Switchable pyrrole-based hydrogen bonding motif in enantioselective trifunctional organocatalysis

Article abstract of DOI:10.1016/j.tet.2018.12.016

Pyrroles are versatile chemical motifs for molecular recognition or ligand design but their utility as catalytic components are underexplored. We incorporated a pyrrole motif into our acid-switchable, MAP-based trifunctional organocatalytic system. The sw

Full text of DOI:10.1016/j.tet.2018.12.016

Tetrahedron 75 (2019) 518e526
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Switchable pyrrole-based hydrogen bonding motif in enantioselective
trifunctional organocatalysis
,
*
Sviatoslav S. Eliseenko, Fei Liu*
Department of Molecular Sciences, Macquarie University, Sydney, NSW 2109, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrroles are versatile chemical motifs for molecular recognition or ligand design but their utility as
catalytic components are underexplored. We incorporated a pyrrole motif into our acid-switchable,
MAP-based trifunctional organocatalytic system. The switching-on of this system by an external
Brønsted acid, 3-methyl benzoic acid, presented proficient catalysis in both aza-MoritaeBayliseHillman
(MBH, up to >95% conversion and 88% ee over 3 h) and MBH (up to 81% conversion and 77% ee over 6 h)
reactions. The enhanced catalytic generality and proficiency may be due to the new cooperativity via CH/
Received 11 October 2018
Received in revised form
10 December 2018
Accepted 11 December 2018
Available online 19 December 2018
p
interactions between pyrrole and the acid switch.
Keywords:
© 2018 Elsevier Ltd. All rights reserved.
Switchable catalysis
Cooperativity
Trifunctional organocatalysis
Enantioselectivity
Pyrroles
MoritaeBayliseHillman reaction
1. Introduction
typical role of pyrrole as a coordination or pH switching site.
We have, in our prior work, originated a switchable, enantio-
selective trifunctional organocatalytic prototype for activating
enones in carbon-carbon bond forming reactions such as the
MoritaeBayliseHillman (MBH) reaction (Fig. 1a) [9]. The prototype
trifunctional system is built on a very versatile MAP-based chemical
system [10]. The MAP-based catalysts typically contain three cata-
lytic motifs: a phosphine nucleophile for reaction initiation, an
amine Brønsted base for responding to the external acid switch,
and a phenol Brønsted acid for H-bonding interactions that help
stabilize the formation of zwitterionic intermediates [9,11]. An
external, strong Brønsted acid additive, such as benzoic acid,
switches the catalysis from slow and racemic to fast and enantio-
selective, particularly for the aza-MBH reactions that are often slow
in rate with capricious catalytic scope [12]. We have also investi-
gated multiple generations of this system by tuning the acidity of
the internal Brønsted acid motif [12f,13a,11,13b,c,9], and in all cases,
benzoic acid has been the best additive to switch on the fast and
enantioselective catalysis. One persistent issue for this switchable
system however is to extend the generality to cover not just the
aza-MBH but also the MBH reactions. One potential solution is to
find more synergistic noncovalent interactions between the acid-
activator and the catalyst. This may also address a long-standing
challenge of engineering compact molecular assemblies with
Pyrroles are chemical motifs prevalent in bioactive compounds
[1], ligands [2], sensors [3], and molecular assemblies [4]. The
versatile chemistry of pyrroles in part derives from the multifunc-
tional pyrrolyl NH group that is weakly acidic and basic, in addition
to the electron-rich
p system primed for electrophilic substitution
reactions and also hydrogen-bonding interactions [5]. The role of
pyrroles as catalytic components, however were mainly explored
within the context of calix[4]pyrrole systems and remain under
developed [6]. More recently, pyrrole NH motifs have been used in
hydrogen bonding catalysis as part of a tunable H-bonding catalyst
[6a,c], expanding significantly from its normal coordination role as
a ligand. Questions now can be raised on new roles of pyrrole in
switchable catalysis [7] given pyrrole's multifunctional nature. Here
we report a novel example of a pyrrole-containing, acid-switchable,
enantioselective trifunctional organocatalytic system with
enhanced generality and enantioselectivity, likely due to the
multifunctional aspect of the pyrrole motif involving not only the
NH hydrogen-bond donor but also the
p electron system through
CH/ hydrogen bonding [8]. This catalysis extends beyond the
p
* Corresponding author.
E-mail address: fei.liu@mq.edu.au (F. Liu).
tunable catalytic properties that require
a more synergistic
https://doi.org/10.1016/j.tet.2018.12.016
0040-4020/© 2018 Elsevier Ltd. All rights reserved.

S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
519
Fig. 1. a) Switchable and enantioselective trifunctional organocatalytic prototype
given a general mechanism of a test MBH reaction; b) Enhancing switchable catalysis
with multifunctional recognition motifs such as pyrroles.
Scheme 1. Synthesis of catalysts 1aef.
network of molecular recognition arrangements.
To test this hypothesis, we investigated the potential of the
multifunctional pyrrole motif that contains weakly acidic NH group
factor. Considering that changing the Brønsted acid motif acidity
can improve the catalytic proficiency [13c], catalysts 1def con-
taining more acidic imidazole motifs were also investigated for
comparison. The additional steric variation may influence the
enantioselectivity by biasing the substrate approach. To investigate
the steric influence around the pyrrolic NH center, catalysts 1b, c, f
containing sterically bulky and electron withdrawing bromine
atoms or fused benzene ring were synthesized. Catalysts 1c and 1f
contain benzimidazolyl and benzopyrrolyl fragments with a more
for H-bonding interactions and the electron-rich
p system that
could act, in close spatial proximity, as an H bond acceptor that may
enhance the interaction with the external acid activator (Fig. 1b).
