitrogen atom that might result as a combination of the loss of negative effects of the effects of proton sponge, HCl and
the internal hydrogen bond and from complexation of the chloride ions (in the form of n-BuN4Cl). None of these additives
carbonyl group to the silane. The spectrum also has catalysed the reaction in the absence of the catalysts, and
considerably better resolved signals than that obtained for the reactions conducted with the hydroxy 17 and methoxy 26
parent catalyst at room temperature, implying fewer catalysts showed that the presence of HCl was essential for
equilibrating rotameric and / or hydrogen bonded species. In reactivity (Table 3, entries 2 and 7).
retrospect, this is what one would expect from the natural
Table 3. Effect of proton sponge, n-Bu4NCl, and HCl on catalysts 17 and 26 according to
reactivity of a chlorosilane with an alcohol to generate a silyl
reaction shown in Scheme 1.a
ether and HCl. Given the formation of the latter, it is also very
likely that the imidazole of the catalyst will be protonated.
Importantly, this preformed catalyst – trichlorosilane complex
40 demonstrated the same catalytic activity in the standard
Entry Catalyst (loading / mol%) Additive (equiv)
Conversion / %b
1
17 (0.1)
17 (0.1)
17 (0.1)
17 (0.1)
17 (0.1)
26 (0.01)
26 (0.01)
26 (0.01)
26 (0.01)
26 (0.01)
None
57
0
2
Proton sponge (1)
n-Bu4NCl (0.1)
HCl (0.005)
HCl (0.05)
3
61
60
58
13
0
4
5
6
None
7
Proton sponge (1)
n-Bu4NCl (0.1)
HCl (0.005)
HCl (0.05)
8
15
15
16
9
10
a Reactions conducted with N-PMP-ketimine 5 (1 mmol), HSiCl3 (2 mmol) with the
specified additive and catalyst loading in DCM (5 mL) at 0 oC for 1 h, followed by
b
aqueous workup; Conversion calculated by comparison of the value of the
integrals for the product to residual ketimine and ketone (from hydrolysis).
As conducted with catalysts
3 and 4, investigation of the
reactive catalyst species was conducted by in-situ infra-red
analysis (Figure 10 and Figure 11). Upon addition of 1 equiv of
HSiCl3, the hydroxy catalyst 17 shows a rapid and complete
Figure 9. 1H NMR spectrum of catalyst 26 before and after addition of 4 equiv HSiCl3.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 8 of 14
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
Journal Name
Figure 10. In-situ IR data of catalyst 17 treated with HSiCl3 as a function of time.
Figure 11. In-situ IR data of catalyst 26 treated with HSiCl3 as a function of time.
Dual activation with hydroxy catalyst 17
Ph
Ph
Me
Ph
Cl
Si
Ph
N
O
N
H
PMP
Ph
Ph
O
N
N
N
O
Cl
O
Me
HSiCl3
H
SiCl3
N
H
O
Me
Si
N
17
Ph
O
6
H
Cl
Cl
N
N
Cl
N
42
41
Cl3SiH
40
NH Cl
Ph
Ph
MeO
Ph
Ph
Resting state
N
O SiCl2H
HCl
HSiCl3
Me
O
N
O
N
HCl2Si
PMP
Me
SiCl3
O
N
NH
N
39
NH Cl
Ph
SiCl4
Figure 12. Proposed dual activation mechanism for catalyst 17.
change in the stretching frequency of the carbonyl group, activated by a hydrogen bond to the protonated imidazole,
whilst catalyst 26 shows a rapid but incomplete change, and placed in the correct orientation to facilitate hydride
suggesting an equilibrium process. This is very similar to the delivery from the activated siloxane. Importantly, the N-PMP-
behaviour with the simpler catalysts
3 and 4, however the amine product 6 then undergoes reaction with more
reactivity is inverted, with catalyst 26 showing incomplete trichlorosilane to generate the observed N-SiHCl2 product 39
,
complexation being more active. Since no direct reaction with whilst the inactive catalyst 42 turns-over by protonation and
HSiCl3 is possible here as corroborated by 29Si NMR data, the reaction with more trichlorosilane, generating silicon
1
changes in the H NMR and IR data indicate a different resting tetrachloride. This accounts for the observation that the
state for the catalyst, perhaps with the imidazole being reaction slows considerably when using less than 2 equivalents
protonated by the small quantities of HCl present in the HSiCl3. of HSiCl3.
Catalyst 17 reacts stoichiometrically with HSiCl3, in doing so This model essentially inverts that proposed by Matsumura
generating HCl to completely protonate the imidazole.
(Scheme 3), with the crucial hydrogen bond now being located
Based on these results, a new ‘dual activation’ mechanistic at the imidazole nitrogen atom. However, the deoxy catalyst
model is proposed that involves a Lewis basic site to activate 23 may still react via the previously accepted model, especially
the HSiCl3 and an additional Brønsted base capable of reacting as there is some similarity between the sense and magnitude
with HCl generated or present in the reaction (Figure 12). of the selectivity observed with catalyst 14 (Figure 4).
Reaction of the hydroxy catalyst 17 with HSiCl3 provides a The process with methoxy catalyst 26 is more complex since
covalently linked siloxane 40 where the imidazole is no evidence could be obtained for a species whereby HSiCl3 is
1
protonated by HCl, either as a by-product from reaction with bound to the catalyst. Clearly there is a change in the H NMR
the alcohol, or from adventitious HCl in the HSiCl3. This is the and IR data on addition of HSiCl3 that may be due to reaction
resting state for the catalyst that is set up for forming a key with HCl (Figure 13). Naturally this means that no Si-O bond
hydrogen bond with the ketimine substrate.
Coordination of the silane with the Lewis basic amide inferred therefore the catalyst can turn-over more quickly, perhaps
from the in situ infra-red studies must involve twisting of the explaining the enhanced catalytic activity. completely
needs to be broken after reduction of the C=N bond and
A
amide bond to negate steric interactions, leading to a reactive different mechanism is unlikely due to the similar levels of
hexa-coordinate species 41. The ketimine substrate is now enantioselectivity that catalysts 17 and 26 provide.
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 9 of 14
View Article Online
DOI: 10.1039/C6OB02537D
Journal Name
ARTICLE
13C NMR and 29Si spectra were measured using CDCl3 as
solvent unless otherwise stated. 13C NMR spectra were
recorded using the JMOD method. Specific rotations were
measured at 589 nm (Na D-Line) at 20 oC unless otherwise
stated, and are given in 10-1 deg cm2 g-1. All chemicals were
used as received without further purification. Previously
reported methods were used to prepare the following
compounds: N-PMP-ketimine 5, (S)-α,α- diphenylprolinol 13,
N-Me-catalyst 17, (S)-N-ethoxycarbonylproline methyl ester
18, ethyl N-methyl imidazole-1-carboxylate 20, 4-methoxy-N-
[1-(4-nitrophenyl)ethylidene]benzenamine 31, 4-methoxy-N-
Figure 13. Postulated resting state 43 and intermediate in dual activation mechanism
with methoxy catalyst 26.
[1-(2-naphthalenyl)ethylidene]benzenamine 33 16
(1-phenylethylidene)benzenamine 29 4-methoxy-N-[1-(4-
methoxyphenyl)ethylidene]benzenamine 30
N-[1-(2-thienyl)ethylidene]benzenamine 32 19
;
4-fluoro-N-
Such a dual activation model is obviously transferable to the
Matsumura and related picoline systems, the difference in
reactivity probably now coming from the different torsional
freedom and basicity provided by the 2-pyridyl moiety. The
model previously proposed for related N-formamide catalysts
such as Sigamide® 28 also contains key elements of this dual
activation mechanism, with the Brønsted acid now being the
relatively acidic aniline NH proton (Figure 14).
,
26
;
N-4-methoxy-
.
1-t-Butylimidazole 2
The title compound was prepared using a modified literature
procedure.20 A 250 mL three-necked flask containing distilled
water (50 mL) was equipped with two dropping funnels and a
condenser. One dropping funnel was filled with a mixture of
40% aqueous glyoxal (11.5 mL, 0.1 mol) and 37% aqueous
formaldehyde (8.10 g, 0.1 mol), the other with t-butylamine
(10.6 mL, 0.1 mol) and 35% aqueous ammonia (4.86 g, 0.1
mol). The water was heated until boiling, and then both
solutions were added simultaneously at the same addition
rate. The resulting mixture turned brown and was stirred for
30 min at reflux after complete addition, and then cooled to rt.
Cl
Cl
H
O
H
Si
Cl
N
O
N
H
N
The mixture was extracted with DCM (3
× 150 mL), the
combined organic phases were washed with brine (50 mL) and
dried over MgSO4. The desiccant was filtered off and the
filtrate was evaporated. The brown residue was purified by
28
t-Bu
t-Bu
Figure 14. Previously reported model for Sigamide 28 illustrating dual activation.
vacuum distillation to give the product
2 as a colourless oil
(4.80 g, 39%); δH (400 MHz, CDCl3): 1.55 [9H, s, (CH3)3C], 7.03
(1H, s, ArCH), 7.04 (1H, s, ArCH), 7.60 (1H, s, ArCH); δC (100
MHz, CDCl3): 30.6 [C(CH3)3], 54.7 [C(CH3)3], 116.3 (ArCH), 129.1
(ArCH), 134.3 (ArCH); Data were in accordance with the
literature.
Conclusion
In summary, a dual-activation mechanism is proposed for the
organocatalyzed asymmetric hydrosilylation of ketimines. This
model fits the available mechanistic and characterization data
and in doing so has provided an example of a new catalyst
system displaying catalytic activity at unprecedented low levels
of catalyst loading. Computational studies on these systems
may reveal more details to support these studies. This work
should provide valuable insights for the future design and
mechanistic rationale for new catalysts in this area.
1-Methyl-N,N-dimethyl-1H-imidazole-2-carboxamide 327
N-Methylimidazole
(20 mL) and cooled to -78
25 mmol) was added dropwise by syringe. The resulting
mixture was stirred at -78 C for 2 h. This solution was added
dropwise to a solution of dimethylcarbamoyl chloride (2.99 g,
28 mmol) in diethyl ether (25 mL) at -78 C and stirred for 1 h
1
(1.64 g, 20 mmol) was dissolved in THF
°C. n-BuLi (2.5 M in hexanes, 10 mL,
°
°
at the same temperature. The reaction mixture was then
warmed to rt and quenched with water (50 mL). The organic
solvent was evaporated and the aqueous was extracted with
Experimental section
General experimental methods
DCM (3
× 30 mL) and dried over MgSO4. The desiccant was
filtered off and the filtrate was evaporated to give the crude
residue, which was purified by chromatography on silica gel
[50% ~ 100% ethyl acetate in petroleum ether (40-60)] to yield
All solvents were obtained from a dry solvent system and
glassware was flame dried and cooled under vacuum before
use. All dry reactions were carried out under a nitrogen
atmosphere. TLC was carried out using aluminium TLC sheets
(silica gel 60 F254), and visualised using a UV lamp or by dipping
in KMnO4 solution then exposure to heat. Flash column
the product
3 as a colourless oil (1.10 g, 36%); δH (400 MHz,
CDCl3): 3.12 (3H, s, CH3), 3.41 (3H, s, CH3), 3.89 (3H, s, CH3),
6.94 (1H, d, J 1.0, ArCH), 7.05 (1H, d, J 1.0, ArCH); δC (100 MHz,
CDCl3): 35.0 (CH3), 35.7 (CH3), 39.3 (CH3), 123.6 (ArCH), 127.3
chromatography was carried out with silica gel 40-63ꢀ
60Å. 1H,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 10 of 14
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
Journal Name
(ArCH), 140.1 (ArC), 160.9 (CO); Data was in accordance with 30% ethyl acetate in petroleum ether(40-60)] to yield the
the literature.
product 8 as a colourless oil (2.50 g, 37%); νmax (thin film) 2980
(m), 1721 (s), 1403 (m); δH (400 MHz, CDCl3): 1.41 (3H, t, J 7.1,
1-t-Butyl-N,N-dimethyl-1H-imidazole-2-carboxamide 4
CH3), 1.50 [9H, s, (CH3)3], 4.38 (2H, q, J 7.1, CH2), 7.06 (1H, s,
1-t-Butylimidazole 2 (2.48 g, 20 mmol) was dissolved in THF ArCH), 7.23 (1H, s, ArCH); δC (100 MHz, CDCl3): 14.2 (CH3), 30.1
(20 mL) and cooled to -78 C. n-BuLi (2.0 M in hexanes, 12.5 [(CH3)3], 58.7 [(CH3)3C], 61.6 (CH2), 122.2 (ArCH), 127.8 (ArCH),
mL, 25 mmol) was added dropwise by syringe. The resulting 137.4 (ArC), 160.0 (CO); HRMS (ES+ TOF): found 197.1299 ([M +
mixture was stirred at -78
C for 2 h. This solution was added H]+); C10H17N2O2 requires 197.1290.