We found that a pyrrole-based catalyst, activated by 3-methyl
benzoic acid, provided catalytic improvement in MBH catalysis
with an increase in ee by 15% (approx. 1.5 fold by e.r., up to 73%), in
comparison to our earlier generations of catalysts such as trifunc-
tional catalyst TF-1. Pyrrole phosphines were previously used as N-
phosphinepyrrole ligands in complexes with Rh in hydro-
formylations [14], Pd in CO-ethene co-polymerization [15], Pt in
benzene vinylation [16], and Ir in enantioselective hydrogenation
[17]. The complexation patterns of N-pyrrole-phosphine ligands
with Cr, Ru, Mo, W, and Se were also reported [18]. The 2-
phosphino-N-aryl or alkyl substituted pyrroles were investigated
as ligands for Pd [19] and Ru [20]. The ligands where both pyrrole
and phosphine fragments bind Ni [21] or Cu [22] were also
described. Pyrrole-containing phosphines are also known as
bioactive molecules [23]. However, phosphine pyrroles have not
been used previously as organocatalysts and our chiral
phosphineepyrrole system here represents the first set of such
examples.
extended
p system that may also influence the catalytic proficiency
via interactions with the substrate or external acid activator.
p
Tuning of the phosphine Lewis base was not attempted, as our prior
investigations (unpublished data) indicated that adding sub-
stituents onto the aryl phosphine to increase the Lewis base
nucleophilicity actually resulted in loss of catalysis, likely due to
unexpected interference with the acid switch.
The synthesis of new catalysts 1aef was performed by modified
reported procedures [9] from the key intermediate (S)-MAPO 6
[10a-c,24,9] in 2 steps (Scheme 1). For the synthesis of pyrrolyl- and
indolyl-containing catalysts 1aec, the aminophosphine 2 was
initially synthesized from 6 by chemoselective phosphine oxide
reduction. Further reductive amination of the corresponding al-
dehydes 3e5 by aminophosphine 2 furnished catalysts 1aec
(Scheme 1). Attempts to synthesize imidazolyl- and
benzimidazolyl-containing catalysts 1def were met with signifi-
cant difficulties as phosphine oxidation occurred during the
reductive amination step. Therefore, the reductive amination of
aldehydes 7e9 was performed with (S)-MAPO 6, followed by a
subsequent phosphine oxide reduction to afford catalysts 1def
2. Results and discussion
A series of pyrrole-containing catalysts were designed and
synthesized (Scheme 1). The unsubstituted pyrrole catalyst 1a was
synthesized as the base model, and other catalysts, 1bef, were
developed to vary the acidity of the pyrrole NH motif and its steric

520
S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
Table 2
(Scheme 1).
Acid additive and loading screening of aza-MBH and MBH reactions.
The synthesis of 11 and 1e required up to 70 h of reactions
whereas all other catalysts and their phosphine oxide precursors
can be synthesized in much less time (~20 h). The purification of
catalysts 1aef and precursors 10e12 were challenging due to the
low stability of these compounds [25]. Catalyst 1b was chosen for
solvent screening due to its easier purification process (Table 1).
Consistent with earlier hallmark profiles of our trifunctional orga-
nocatalysts, dichloromethane and diethyl ether were the best sol-
vents for the aza-MBH and MBH model reactions, respectively
(Table 1, entries 1 and 10) [11,13c,9]. More polar solvents such as
acetonitrile resulted in poor yields and low enantioselectivity
(Table 1, entries 6 and 13). No product formation occurred in polar
protic solvents such as methanol (Table 1, entries 7 and 14). This
confirms our working hypothesis that this enantioselective tri-
functional catalysis relies on ion pairing upon activation by an acid
additive.
After the identification of the best solvent for the aza-MBH and
MBH test reactions, the external acid additives were screened
(Table 2). For comparison, model TF-1 (Scheme 1) was also tested
(Table 2, entries 24, 25). The response of switching on catalytic
proficiency (coupled rate and ee enhancement) to the acid activa-
tion is one of the main criteria of a trifunctional catalysis mode [9],
in which the activation by an external acid likely occurs via the
participation of its counterion in the irreversible, final proton-
transfer step [9,11]. Benzoic acid (pKa 4.20) was found to be the
best activator for previous generations of catalysts [11,13c,9].