dropwise to a solution of dimethylcarbamoyl chloride (2.99 g,
28 mmol) in diethyl ether (20 mL) at -78 C and stirred for 1 h
°
°
1-Methyl-2-pyrrolecarboxylic acid 10
°
at the same temperature. The reaction mixture was then Aqueous KOH (2.5 M, 20 mL, 50 mmol) was added to a
warmed to rt and quenched with water (50 mL). The organic solution of methyl 1-methylpyrrole-2-carboxylate 12 (2.1 g, 6.6
solvent was evaporated and the aqueous was extracted with mmol) dissolved in methanol (20 mL) at rt and the resulting
DCM (3
× 100 mL) and dried over MgSO4. The desiccant was reaction mixture was stirred overnight. Methanol was
filtered off and the filtrate was evaporated to give the crude evaporated and the remaining solution was carefully acidified
residue. Pure product 4 was obtained as a white solid after to pH 2 with hydrochloric acid (6 M). The white precipitate was
recrystallization from ethyl acetate (1.69 g, 43%); m.p. 146– collected by filtration and washed with water. The precipitate
148 °C; νmax (thin film): 3157 (w), 2931 (w), 1638 (s), 1524 (w); was dissolved in DCM (50 mL) and dried over MgSO4. The
δH (400 MHz, CDCl3): 1.60 [9H, s, (CH3)3C], 2.96 (3H, s, CH3), desiccant was filtered off and the filtrate was evaporated to
3.09 (3H, s, CH3), 6.97 (1H, d, J 1.2, ArCH), 7.05 (1H, d, J 1.2, give the product 10 as a white solid (1.1 g, 57%); m.p. 136–138
ArCH); δC (100 MHz, CDCl3): 30.4 (CH3), 35.0 (CH3), 38.6 (CH3),
° °C); δH (400 MHz, CDCl3): 3.96 (3H, s, CH3),
C (lit.28 135–136
57.0 [(CH3)2C], 117.9 (ArCH), 126.8 (ArCH), 140.3 (ArC), 164.5 6.18 (1H, dd, J 4.0, 2.1, ArCH), 6.87 (1H, t, J 2.1, ArCH), 7.13
(CO); HRMS (ES+ TOF): found 196.1442 ([M + H]+); C10H18N3O (1H, dd, J 4.0, 2.1, ArCH), 12.20 (1H, br s, OH); δC (63 MHz,
requires 196.1450.
CDCl3): 37.0 (CH3), 108.4 (ArCH), 120.1 (ArCH), 121.8 (ArC),
130.8 (ArCH), 166.6 (CO). NMR data was not previously
reported in the literature.
Kinetic analysis of the reduction of ketimine 5 to amine 6
N-PMP-Ketimine 5 (0.225 g, 1.0 mmol) and catalyst (mol% as
specified) were dissolved in DCM (1 mL) at 0 oC. HSiCl3 (0.2 mL,
1-t-Butyl-1H-imidazole-2-carboxylic acid 11
2.0 mmoL) was added and the reaction left to stir for the Aqueous KOH (2.5 M, 20 mL, 50 mmol) was added to a
specified time. Work-up, either after the reaction was solution of ethyl 1-t-butyl-1H-imidazole-2-carboxylate (1.29
8
complete, or by removal of samples during the reaction, was g, 6.6 mmol) in methanol (20 mL) at rt. The reaction mixture
accomplished by dilution with DCM (20 mL per mL aliquot), was stirred overnight, the methanol was evaporated and the
quenching with aqueous NaOH (1 M, approximately 20 mL per mixture carefully acidified to pH 2 with concd. HCl. The
mL aliquot), and separation of the organic layer. The aqueous resulting mixture was evaporated to give a white solid that
layer was further extracted with DCM (2 × 20 mL per mL was treated with methanol (30 mL) and filtered. The filtrate
aliquot), the combined organic layers dried over MgSO4, was evaporated to give the crude product 11 as a white solid
filtered and evaporated. Conversion was calculated from (0.70 g) that was contaminated with a small amount of the t-
comparison of the integrals corresponding to ketimine starting butyl imidazole compound formed by decarboxylation (~10%)
material(s) and ketone (from hydrolysis of the ketimine) and but was used in the next step without further purification; δH
that of the product amine
6. δH (400 MHz, CDCl3): 1.52 (3H, d, J (400 MHz, MeOD): 1.86 [9H, s, (CH3)3C], 7.71 (1H, d, J 1.8,
7.1, CH3), 3.70 (3H, s, CH3), 4.43 (1H, q, J 7.1, CH), 6.49 [2H, ArCH), 8.02 (1H, d, J 1.8, ArCH); δC (100 MHz, MeOD): 28.3
(AX)2, ArCH], 6.72 [2H, (AX)2, ArCH], 7.21–7.40 (5H, m, ArCH).
Ethyl 1-t-butyl-1H-imidazole-2-carboxylate 8
[(CH3)3], 63.9 [(CH3)3C], 119.1 (ArCH), 124.3 (ArCH), 134.8
(ArC), 154.8 (CO); HRMS (ES+ TOF): found 169.0978 [M + H]+;
C8H13N2O2 requires 169.0977;. Data for the N-t-butylimidazole
1-t-Butylimidazole
(30 mL) and cooled to -78
40 mmol) was added dropwise by syringe. The resulting
mixture was stirred at -78 C for 2 h, and this solution added to
a solution of ethyl chloroformate (7.56 g, 70 mmol) in THF (20
mL) by cannula at -78
same temperature. The reaction mixture was then warmed to 1-methyl-1H-imidazole-4-carboxylic acid
2
(4.34 g, 35 mmol) was dissolved in THF contaminant; δH (400 MHz, MeOD): 1.72 [9H, s, (CH3)3], 7.63
°C. n-BuLi (2 M in hexanes, 20 mL, (1H, s, ArCH), 7.91 (1H, s, ArCH), 9.10 (1H, s, ArCH).
(S)-[2-(Hydroxydiphenylmethyl)pyrrolidin-1-yl](1-methyl-1H-
°
imidazol-4-yl)methanone 14
°
C, followed by stirring for 1 h at the Oxalyl chloride (0.18 mL, 2.1 mmol) was added to a mixture of
(132 mg, 1.05
9
rt and quenched with saturated aqueous ammonium chloride mmol) in DCM (5 mL) at rt. One drop of DMF was added and
(50 mL). The resulting mixture was extracted with ethyl the reaction mixture was stirred at room temperature for 2 h.
acetate (4 × 100 mL), and the combined organic layers were Excess oxalyl chloride and DCM were removed by evaporation
washed with brine (100 mL) and dried over MgSO4. The under reduced pressure. The residue was dissolved in DCM (5
desiccant was filtered off and the filtrate was evaporated. The mL) and added to a solution of amino alcohol 13 (253 mg, 1.0
residue was purified by chromatography on silica gel [(20%
∼
mmol) and triethylamine (0.2 mL, 1.4 mmol) in DCM (5 mL).