Therefore, a set of aromatic acids with comparable pKa values was
tested along with other types of organic acids such as phenyl-
phosphinic and acetic acids (Table 2). Interestingly, 3-methyl ben-
zoic acid (pKa 4.24) was found to be the best acid additive for both
the aza-MBH and MBH test reactions, providing the corresponding
products in the good ee (88% for aza-MBH; 73% for MBH) and good
yields (Table 2, entries 6 and 13). Notably, benzoic acid, which was
the best activator for previous generations of catalysts, demon-
strated lower proficiency than 3-methyl benzoic acid, providing
aza-MBH and MBH products in 84% and 70% ee, respectively
(Table 2, entries 1 and 11). The 3-chloro- and 4-cyanobenzoic acid
additive with lower pKa values (3.83 and 3.55 correspondingly)
Entry Catalyst X (Y)
Acid additive
Solvent Time Conva (eeb)
[h]
[%]
1
2
3
4
5
6
7
8
9
10
1b
1b
1b
1b
1b
1b
1b
1d
1d
1d
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
NTs
(Br)
BzOH
DCM
DCM
DCM
DCM
3
77 (84)
4-F-BzOH
2-Naphthoic
Acetic
3
62 (85)
60 (81)
>95 (80)
8 (ꢀ2)
3
3
Phenylphosphinic DCM
24
3
3-Me-BzOH
2-Me-BzOH
BzOH
DCM
DCM
DCM
DCM
DCM
89 (88)
>95 (86)
29 (56)
25 (54)
27 (60)
3
3
4-F-BzOH
3-Me-BzOH
3
3
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1d
1d
1d
TF-1
O (NO2) BzOH
Ether
Ether
Ether
Ether
Ether
Ether
Ether
6
6
6
6
6
6
6
24
6
75 (70)
70 (69)
81 (73)
85 (74)
11 (69)c
>5 (61)c
81 (51)
7 (34)
35 (69)
62 (73)
70 (39)
93 (39)
70 (37)
89 (89)
O (NO2) 4-F-BzOH
O (NO2) 3-Me-BzOH
O (NO2) 2-Me-BzOH
O (NO2) 3-Cl-BzOH
O (NO2) 4-CN-BzOH
O (NO2) Acetic
O (NO2) Phenylphosphinic Ether
O (NO2) 1-Naphthoic
O (NO2) 2-Naphthoic
O (NO2) BzOH
O (NO2) 3-Me-BzOH
O (NO2) 2-Naphthoic
Ether
Ether
Ether
Ether
Ether
DCM
6
24
24
24
3
NTs
(Br)
3-Me-BzOH
25
TF-1
O (NO2) 3-Me-BzOH
Ether
6
79 (58)
Table 1
a
Calculated by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
ee level determined for conversion after 24 h.
Solvent screening of 1b-catalyzed aza-MBH and MBH reactions.
b
c
provided significant rate loss in the MBH reaction (Table 2, entries
15, 16), suggesting likely quenching of the zwitterionic intermedi-
ate via protonation [12d].
Benzoic acid and 3-methyl benzoic acid both have comparable
pKa values, but 3-methyl benzoic acid provided better results with
Entry
X (Y)
Solvent
Time [h]
Conva (eeb) [%]
1
2
3
4
5
6
7
8
NTs (Br)
NTs (Br)
NTs (Br)
NTs (Br)
NTs (Br)
NTs (Br)
NTs (Br)
O (NO2)
O (NO2)
O (NO2)
O (NO2)
O (NO2)
O (NO2)
O (NO2)
DCM
Chloroform
Ether
3
3
3
3
3
3
24
6
6
6
6
6
6
77 (84)
little observable steric interference.
A further test of 2-
73 (79)
95c (59)
methylbenzoic acid with significantly lower pKa than 3-
a
THF
89 (76)
methylbenzoic acid (3.91 vs. 4.24 correspondingly) demonstrated
a comparable proficiency in both aza-MBH and MBH reactions
(Table 2, entries 6 and 13 vs. 7 and 14). These results suggest an
important role of the methyl substituent in the acid additive for the
proficient catalysis that is independent of the pKa. Such an
improvement with a bulkier acid activator is unexpected and may
Toluene
Acetonitrile
Methanol
DCM
Chloroform
Ether
>95c (73)
50c (18)
No reaction (n.d.)
17 (69)
18 (64)
75 (70)
29 (69)
53 (73)
8 (39)
No reaction (n.d.)
9
10
11
12
13
14
THF
be explained by the additional CH/
p hydrogen bonding stabiliza-
Toluene
Acetonitrile
Methanol
tion possibly between the electron rich pyrrole fragment of the
catalyst and methyl group of the external acid additive (Scheme
1b).
The screening of the acid additive influence on the imidazolyl-
containing catalyst 1d provided a comparable trend albeit at
24
a
Calculated by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
27 mol% loading of 1b.
b
c

S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
521
lower proficiency (Table 2, entries 8e10 and 21e23). We have
shown [13c] that the acidity and the spatial position of the Brønsted
acid motif on the catalyst will impact on the proficiency of the
catalysis. The lower proficiency (e.g. slower rate and lower enan-
tioselectivity) of the imidazole-containing catalysts, compare to the
pyrrole series, may be due to the higher acidity of the imidazole NH
and also the position of the NH proton. The activity of 1b, activated
by 3-methyl benzoic acid, is comparable to the control, phenol-
containing catalyst TF-1 in the test aza-MBH reaction, but notice-
ably higher in the MBH reaction (Table 2, entries 1, 11 vs 24, 25).
Thus, catalyst 1b provided the highest enantioselectivity in MBH
test reactions among other generations of MAP-base trifunctional
catalysts, likely due to the aforementioned additional CH/
eration in the switchable catalytic system [11,13c,9].
p coop-
For catalyst 1b, the acid additive loading effect was next inves-
tigated and found to be consistent for both aza-MBH and MBH
reactions (Table 3). The use of an acid loading more than the
equimolar loading to catalyst 1b showed significant erosion of both
reaction rate and enantioselectivity in the aza-MBH reaction
(Table 3, entries 5, 6 vs 4), but only erosion of the reaction rate in
the MBH test reaction (Table 3, entries 14, 13 vs 12). Less than
equimolar acid additive loading to that of the catalyst demon-
strated slight reduction in proficiency for aza-MBH test reactions
(Table 3, entry 3 vs 4) and slightly higher reaction rates in MBH test
reactions albeit in lower enantioselectivity (Table 3, entry 11 vs 12).