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 11 of 14
Journal Name
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
The resulting mixture was stirred at rt for 2 h and then (ArC), 165.5 (CO); HRMS (ES+ TOF): found 361.1913 [M + H]+;
quenched with aqueous saturated NaHCO3 (15 mL). The C23H25N2O2 requires 361.1916.
aqueous phase was extracted with DCM (3 × 15 mL), and the
combined organic extracts washed with brine (15 mL) and
(S)-(1-t-Butyl-1H-imidazol-2-yl)[2-
(hydroxydiphenylmethyl)pyrrolidin-1-yl]methanone 16
dried over MgSO4. The desiccant was filtered off and the
filtrate was evaporated. The residue was purified by Oxalyl chloride (0.18 mL, 2.1 mmol) was added to the crude
chromatography on silica gel (diethyl ether to flush off excess mixture of 1-t-butyl-1H-imidazole-2-carboxylic acid 11 (0.133
amino alcohol then 2% methanol in ethyl acetate) to yield the mg, 1.05 mmol) in DCM (5 mL) at room temperature. One drop
product 14 as a white solid (91 mg, 25%); m.p. 68–70
-116.3 (c 0.94, CHCl3); νmax (thin film) 2924 (s), 2854 (m), 1587 at rt for 2 h. The excess oxalyl chloride and DCM were
(m), 1556 (m), 1446 (m), 1434 (m); δH (500 MHz, 100 C, removed by evaporation under reduced pressure. The residue
°
C; [ꢀ]ꢂꢁꢃ of DMF was added and then the reaction mixture was stirred
°
DMSO-d6): 1.30–1.39 (1H, m, CHH), 1.51–1.60 (1H, m, CHH), was dissolved in DCM (5 mL) and this added to a solution of
1.88–1.94 (1H, m, CHH), 1.99–2.07 (1H, m, CHH), 3.28–3.34 amino alcohol 13 (253 mg, 1 mmol) and triethylamine (0.2 mL,
(1H, m, CHH), 3.63 (3H, s, CH3), 4.08–4.13 (1H, m, CHH), 5.67 1.4 mmol) in DCM (5 mL). The resulting mixture was stirred at
(1H, br s, CH), 6.63 (1H, s, ArCH), 7.15–7.20 (3H, m, ArCH), rt for 2 h and then quenched with aqueous saturated NaHCO3
7.22–7.25 (1H, m, ArCH), 7.28–7.36 (5H, m, ArCH), 7.43–7.45 (15 mL). The aqueous phase was extracted with DCM (3 × 15
(2H, m, ArCH), 7.50 (1H, s, ArCH); δC (126 MHz, 100 C, DMSO- mL), and the combined organic extracts washed with brine (15
°
d6): 22.4 (CH2), 27.6 (CH2), 32.4 (CH3), 48.3 (CH2), 64.3 (CH), mL) and dried over MgSO4. Filtration and evaporation was
80.8 (C), 125.1 (ArCH), 125.7 (ArCH), 126.0 (ArCH), 126.5 (2 × followed by purification by chromatography on silica gel
ArCH), 126.7 (2 × ArCH), 126.8 (2 × ArCH), 127.1 (2 × ArCH), [diethyl ether to flush off excess amino alcohol, then 50% ethyl
136.4 (ArCH), 136.9 (ArC), 144.6 (ArC), 146.1 (ArC), 163.6 (CO); acetate in petroleum ether (40–60)] yielding the product 16 as
HRMS (ES+ TOF): found 362.1876 [M + H]+; C22H24N3O2 requires a white solid (110 mg, 26%); m.p. 157–159
°
C; ; [ꢀ]ꢂꢁꢃ -153.7 (c
max (thin film) 2979 (w), 1618 (s), 1449 (s); δH (500
C, DMSO-d6): 1.40 (1H, br s, CHH), 1.45 [9H, s,
362.1869.
0.8, CHCl3);
MHz, 100
ν
°
(S)-[2-(Hydroxydiphenylmethyl)pyrrolidin-1-yl](1-methyl-1H-
(CH3)3], 1.53–1.62 (1H, m, CHH), 1.93–1.99 (1H, m, CHH), 2.01–
pyrrol-2-yl)methanone 15
2.08 (1H, m, CHH), 3.19–3.24 (1H, m, CHH), 3.46 (1H, br s,
Oxalyl chloride (0.18 mL, 2.1 mmol) was added to a solution of CHH), 5.41 (1H, dd, J 8.3, 3.3, CH), 6.22 (1H, br s, ArCH), 6.86
1-methyl-2-pyrrolecarboxylic acid 10 (131 mg, 1.05 mmol) in (1H, s, ArCH), 7.13–7.16 (1H, m, ArCH), 7.20–7.25 (4H, m,
DCM (5 mL) at room temperature. One drop of DMF was ArCH), 7.29–7.32 (2H, m, ArCH), 7.42 (2H, d, J 7.5, ArCH), 7.48
added and then the reaction mixture was stirred at rt for 2 h. (2H, d, J 7.7, ArCH); δC (126 MHz, 100 °C, DMSO-d6): 22.2 (CH2),
Excess oxalyl chloride and DCM were removed by evaporation 27.6 (CH2), 29.5 [(CH3)3C], 48.6 [(CH3)3C], 56.4 (CH2), 64.5 (CH),
under reduced pressure. The residue was dissolved in DCM (5 80.4 (C), 118.4 (ArCH), 125.4 (ArCH), 125.8 (ArCH), 126.1
mL) and added to a solution of amino alcohol 13 (253 mg, 1 (ArCH), 126.6 (2 × ArCH), 126.7 (2 × ArCH), 126.9 (ArCH), 140.4
mmol) and triethylamine (0.2 mL, 1.4 mmol) in DCM (5 mL). (ArC), 144.9 (ArC), 145.8 (ArC), 163.7 (CO); HRMS (ES+ TOF):
The resulting mixture was stirred at rt for 2 h and then found 404.2348 [M + H]+; C25H30N3O2 requires 404.2338.
quenched with aqueous saturated NaHCO3 (15 mL). The
General procedure A for the reduction of ketimines with catalysts
aqueous phase was extracted with DCM (3
× 15 mL), and the
combined organic extracts washed with brine (15 mL) and Ketimine (1.0 mmol) and catalyst (mol% as specified) were
dried over MgSO4. The desiccant was filtered off, the filtrate dissolved in DCM (1 mL) at 0 oC. HSiCl3 (0.2 mL, 2.0 mmoL) was
evaporated, and the residue purified by chromatography on added and the reaction left to stir for the specified time. The
silica gel [15% ethyl acetate in petroleum ether (40-60)] to reaction was quenched with aqueous HCl (1 M, 2 mL – care,
yield the product 15 as a white solid (195 mg, 54%); m.p. 184– gas evolution), followed by addition of DCM (20 mL) and
186 °
C; ; [ꢀ]ꢂꢁꢃ -83.7 (c 0.86, CHCl3); (Found: C, 76.28; H, 6.64; aqueous NaOH (1 M, 20 mL), and stirred until the precipitate
N, 7.69. C23H24N2O2 requires C, 76.64; H, 6.71; N, 7.77%); νmax dissolved. The organic layer was separated and the aqueous
(thin film) 3246 (w), 2958 (w), 1588 (s), 1435 (s); δH (400 MHz, layer was further extracted with DCM (2 × 20 mL). The
CDCl3): 1.42 (1H, pent d, J 7.5, 4.1, CHH), 1.61 (1H, d pent, J combined organic layers were dried over MgSO4, filtered and
12.4, 8.8, CHH), 1.94–2.03 (1H, m, CHH), 2.18 (1H, dtd, J 12.4, evaporated. Purification and analysis is detailed in individual
8.8, 4.1, CHH), 2.92 (1H, td, J 10.0, 7.3, CHH), 3.76–3.79 (1H, m, amine products.