The catalytic profile of the pyrrole catalysts is different from that of
phenol-containing catalyst TF-1 as this catalyst demonstrated the
highest proficiency at 5 equivalent loading of an acid additive to the
catalyst [9]. The catalyst loading, as expected, influenced mostly the
reaction rate, providing a higher rate at a higher loading (Table 3).
The enantioselectivity of test reactions did not vary as significantly
with different catalyst loadings (Table 3, entry 1 vs 2, 4, 7 and 8 vs 9,
10, 15). Therefore, a loading at 5 mol% of the catalyst with the acid
additive could also be used in aza-MBH and MBH reactions.
Fig. 2. Activity profile of acid-switchable catalysts 1aef in aza-MBH and MBH test
reactions.
activation to switch on the catalysis. The control reactions without
the acid additive demonstrated a sharp reduction in both the re-
action rate and the level of enantioselectivity (Fig. 2). Again this
concurrent rise of both the enantioselectivity and the reaction rate
with acid activation, which is performed at room temperature to
maintain the catalytic rate (i.e. no enantioselectivity improvement
at lower temperatures), is consistent with our switchable trifunc-
tional catalytic mode as noted before for trifunctional MAP-based
catalysts [9,11]. The aza-MBH product 14a of opposite enantiose-
lectivity (up to ꢀ35% ee) were observed in aza-MBH reactions
without the acid additive (Fig. 2, 1a, b, def).
With the conditions optimized, new catalysts 1aef were tested
in aza-MBH and MBH reactions in the presence and absence of the
3-methyl benzoic acid additive (Fig. 2). All catalysts require the acid
The substituted pyrrole-containing catalysts 1b and 1c (fused
benzene ring), compared to the unsubstituted catalyst 1a, provided
higher enantioselectivity in both aza-MBH and MBH reactions,
albeit in lower reaction rates due to likely higher steric congestion
(Fig. 2). The imidazolyl-containing catalysts 1def were less active
than pyrrolyl-containing analogs with lower reaction rates. The 4-
imidazolyl-containing catalyst 1d showed the lowest activity,
resulting in the formation of aza-MBH product 14a in only 41%
conversion and 57% ee over 3 hours and the MBH product in 48%
conversion and 38% ee over 6 hours (Fig. 2). As discussed earlier,
this may be explained by possible imidazole ring tautomerization
that makes the position of the Brønsted acid function less optimal
for hydrogen bonding interactions between all catalytic motifs. The
imidazole ring tautomerization in catalysts 1e or 1f does not seem
to influence significantly the catalytic proficiency, as both of the
Table 3
Acid activator loading screening of 1b-catalyzed aza-MBH and MBH reactions.
Entry 1b loading 3-MeBzOH
X (Y)
Solvent Time Conva (eeb)
[mol %]
loading [mol %]
[h]
[%]
1
2
3
4
5
6
7
8
1
5
1
5
5
10
25
50
20
1
NTs (Br) DCM
NTs (Br) DCM
NTs (Br) DCM
NTs (Br) DCM
NTs (Br) DCM
NTs (Br) DCM
NTs (Br) DCM
O (NO2) Ether
O (NO2) Ether
O (NO2) Ether
O (NO2) Ether
O (NO2) Ether
O (NO2) Ether
O (NO2) Ether
O (NO2) Ether
3
3
3
3
3
3
3
24
6
6
6
6
6
6
3
19 (88)
57 (86)
76 (84)
89 (88)
49 (78)
24 (75)
>95 (84)
14 (67)
70 (69)
81 (73)
66 (63)
62 (73)
46 (74)
35 (74)
>95 (72)
10
10
10
10
20
1
nitrogen centers are in equal a-positions to the methylene bridge.
Therefore 2-imidazolyl-containing catalysts 1e or 1f provided
products in comparable enantioselectivity to that of pyrrolyl-
containing catalysts 1a or 1c, albeit in lower conversion. This is
consistent with our prior observations that increasing the internal
Brønsted acid acidity can improve the catalytic activity to a certain
point [13c]. Catalyst 1b was found to be the most active in both aza-
MBH and MBH test reactions providing products up to 88% ee at 89%
conversion over 3 hours in the aza-MBH case and 73% ee at 81%
conversion over 6 hours in the MBH case (Fig. 2).
9
5
5
10
11
12
13
14
15
10
10
10
10
10
20
10
5c
10c
25c
50c
20
a
Calculated by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
2-Naphthoic acid was used instead of 3-methyl benzoic acid.
Taking into account the promising activity of new catalysts, the
substrate scope of the best catalyst 1b was investigated in the aza-
b
c

522
S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
Table 4
catalytic system was also used for proficient catalysis of both aza-
Substrate scope investigation with 1b.
MBH [32] and MBH [33] reactions, however, substrates such as
MVK and aromatic electrophiles were not tested with this catalytic
system. The ability of pyrrolyl-containing catalyst 1b to catalyze
both aza-MBH and MBH reactions with expanded substrate scope is
suggestive of an enhanced molecular recognition network provided
by the pyrrole motif in the presence of 3-methyl benzoic acid and
encouraging for future work of catalyst design that may help find
additional solutions to the generality limitation of this type of
reactions.