CH), 3.81 (3H, s, CH3), 5.50 (1H, dd, J 8.4, 7.4, CH), 6.08 (1H, dd,
Catalyst evaluation using (S)-N-(4-methoxyphenyl)-α-methyl-
J 3.9, 2.0, ArCH), 6.23 (1H, dd, J 3.9, 2.0, ArCH), 6.70 (1H, app t,
benzenemethanamine 6
J 2.0, ArCH), 6.75 (1H, br s, OH), 7.27–7.39 (6H, m, ArCH),
7.48–7.50 (2H, m, ArCH), 7.55–7.58 (2H, m, ArCH); δC (100 Prepared by general procedure A, using 4-methoxy-N-(1-
MHz, CDCl3): 24.5 (CH2), 29.3 (CH2), 36.3 (CH3), 51.6 (CH2), 66.8 phenylethylidene)-benzenamine
5
(225 mg, 1 mmol) and
. Conversion to
(CH), 82.7 (C), 107.1 (ArCH), 114.6 (ArCH), 125.5 (ArC), 127.1 specified catalyst, gave the title compound
6
(ArCH), 127.2 (ArCH), 127.3 (ArCH), 127.4 (2 × ArCH), 127.9 (2 × product was determined by comparison of the integrals of
ArCH), 128.0 (2 × ArCH), 128.2 (2 × ArCH), 143.1 (ArC), 145.7 signals in the 1H NMR spectrum, whilst the enantiomeric
excess was determined by chiral phase HPLC analysis; δH (400
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 12 of 14
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
Journal Name
MHz, CDCl3): 1.52 (3H, d, J 7.1, CH3), 3.70 (3H, s, CH3), 4.43 (1H, 65.2 (CH), 72.4 (C), 123.5 (ArCH), 126.1 (ArCH), 140.4 (ArC),
q, J 7.1, CH), 6.49 [2H, (AX)2, ArCH], 6.72 [2H, (AX)2, ArCH], 160.4 (CO); HRMS (ES+ TOF): found 238.1556 [M + H]+;
7.21–7.40 (5H, m, ArCH); Phenomenex Lux 3ꢀm cellulose-1, C12H20N3O2 requires 238.1550.
hexane/i-PrOH = 98/2, flow rate = 1.0 mL/min, 254 nm, (R)
(S)-[2-(Hydroxydiphenylmethyl)pyrrolidin-1-yl](pyridin-2-
enantiomer tR = 16.5 min, (S) enantiomer tR = 19.3 min.
yl)methanone 23
(S)-α,α-Dimethyl-2-pyrrolinol 1929
Oxalyl chloride (1.32 mL, 15 mmol) was added dropwise to a
Mg (1.92 g, 80 mmol), iodine (one granule) and diethyl ether solution of picolinic acid (615 mg, 5 mmol) in DCM (15 mL).
(20 mL) were added to a dry three-necked flask. A solution of The resulting mixture was stirred at rt for 4 h, followed by
MeI (4.98 g, 80 mmol) in THF (80 mL) was added dropwise evaporation to give a black solid. DCM (20 mL) was added and
(initiated by heat after about 5–10 mL addition). The mixture the suspension transferred into
a solution of (S)-α,α-
was stirred at rt for 2 h and then cooled to 0 °C. A solution of diphenylprolinol 13 (1.02 g, 4 mmol) in toluene (20 mL) and
(S)-N-ethoxycarbonylproline methyl ester 18 (4.02 g, 20 mmol) the resulting mixture stirred at rt overnight. The reaction was
in diethyl ether (20 mL) was added dropwise. The resulting quenched by aqueous ammonium chloride (20 mL) and
mixture was stirred at rt overnight, cooled to 0 °C and extracted with ethyl acetate (3 × 20 mL). The combined
quenched with saturated aqueous ammonium chloride (50 organic extracts were dried over Na2SO4, filtered, evaporated
mL). The organic layer was separated and the aqueous layer under reduced pressure, and the residue purified by
extracted with diethyl ether (2
extracts were evaporated to afford a yellow oil (3.36 g). This petroleum ether (40-60)] to yield the product 23 as white solid
residue was treated with KOH (9.3 g, 0.166 mol), water (60 mL) (950 mg, 66%); m.p. 129–131 C (not reported in literature);
and ethanol (40 mL), and heated at reflux overnight. The [ꢀ]ꢂꢁꢃ -118.7 (c 0.8, CHCl3, not reported in literature);
max (thin
× 50 mL). The combined organic chromatography on silica gel [20% ~ 100% ethyl acetate in
°
ν
mixture was cooled to rt and the ethanol removed under film) 3058 (w), 2989 (w), 1608 (s), 1565 (s); δH (500 MHz,
o
reduced pressure. The resulting solution was extracted with DMSO-d6, 100 C): 1.63–1.80 (2H, m, CH2), 1.92–1.98 (1H, m,
DCM (2
× 50 mL), the combined extracts were washed with CHH), 2.05–2.12 (1H, m, CHH), 3.47–3.52 (1H, m, CHH), 3.65
brine (30 mL) and dried over MgSO4. After filtration, the (1H, br s, CHH), 5.72 (1H, br s, OH), 5.85 (1H, br s, CH), 7.06–
filtrate was evaporated under reduced pressure to afford the 7.26 (7H, m, ArCH), 7.32–7.35 (3H, m, ArCH), 7.48 (2H, d, J 7.6,
title compound 19 as a brown, low melting solid (1.87 g, 72%); ArCH), 7.69 (1H, br s, ArCH), 8.48 (1H, d, J 3.9, ArCH); δC (126
[ꢀ]ꢂꢁꢃ -28.0 (c 2, MeOH, lit. -32.3,29 c 1.84, MeOH); δH (400 MHz, d6-DMSO, 100 oC): 22.7 (br, CH2), 27.4 (CH2), 48.6 (br,
MHz, CDCl3): 1.14 (3H, s, CH3), 1.18 (3H, s, CH3), 1.60–1.82 (4H, CH2), 63.9 (CH), 81.0 (C), 122.8 (ArCH), 123.7 (ArCH), 125.8 (2 ×
m, 2 × CH2), 2.84 (2H, br s, NH & OH), 2.90–3.05 (3H, m, CH2 & ArCH), 126.1 (2 × ArCH), 126.5 (2 × ArCH), 126.7 (2 × ArCH),
CH); δC (100 MHz, CDCl3): 25.2 (CH3), 26.1 (CH2), 26.3 (CH2), 127.0 (2 × ArCH), 136.1 (ArCH), 145.0 (ArC), 145.4 (ArC), 146.9
28.6 (CH3), 47.0 (CH2), 67.0 (CH), 70.3 (C); Data was in (br, ArC), 154.0 (ArCH), 166.9 (br, CO); HRMS (ES+ TOF): found
accordance with the literature.
359.1769 [M + H]+; C23H23N2O2 requires 359.1760.