Entry
X (Y)
Solvent
Time [h]
Conva [%]
eeb [%]
1
2
3
4
5
6
7
8
NTs (4-Br) 14a
NTs (3-NO2) 14b
NTs (2-Cl) 14c
NTs (4-Me) 14d
NTs (2-NO2) 14e
NTs (4-Cl) 14f
NTs (4-F) 14g
NTs (4-CN) 14h
O (4-NO2) 16a
O (3-NO2) 16b
O (4-CN) 16c
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Ether
Ether
Ether
Ether
Ether
Ether
3
3
3
3
3
3
3
3
6
6
6
6
6
6
89 (>95c)
>95
88
77
3. Conclusions
40 (>95c)
18 (86c)
53 (>95c)
59 (>95c)
21 (>95c)
55 (>95c)
81 (>95c)
68 (>95c)
64 (95c)
16 (56c)
14 (58c)
10 (48c)
76
86d
58
In conclusion, new catalytic roles of a pyrrole motif have been
established in a switchable and enantioselective trifunctional
organocatalytic cycle that improved the generality of the catalytic
systems. Such improvement may be attributed to additional,
82
79
57
73
9
favourable CH/p hydrogen bonding interactions between the
10
11
12
13
14
73
73
electron rich pyrrolyl moiety and the external activator, 3-methyl
benzoic acid to switch on the catalysis. While pyrrole phosphines
have commonly been used as ligands before, we show here for the
first time that they can be effective organocatalysts. This will
facilitate future work in developing the pyrrole motif in catalysis
beyond its common ligand role. Further work will involve addi-
tional investigation and characterization of substituted pyrroles
and acid switches with compact molecular recognition network for
new or enhanced catalysis. This may also, in general, contribute to
the new use of pyrroles for building molecular assemblies in roles
different from the established utility as a coordination or pH-
switching site.
O (4-Br) 16d
O (2-NO2) 16e
O (3-Br) 16f
75d
59d
77d
Calculated by 1H NMR spectroscopy.
Determined by chiral HPLC analysis.
Conversion in 24 h.
a
b
c
d
ee level determined for conversion after 24 h.
MBH and MBH reaction (Table 4). Substituted N-tosyl benzaldi-
mines with ortho-, meta-, and para-substituents and aromatic al-
dehydes bearing electron-withdrawing groups were investigated
under the optimized conditions.
Catalyst 1b catalyzed both aza-MBH and MBH reactions and
demonstrated the widest scope in all of our generations of tri-
functional organocatalysts. Most of the aza-MBH substrates, con-
taining para-substituents, provided the corresponding adducts in
comparable enantioselectivity (79e88% ee) although with lower
conversion for deactivated imine 13d as expected (Table 4, entries 4
vs. 1). The aza-MBH reactions with substrates containing meta- and
ortho-substituents (Table 4, entries 2, 3, 5) showed some loss in
enantioselectivity or rate, again consistent with prior observations
for substrates that are more sterically congested.
For the MBH reactions, aromatic substrates bearing electron-
withdrawing groups provided adducts with consistent ee around
73e77% (Table 4. Entries 9e11). Less active 4-bromo- or 3-bromo-
substituted aldehydes (15d or 15f) demonstrated only 10e16%
conversion in 6 h but longer reaction time to 24 h improved con-
version significantly without ee erosion (Table 4, entries 12, 14).
Substrates with larger ortho-substitution, such as imine 14e and
aldehyde 15e, provided reduced reaction rate and enantiose-
lectivity, suggesting unfavorable steric interactions at that position
(Table 4, entries 5 and 13). To date there have been many proficient
catalysts reported for the aza-MBH or MBH reactions [12f], how-
ever, only a few can demonstrate good proficiency in both re-
actions, due to the very complex mechanisms behind this reaction
4. Experimental section
4.1. General information
All reagents unless specified otherwise are commercially avail-
able and purified by standard procedures [34]. Chloroform-d was
purchased from Cambridge Isotope Laboratories, USA and stored
over anhydrous potassium carbonate before use. Bromomethyl
methyl ether was distilled from anhydrous sodium sulfate and used
immediately after distillation. Cesium carbonate was dried before
reactions. Air and moisture sensitive reactions were performed
under a nitrogen atmosphere. Reactions were magnetically stirred
and monitored by thin-layer chromatography (TLC) using Merck
silica gel 60 F254 aluminium pre-coated plates (0.25 mm). Flash
column chromatography was performed on Merck silica gel 60
(0.015e0.040 mm). 1H, 13C, and 31P experiments were performed at
298 K on either a Bruker DPX 400 MHz spectrometer equipped with
a 5 mm QNP probe. Chemical shifts were reported in ppm using the
residual CHCl3 peak as an internal reference (dH ¼ 7.26 ppm,
dC ¼ 77.16 ppm). All 31P NMR spectroscopy was performed on a
Bruker DPX 400 MHz spectrometer at 298 K, and all spectra were
referenced to external H3PO4 (0 ppm). All spectra were processed
using Bruker TOPSPIN software versions 3.5pl7. Infrared spectra
were taken on Thermo Scientific Nicolet iS5FT-IR Spectrometer
with an attenuated total reflectance (ATR) accessory and maximum
absorption peaks were reported in cmꢀ1. High-resolution mass