(S)-[2-(2-Hydroxypropan-2-yl)pyrrolidin-1-yl](1-methyl-1H-
(S)-[2-(Methoxydiphenylmethyl)pyrrolidin-1-yl](1-methyl-1H-
imidazol-2-yl)methanone 21
imidazol-2-yl)methanone 26
(S)-α,α-Dimethyl-2-pyrrolinol 19 (1.29 g, 10 mmol) was NaH (60% dispersion in mineral oil, 44 mg, 1.1 mmol) was
dissolved in toluene (10 mL) and NaH (60% dispersion in added to a solution of hydroxy catalyst 17 (361 mg, 1 mmol) in
mineral oil, 600 mg, 15 mmol) was added at rt. After stirring THF (10 mL). After stirring for 20 min at rt, MeI (156 mg, 1.1
for 30 min, ethyl 1-methylimidazole-2-carboxylate 20 (1.69 g, mmol) was added dropwise at the same temperature and then
11 mmol) was added. The resulting reaction mixture was stirred overnight. The resulting mixture was quenched with
slowly warmed to 70
cooled to rt, quenched by addition of water (20 mL) and phase was separated and the aqueous phase was extracted
extracted with ethyl acetate (3 30 mL). The combined with DCM (3 10 mL). The combined organic extracts were
organic phases were dried over MgSO4. After filtration, the dried over MgSO4. After filtration and evaporation, the residue
filtrate was evaporated and purified by chromatography on was purified by chromatography on silica gel [20% 50% ethyl
°C and stirred for 40 h. The reaction was saturated aqueous ammonium chloride (10 mL). The organic
×
×
∼
silica gel [50% ~ 100% ethyl acetate in petroleum ether (40- acetate in petroleum ether (40-60)] to yield the product 26 as
60)] to yield the product 21 (0.896 g, 39%) as a white solid; a white foam as a 4.6:1 mixture of two rotamers A and B (0.21
C; [ꢀ]ꢂꢁꢃ -124 (c 1.1, CHCl3); (Found: C, 60.70; H, g, 56%); m.p. 93–95 C; [ꢀ]ꢁꢂꢃ -68 (c 0.5, CHCl3);
m.p. 84–86 ° ° νmax (thin film)
7.98; N, 17.70. C12H19N3O2 requires C, 60.74; H, 8.07, N, 2927 (w), 1624 (s), 1524 (m), 1463 (s); δH (400 MHz, CDCl3,
17.71%); νmax (thin film) 3353 (br m), 2974 (m), 1607 (s), 1455 rotamer A): 1.03–1.16 (1H, m, CHH), 1.57–1.68 (1H, m, CHH),
(s); δH (500 MHz, DMSO-d6, 100 oC): 1.07 [6H, s, 2 x CH3], 1.65– 1.98–2.05 (1H, m, CHH), 2.25–2.48 (2H, m, CH2), 2.38 (3H, s,
1.70 (1H, m, CHH), 1.89–1.95 (3H, m, CH2 & CHH), 3.49–3.54 CH3), 3.54–3.61 (1H, m, CH), 3.79 (3H, s, CH3), 6.31 (1H, d, J
(1H, m, CHH), 3.79 (3H, s, CH3), 3.97–4.03 (1H, m, CHH), 4.42– 8.9, CH), 6.79 (1H, d, J 0.9, ArCH), 6.95 (1H, d, J 0.9, ArCH),
4.62 (1H, br m, OH), 4.71 (1H, br s, CH), 6.95 (1H, s, ArCH), 7.19 7.26–7.36 (7H, m, ArCH), 7.46–7.52 (1H, m, ArCH); δH (400
(1H, s, ArCH); δC (126 MHz, DMSO-d6, 100 ºC): 23.4 (br, CH2), MHz, CDCl3, rotamer B): 1.03–1.16 (1H, m, CHH), 1.45–1.53
25.6 (CH2), 25.7 (CH3), 26.9 (CH3), 33.8 (CH3), 48.7 (br CH2), (1H, m, CHH), 1.98–2.05 (1H, m, CHH), 2.95–3.02 (1H, m, CHH),
12 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 13 of 14
Journal Name
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
3.00 (3H, s, CH3), 3.70–3.76 (1H, m, CHH), 3.86 (3H, s, CH3), yellow oil; ; [ꢀ]ꢂꢁꢃ +23.8 (c 1.05, CHCl3, 87% ee, lit.26 -16.8, c
5.72 (1H, dd, J 8.7, 3.1, CH), 6.89 (1H, s, ArCH), 7.07 (1H, s, 1.0, CHCl3, 84% ee for R-enantiomer); δH (400 MHz, CDCl3):
ArCH), 7.26–7.36 (8H, m, ArCH); δC (100 MHz, CDCl3, rotamer 1.52 (3H, d, J 6.6, CH3), 4.03 (1H, br s, NH), 4.45 (1H, q, J 6.6,
A): 21.8 (CH2), 27.6 (CH2), 34.2 (CH3), 47.4 (CH2), 51.8 (CH3), CH), 6.43–6.47 (2H, m, ArCH), 6.79–6.84 (2H, m, ArCH), 7.23–
63.5 (CH), 86.8 (C), 122.4 (ArCH), 126.6 (ArCH), 127.6 (3 × 7.28 (1H, m, ArCH), 7.32–7.38 (4H, m, ArCH); δC (101 MHz,
ArCH), 127.7 (3 × ArCH), 129.4 (2 × ArCH), 130.0 (2 × ArCH), CDCl3): 25.1 (CH3), 54.1 (CH), 114.1 (d, JC-F 6.9, ArCH), 115.5 (d,
138.8 (ArC), 139.7 (ArC), 142.6 (ArC), 161.2 (CO); δC (100 MHz, JC-F 22.2, ArCH), 125.9 (ArCH), 127.0 (ArCH), 128.8 (ArCH),
CDCl3, rotamer B): 23.9 (CH2), 26.6 (CH2), 29.7 (CH2), 35.4 (CH3), 143.7 (ArC), 145.1 (ArC), 155.5 (d, JC-F 234.6, ArC); HPLC
50.7 (CH2), 52.5 (CH3), 60.4 (CH), 86.7 (C), 123.9 (ArCH), 127.4 (Kromasil 3-Cellucoat OD, hexane/i-PrOH = 99/1, flow rate =
(2 × ArCH), 127.5 (2 × ArCH), 127.8 (3 × ArCH), 129.6 (3 × 1.0 mL/min, 254 nm): (R) enantiomer tR = 6.9 min, (S)
ArCH), 129.9 (ArCH), 140.1 (ArC), 140.9 (ArC), 141.2 (ArC), enantiomer tR = 7.8 min.
161.2 (CO); HRMS (ES+ TOF): found 376.2023 [M + H]+;
(S)-N-[1-(4’-Methoxyphenyl)ethyl]-4-methoxyaniline 3516
C23H26N3O2 requires 376.2025.