analysis was provided by Australian Proteome Analysis Facility
(APAF), Macquarie University, Sydney, Australia. Chiral HPLC anal-
ysis was performed using a Shimadzu Prominence system with
either a Daicel Chiral Columns CHIRALPAK® ADeH column or a
Regis Chiral Technologies Whelk-O1 column. HPLC grade solvents
were degassed before use. Specific rotation was measured at
23e24 ꢁC on a P1010 digital polarimeter (Jasco, Japan). The
commercially available aldehydes were used for catalysts synthesis
class [12f]. Bifunctional catalyst b-isocupreidine (b-ICD) provided
aza-MBH [26] products in up to 99% ee and 54e80% yield over
24e36 h at ꢀ30 ꢁC, but demonstrated significantly lower profi-
ciency in MBH [27] product formation (up to 49% ee and 43e88%
yield over 72 h at ꢀ30 ꢁC), except for very reactive isatins [28] or
1,1,1,3,3,3-hexafluoroisopropyl acrylate (HFIPA) [29] as an activated
alkene. Other examples of bifunctional catalytic systems, active in
both aza-MBH and MBH reactions between MVK and aromatic
electrophiles are MOP-based Shi's [30] and He's [31] catalysts that
demonstrated low proficiency in MBH despite the promising ac-
tivity in the aza-MBH analogs. The chiral proline/imidazole

S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
523
except for 4,5-dibromopyrrole-2-carboxaldehyde 4 that was ob-
tained [35] via the bromination of pyrrole-2-carboxaldehyde 3. (S)-
MAPO 6 and aminophosphine 2 were synthesized by established
procedures [9,24]
portion and stirred at room temperature for 7.5 h. The mixture was
treated with water and the organic phase was extracted by
dichloromethane 3 times. The combined organic phases were
washed with brine, dried over anhydrous magnesium sulfate and
concentrated under vacuum. The residue was purified by flash
chromatography on silica gel (hexane/dichloromethane gradient)
to furnish 1b (44 mg, 51% yield) as a white solid. 1H NMR (400 MHz,
4.2. Experimental details
CDCl3) d 3.92 (bs, 1H), 4.18e4.34 (m, 2H), 5.96e6.12 (m, 1H), 6.36 (d,
4.2.1. General procedure for MBH or aza-MBH reactions
J ¼ 8.5 Hz, 1H), 6.73e6.81 (m, 1H), 6.94e7.13 (m, 7H), 7.21e7.33 (m,
4H), 7.34e7.39 (m, 3H), 7.42 (dd, J ¼ 3.3, 8.5 Hz, 1H), 7.49e7.55 (m,
1H), 7.62 (d, J ¼ 8.0 Hz, 1H), 7.79 (d, J ¼ 8.9 Hz, 1H), 7.92 (d,
J ¼ 8.6 Hz, 1H), 7.93 (d, J ¼ 8.1 Hz, 1H), 9.74 (bs, 1H); 31P NMR
Catalyst (10 mol%, 0.0025 mmol), imine or aldehyde
(0.025 mmol) and acid additive (10 mol%, 0.0025 mmol) were
combined under N2 from dichloromethane stock solutions in a
1.5 mL teflon capped vial with 4 Å molecular sieves. Dichloro-
methane was evaporated by nitrogen flow. Then reaction solvent
was added to the mixture (final concentration C ¼ 0.2 M to imine or
aldehyde after addition of MVK in the reaction solvent). A solution
of MVK (0.075 mmol) was added to the mixture at stirring at room
(162 MHz, CDCl3)
d
ꢀ12.38; 13C NMR (100 MHz, CDCl3)
d 41.08,
98.21, 108.20, 113.25, 121.99, 124.28, 126.09 (d, JCeP ¼ 2.2 Hz),
126.20, 127.22, 127.36, 127.42, 127.71, 128.19, 128.27, 128.38, 128.73
(d, JCeP ¼ 1.5 Hz), 128.85, 128.91 (d, JCeP ¼ 2.2 Hz), 130.07, 130.19,
131.70, 133.20, 133.57, 133.76, 134.08, 134.29, 134.36, 136.47 (d,
temperature. Aliquots (10 mL) of the reaction mixture were taken at
JCeP ¼ 8.1 Hz), 136.99 (d, JCeP ¼ 6.6 Hz), 141.69; IR (ATR, cmꢀ1
) n
0.5, 3, 6, 24 h and dried immediately by nitrogen flow to remove the
volatiles. The residue was re-dissolved in chloroform-d and filtered
to determine the conversion of starting material to product by 1H
NMR and then analyzed by chiral HPLC (1:4 i-propanol:hexane) to
determine ee ratios.
3416, 3051, 1617, 1596, 1512, 1492, 1431, 1293, 1254, 1152, 1092,
1024, 968; HRMS Found [MþH]þ, 691.03129. C37H28Br2N2P requires
[MþH]þ, 691.03364; [
a]
23 -41.98 (c 0.77, CHCl3).
D
4.2.4. (S)-N-((1H-indol-2-yl)methyl)-20-(diphenylphosphaneyl)-
[1,10-binaphthalen]-2-amine (1c)
4.2.2. (S)-N-((1H-pyrrol-2-yl)methyl)-20-(diphenylphosphaneyl)-
[1,10-binaphthalen]-2-amine (1a)
To a solution of (S)-(þ)-2-(diphenylphosphine)-1,10-binaphthyl-
20-amine 2 (100 mg, 0.221 mmol) and 2-pyrrolecarboxaldehyde
(42 mg, 0.441 mmol) in dry toluene (4 mL) was added a drop of
formic acid at room temperature and the reaction mixture was
stirred for 15 h. The mixture was pre-cooled (ice/NaCl bath) and dry
To a solution of (S)-(þ)-2-(diphenylphosphine)-1,10-binaphthyl-
20-amine
2 (50 mg, 0.11 mmol) and 2-indolecarboxaldehyde
(48 mg, 0.331 mmol) in dry toluene (2 mL) was added a drop of
formic acid at room temperature and the reaction mixture was
stirred for 15 h. The mixture was pre-cooled (ice/acetone bath) and
dry methanol (134 mL, 3.308 mmol) was added followed by the
addition of NaBH3CN (69.3 mg, 1.103 mmol, 10 eq) in one portion
and stirred 40 ꢁC for 3.5 h. The mixture was treated with water and
the organic phase was extracted by dichloromethane 3 times. The
combined organic phases were washed with brine, dried over
anhydrous magnesium sulfate and concentrated under vacuum.
The residue was purified by flash chromatography on silica gel
(hexane/dichloromethane gradient) to furnish 1c (45 mg, 70%
methanol (15 mL) was added followed by the addition of NaBH4
(21 mg, 0.551 mmol) in one portion and stirred at room tempera-
ture for 10 min. The mixture was treated with water and the
organic phase was extracted by dichloromethane 3 times. The
combined organic phases were washed with brine, dried over
anhydrous magnesium sulfate and concentrated under vacuum.
The residue was purified by flash chromatography on silica gel
(toluene; crude mixture/SiO2 as 1/250 w/w) to furnish 1a (28 mg,
yield) as a white solid. 1H NMR (400 MHz, CDCl3)
d 3.92 (bs, 1H),
24% yield) as a white solid. 1H NMR (400 MHz, CDCl3)
d 3.72 (bs,1H),
4.34e4.51 (m, 2H), 6.28e6.35 (m, 1H), 6.50 (d, J ¼ 8.5 Hz, 1H),
6.83e6.91 (m, 1H), 6.99e7.20 (m, 10H), 7.29e7.40 (m, 7H), 7.47 (dd,
J ¼ 3.0, 8.5 Hz, 1H), 7.50e7.57 (m, 2H), 7.66 (d, J ¼ 8.0 Hz, 1H), 7.76
(d, J ¼ 8.9 Hz, 1H), 7.93 (d, J ¼ 8.5 Hz, 1H), 7.94 (d, J ¼ 8.2 Hz, 1H),
4.15e4.28 (m, 2H), 5.93e5.98 (m,1H), 6.05e6.10 (m, 1H), 6.44e6.50
(m, 1H), 6.53 (d, J ¼ 8.0 Hz, 1H), 6.87e6.94 (m, 1H), 6.97e7.03 (m,
2H), 7.05e7.20 (m, 5H), 7.24e7.38 (m, 7H), 7.44 (dd, J ¼ 2.9, 8.6 Hz,
1H), 7.49e7.55 (m, 1H), 7.69 (d, J ¼ 8.0 Hz, 1H), 7.81 (d, J ¼ 8.9 Hz,
8.82 (bs, 1H); 31P NMR (162 MHz, CDCl3)
(100 MHz, CDCl3) d 41.82, 98.73,111.02,113.51,119.67,120.02,121.19,
d
ꢀ13.01; 13C NMR
1H), 7.91 (d, J ¼ 8.5 Hz, 1H), 7.92 (d, J ¼ 8.2 Hz, 1H), 8.23 (bs, 1H); 31
P
NMR (162 MHz, CDCl3)
d
ꢀ13.06; 13C NMR (100 MHz, CDCl3)
d 41.59,
121.97, 124.26, 126.25, 127.14, 127.37, 127.43, 127.83, 128.25, 128.32,
128.41, 128.69, 128.75, 128.86, 128.92, 129.02, 130.06, 130.41, 133.16
(d, JCeP ¼ 7.2 Hz), 133.52, 133.71, 133.88, 133.93 (d, JCeP ¼ 2.2 Hz),
134.08, 134.41, 135.80, 135.87, 135.96, 137.26, 137.36 (d,
104.80, 108.43, 113.59, 116.97, 121.88, 124.22, 125.44, 126.25, 126.33
(d, JCeP ¼ 2.2 Hz), 127.09, 127.36, 127.90, 128.23, 128.30, 128.35,
128.37, 128.50, 128.64, 128.68, 128.78, 128.84, 129.18, 129.93 (d,
JCeP ¼ 2.9 Hz), 130.69 (d, JCeP ¼ 1.5 Hz), 133.61 (d, JCeP ¼ 8.07 Hz),
133.81 (d, JCeP ¼ 8.5 Hz), 134.02 (d, JCeP ¼ 2.2 Hz), 134.41, 137.75,
JCeP ¼ 2.9 Hz), 137.52, 141.10, 141.43, 142.80; IR (ATR, cmꢀ1
) n 3416,
3050, 1886, 1618, 1596, 1512, 1490, 1455, 1430, 1339, 1292, 1216,
1152, 1091, 1023; HRMS Found [MþH]þ, 583.22877. C41H32N2P re-
141.43, 141.78, 143.42 (d, JCeP ¼ 2.2 Hz); IR (ATR, cmꢀ1
) n 3427, 3051,
23
quires [MþH]þ, 583.23031; [
a
]
-122.07 (c 1.0, CHCl3).
D
1618, 1596, 1511, 1492, 1430, 1332, 1298, 1255, 1214, 1151, 1089,
1024; HRMS Found [MþH]þ, 533.21356. C37H30N2P requires
[MþH]þ, 533.21466; [
a]
23 -15.94 (c 1.0, CHCl3).
4.2.5. (S)-(20-(((1H-imidazol-5-yl)methyl)amino)-[1,10-
D
binaphthalen]-2-yl)diphenylphosphine oxide (10)
4.2.3. (S)-N-((4,5-dibromo-1H-pyrrol-2-yl)methyl)-20-
(diphenylphosphaneyl) -[1,10-binaphthalen]-2-amine (1b)
To a solution of (S)-(þ)-2-(diphenylphosphine)-1,10-binaphthyl-
A
mixture of (S)-(þ)-2-(diphenylphosphine oxide)-1,10-
binaphthyl-20-amine
6
(150 mg, 0.320 mmol) and 4(5)-for-
mylimidazole (61.4 mg, 0.640 mmol) in the presence of 4 Å mo-
lecular sieves (0.7 g) in dry toluene (5.8 mL) was stirred at 110 ꢁC for
17 h in a pressure tube. The mixture was cooled down to room
temperature and then pre-cooled (ice/NaCl bath). After cooling, dry
methanol (0.5 mL) was added and then NaBH3CN (20 mg,
0.320 mmol) was added in one portion and stirred at room tem-
perature for 2.5 h. The mixture was filtered through folded filter.
20-amine
2
(56 mg,
0.124 mmol)
and
4,5-dibromo-2-
pyrrolecarboxaldehyde (63 mg, 0.248 mmol) in dry toluene
(2.3 mL) was added a drop of formic acid at room temperature and
the reaction mixture was stirred for 4.5 h. The mixture was pre-
cooled (ice/acetone bath) and dry methanol (15
mL) was added
followed by the addition of NaBH3CN (15.5 mg, 0.247 mmol) in one

524
S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
The reaction mixture was treated with water and the organic phase
was extracted with ethyl acetate (3 times). The combined organic
phases were washed with brine, dried over anhydrous magnesium
sulfate and concentrated under vacuum. The residue was purified
by flash chromatography on silica gel (1e10% ethanol in chloro-
form; gradient) to furnish 10 (119.1 mg, 68% yield) as yellow foam.
6.85e6.95 (m, 3H), 7.05e7.14 (m, 4H), 7.25 (d, J ¼ 8.5 Hz, 1H),
7.28e7.34 (m, 1H), 7.37 (d, J ¼ 8.0 Hz, 1H), 7.48e7.63 (m, 6H),
7.84e8.00 (m, 4H), 13.40 (bs, 1H); 31P NMR (162 MHz, CDCl3)
d
28.17; 13C NMR (100 MHz, CDCl3)
d 41.48, 112.39, 113.95 (d,
JCeP ¼ 5.1 Hz), 121.49, 124.11, 126.00, 126.72, 127.12, 127.48, 127.60,
127.78, 128.02, 128.32, 128.47, 128.54, 128.67, 128.79, 128.91, 129.04,
129.09, 129.17, 129.53, 129.95, 130.05, 130.53 (d, JCeP ¼ 2.9 Hz),
130.72, 132.07, 132.15, 132.33, 133.12, 133.41, 133.52 (d,
JCeP ¼ 10.3 Hz), 135.71 (d, JCeP ¼ 2.2 Hz), 142.00 (d, JCeP ¼ 8.7 Hz),
1H NMR (400 MHz, CDCl3)
d 4.06 (bs, 1H), 4.33e4.43 (m, 1H),
4.52e4.62 (m, 1H), 6.32 (d, J ¼ 8.3 Hz, 1H), 6.61e6.70 (m, 2H),
6.78e6.88 (m, 2H), 6.91e6.98 (m, 1H), 6.96 (d, J ¼ 9.0 Hz, 1H), 7.00
(s, 1H), 7.02e7.11 (m, 2H), 7.22 (d, J ¼ 8.3 Hz, 1H), 7.26e7.33 (m, 1H),
7.36 (d, J ¼ 7.9 Hz, 1H), 7.48 (d, J ¼ 8.9 Hz, 1H), 7.50e7.65 (m, 5H),
143.58, 147.54; IR (ATR, cmꢀ1
) n 3053, 1618, 1598, 1551, 1498, 1436,
1300, 1178, 1155, 1113, 1096, 1024, 998, 869, 810, 744, 722, 696, 633;
7.70 (s, 1H), 7.87e8.00 (m, 4H). 31P NMR (162 MHz, CDCl3)
d
28.16;
HRMS Found [MþH]þ, 550.20362. C36H29N3OP requires [MþH]þ,
13C NMR (100 MHz, CDCl3)
d
39.41, 113.23, 113.83 (d, JCeP ¼ 5 Hz),
550.20483; [a]
23 33.25 (c 1.0, CHCl3).
D
121.44, 124.23, 126.00, 126.65, 127.19, 127.25, 127.32, 127.83, 128.32,
128.55,128.64,128.67,128.73,128.85,128.92,129.10,129.24,129.62,
129.71, 129.72, 130.12 (d, J ¼ 2.3 Hz), 130.53, 130.59, 131.56, 132.01,
132.05, 132.10, 132.37, 133.41, 133.52, 135.68 (dd, JCeP ¼ 8.8, 2.2 Hz),
4.2.8. (S)-N-((1H-imidazol-2-yl)methyl)-20-
(diphenylphosphaneyl)-[1,10-binaphthalen]-2-amine (1e)
A solution of 11 (18.1 mg, 0.033 mmol) in neat phenylsilane
141.8 (d, JCeP ¼ 9.5 Hz), 144.42; IR (ATR, cmꢀ1
) n 3054, 1618, 1597,
(200 m
L) was heated at 90 ꢁC for 68 hours. The volatiles were
1497,1435,1342,1301,1258,1215,1153,1112; HRMS Found [MþH]þ,
removed via nitrogen blow down and