Obtained using general procedure
employing catalyst 26 (0.1 mol%, 97% conversion, 84% ee) as a
white solid; m.p. 93–95 ºC (not reported in literature); [ꢀ]ꢁꢂꢃ
A with ketimine 30,
(S)-[2-(Methoxydiphenylmethyl)pyrrolidin-1-yl](pyridin-2-
yl)methanone 27
-
NaH (60% dispersion in mineral oil, 80 mg, 2 mmol) was added 14.5 (c 0.96, CHCl3, 81% ee, lit. -15.5,16 c 1.1, CHCl3, 85% ee); δH
to a solution of alcohol 23 (358 mg, 1 mmol) in THF (8 mL). (250 MHz, CDCl3): 1.49 (3H, d, J 6.6, CH3), 3.72 (3H, s, CH3),
After stirring for 15 min at rt, MeI (284 mg, 2 mmol) was added 3.76 (1H, br s, NH), 3.80 (3H, s, CH3), 4.39 (1H, q, J 6.6, CH),
dropwise at rt and left to stir overnight. The resulting mixture 6.49 [2H, (AX)2, ArCH], 6.71 [2H, (AX)2, ArCH], 6.87 [2H, (AX)2,
was quenched with saturated aqueous ammonium chloride ArCH], 7.29 [2H, (AX)2, ArCH]; δC (63 MHz, CDCl3): 25.1 (CH3),
(20 mL). The organic phase was separated and the aqueous 53.7 (CH3), 55.3, (CH3), 55.8 (CH3), 114.0 (2 × ArCH), 114.6 (2 ×
phase was extracted with ethyl acetate (3
× 15 mL). The ArCH), 114.8 (2 × ArCH), 127.0 (2 × ArCH), 137.6 (ArC), 141.7
combined organic extracts were dried over Na2SO4, filtered, (ArC), 151.9 (ArC), 158.5 (ArC); HPLC (Phenomenex Lux 3
ꢀ
m
evaporated, and the resulting residue purified by Cellulose-1, hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min,
chromatography on silica gel [10% ~100% ethyl acetate in 254 nm): (R) enantiomer tR = 9.1 min, (S) enantiomer tR = 10.0
petroleum ether (40-60)] to yield the product 27 as a yellow min.
solid as a 2 : 1 mixture of rotamers A and B (308 mg, 83%);
(S)-N-[1-(4’-Nitrophenyl)ethyl]-4-methoxyaniline 3616
m.p. 104–106 ° νmax (thin film) 3056
C; [ꢀ]ꢂꢁꢃ -154 (c 1.0, CHCl3);
(m), 2961 (m), 1626 (s), 1587 (s), 1556 (s); δH (400 MHz, CDCl3, Obtained using general procedure
A with ketimine 31,
rotamer A): 1.04–1.16 (1H, m, CHH), 1.59–1.70 (1H, m, CHH), employing catalyst 26 (0.1 mol%, 98% conversion, 84% ee) as a
1.94–2.01 (1H, m, CHH), 2.31 (3H, s, CH3), 2.37–2.45 (2H, m, brown oil; [ꢀ]ꢂꢁꢃ -30.8 (c 1.0, CHCl3, 84% ee, lit. -25.9,16 c 0.54,
CH2), 3.65–3.72 (1H, m, CH), 6.20 (1H, dd, J 9.2, 1.6, CH), 7.25– CHCl3, 86% ee); δH (400 MHz, CDCl3): 1.55 (3H, d, J 6.8, CH3),
7.39 (9H, m, ArCH), 7.52 (1H, d, J 9.1, ArCH), 7.60 (1H, d, J 6.7, 3.72 (3H, s, CH3), 3.93 (1H, br s, NH), 4.53 (1H, q, J 6.8, CH),
ArCH), 7.59–7.78 (2H, m, ArCH), 8.54 (1H, d, J 4.8, ArCH); δH 6.43 (2H, d, J 8.2, ArCH), 6.72 (2H, d, J 8.2, ArCH), 7.57 (2H, d, J
(400 MHz, CDCl3, rotamer B): 1.04–1.16 (1H, m, CH), 1.44–1.55 8.8, ArCH), 8.20 (2H, d, J 8.8, ArCH); δC (101 MHz, CDCl3): 25.0
(1H, m, CH), 2.02–2.11 (1H, m, CH), 2.13–2.23 (1H, m, CH), (CH3), 54.0 (CH3), 55.7 (CH), 114.5 (2 × ArCH), 114.8 (2 × ArCH),
2.71–2.78 (1H, m, CH), 3.07 (3H, s, CH3), 3.15–3.21 (1H, m, CH), 124.1 (2 × ArCH), 126.8 (2 × ArCH), 140.8 (ArC), 147.0 (ArC),
5.80 (1H, dd, J 9.1, 3.2, CH), 7.25–7.39 (11H, m, ArCH), 7.59– 152.3 (ArC), 153.6 (ArC); HPLC (Phenomenex Lux
3ꢀm
7.78 (2H, m, ArCH), 8.65 (1H, d, J 4.6, ArCH); δC (100 MHz, Cellulose-1, hexane/i-PrOH = 90/10, flow rate = 1.0 mL/min,
CDCl3, rotamer A): 21.6 (CH2), 27.8 (CH2), 47.7 (CH2), 50.7 (CH), 254 nm): (R) enantiomer tR = 28.3 min, (S) enantiomer tR = 31.8
64.0 (CH3), 87.0 (C), 123.7 (ArCH), 124.3 (ArCH), 127.3 (2 × min.
ArCH), 127.6 (ArCH), 127.7 (2 × ArCH), 127.8 (ArCH), 127.9
(S)-N-[1-(Thiophen-2-yl)ethyl]-4-methoxyaniline 3717
(ArCH), 129.6 (ArCH), 129.8 (ArCH), 129.9 (ArCH), 130.0 (ArCH),
138.4 (ArC), 138.6 (ArC), 146.9 (ArCH), 156.6 (ArC), 168.5 (CO); Obtained using general procedure
A with ketimine 32,
δC (100 MHz, CDCl3, rotamer B): 24.0 (CH2), 26.9 (CH2), 50.6 employing catalyst 26 (0.1 mol%, 77% conversion, 80% ee) as a
(CH2), 52.3 (CH), 59.8 (CH3), 86.6 (C), 124.5 (ArCH), 127.3 yellow oil; [ꢀ]ꢂꢁꢃ -8.0 (c 1.0, CHCl3, 79% ee, lit.17 -8.0, c 1.0,
(ArCH), 127.6 (ArCH), 127.7 (2 × ArCH), 127.8 (ArCH), 127.9 CHCl3, 79% ee); δH (250 MHz, CDCl3): 1.63 (3H, d, J 6.6, CH3),
(ArCH), 129.6 (ArCH), 129.8 (ArCH), 129.9 (ArCH), 130.0 (ArCH), 3.75 (3H, s, CH3), 4.76 (1H, q, J 6.6, CH), 6.62 [2H, (AX)2, ArCH],
136.4 (2 × ArCH), 140.5 (ArC), 141.9 (ArC), 148.7 (ArCH), 155.0 6.75 [2H, (AX)2, ArCH], 6.94–6.98 (2H, m, ArCH), 7.18 (1H, dd, J
(ArC), 169.1 (CO); HRMS (ES+ TOF): found 373.1917 [M + H]+; 4.7, 1.6, ArCH); δC (63 MHz, CDCl3): 24.8 (CH3), 50.6 (CH3), 55.8
C24H25N2O2 requires 373.1916.
(CH), 114.9 (2 × ArCH), 115.2 (2 × ArCH), 123.0 (ArCH), 123.6
(ArCH), 126.7 (ArCH), 141.2 (ArC), 150.6 (ArC), 152.5 (ArC);
(S)-N-[1-Phenylethyl]-4-fluoroaniline 3426
HPLC (Phenomenex Lux 3ꢀm Cellulose-1, hexane/i-PrOH =
98/2, flow rate = 1.0 mL/min, 254 nm): (R) enantiomer tR =
Obtained using general procedure
A
with ketimine 29
,
employing catalyst 17 (1 mol%, 96% conversion, 87% ee) or 15.1 min, (S) enantiomer tR = 17.3 min.
catalyst 26 (0.1 mol%, 95% conversion, 86% ee) as a light
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 13
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 14 of 14
View Article Online
DOI: 10.1039/C6OB02537D
ARTICLE
Journal Name
(S)-N-[1-(Naphthalen-2-yl)ethyl]-4-methoxyaniline 3816
17.
18.
19.
20.
F.-M. Gautier, S. Jones, X. Li, and S. J. Martin, Org. Biomol.
Chem., 2011, 9, 7860–7868.
Obtained using general procedure
employing catalyst 26 (0.1 mol%, 99% conversion, 92% ee) as a
light yellow solid; m.p. 96–98
C (lit.16 95–96 oC); [ꢀ]ꢂꢁꢃ -24.0 (c
A with ketimine 33,
Z. Zhang, P. Rooshenas, H. Hausmann, and P. Schreiner,
Synthesis, 2009, 1531–1544.
°
1.0, CHCl3, 85% ee, lit.16 -26.0, c 1.0, CHCl3, 86% ee); δH (250
MHz, CDCl3): 1.59 (3H, d, J 6.9, CH3), 3.70 (3H, s, CH3), 3.90 (1H,
br s, NH), 4.59 (1H, q, J 6.9, CH), 6.53 [2H, (AX)2, ArCH], 6.71
[2H, (AX)2, ArCH], 7.42–7.55 (3H, m, ArCH), 7.80–7.86 (4H, m,
ArCH); δC (63 MHz, CDCl3): 25.2 (CH3), 54.6 (CH3), 55.8 (CH),
114.7 (ArCH), 114.8 (ArCH), 124.4 (ArCH), 124.5 (ArCH), 125.5
(ArCH), 126.0 (ArCH), 127.7 (ArCH), 127.9 (ArCH), 128.5 (ArCH),
132.8 (ArC), 133.7 (ArC), 141.7 (ArC), 143.1 (ArC), 152.0 (ArC);
A. V Malkov, K. Vranková, S. Stončius, and P. Kočovský, J.
Org. Chem., 2009, 74, 5839–5849.
R. E. Cowley, R. P. Bontchev, E. N. Duesler, and J. M. Smith,
Inorg. Chem., 2006, 45, 9771–9.
21.
22.
M. Braun, Angew. Chem., Int. Ed., 2012, 51, 2550–2562.
S. El-Fayyoumy, M. H. Todd, and C. J. Richards, Beilstein J.
Org. Chem., 2009, 5, 67.
23.
24.
M. Hagemann, A. Mix, R. J. F. Berger, T. Pape, and N. W.
Mitzel, Inorg. Chem., 2008, 47, 10554–64.
A. V Malkov, S. Stončius, K. Vrankova, M. Arndt, and P.
Kočovský, Chem. Eur. J., 2008, 14, 8082–8085.
S. Jones and X. Li, Tetrahedron, 2012, 68, 5522–5532.
T. Imamoto, N. Iwadate, and K. Yoshida, Org. Lett., 2006, 8,
2289–2292.
HPLC (Phenomenex Lux 3ꢀm Cellulose-1, hexane/i-PrOH =
90/10, flow rate = 1.0 mL/min, 254 nm): (R) enantiomer tR
=
10.1 min, (S) enantiomer tR = 12.0 min.
25.
26.
Acknowledgements
27.
28.
29.
R. I. Ngochindo, J. Chem. Soc. Perkin Trans. 1, 1990, 1645–
1648.
We thank The University of Sheffield (XL and FT) and EPSRC
(EP/K007955/1 – ATR) for funding.
P. A. Shirley, D. A.; Gross, B. H.; Roussel, J. Org. Chem.,
1955, 20, 225–31.
K. Nakayama and W. J. Thompson, J. Am. Chem. Soc., 1990,
112, 6936–6942.
Notes and references
1.
F. Iwasaki, O. Onomura, K. Mishima, T. Kanematsu, T. Maki,
and Y. Matsumura, Tetrahedron Lett., 2001, 42, 2525–
2527.
2.
S. Guizzetti and M. Benaglia, Eur. J. Org. Chem., 2010,
5529–5541.
3.
S. Jones and C. J. A. Warner, Org. Biomol. Chem., 2012, 10,
2189–2200.
4.
A. V Malkov, A. Mariani, K. N. MacDougall, and P.
Kočovský, Pavel, Org. Lett., 2004, 6, 2253–2256.
Z. Wang, X. Ye, S. Wei, P. Wu, A. Zhang, and J. Sun, Org.
Lett., 2006, 8, 999–1001.
5.
6.
C. Baudequin, D. Chaturvedi, and S. B. Tsogoeva, Eur. J.
Org. Chem., 2007, 2623–2629.
7.
Y.-C. Xiao, C. Wang, Y. Yao, J. Sun, and Y.-C. Chen, Angew.
Chem., Int. Ed., 2011, 50, 10661–4.
8.
D. Pei, Z. Wang, S. Wei, Y. Zhang, and J. Sun, Org. Lett.,
2006, 8, 5913–5.
9.
D. Pei, Y. Zhang, S. Wei, M. Wang, and J. Sun, Adv. Synth.
Catal., 2008, 350, 619–623.
10.
11.
12.
13.
14.
15.
16.
S. Guizzetti, M. Benaglia, F. Cozzi, and R. Annunziata,
Tetrahedron, 2009, 65, 6354–6363.
H. Zheng, J. Deng, W. Lin, and X. Zhang, Tetrahedron Lett.,
2007, 48, 7934–7937.
O. Onomura, Y. Kouchi, F. Iwasaki, and Y. Matsumura,
Tetrahedron Lett., 2006, 47, 3751–3754.
C. J. A. Warner, A. T. Reeder, and S. Jones, Tetrahedron:
Asymmetry, 2016, 27, 136–141.
M. Bonsignore, M. Benaglia, R. Annunziata, and G.
Celentano, Synlett, 2011, 1085–1088.
M. Sugiura, M. Kumahara, and M. Nakajima, Chem.
Commun., 2009, 3585–3587.
F.-M. Gautier, S. Jones, and S. J. Martin, Org. Biomol.
Chem., 2009, 7, 229–231.
14 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins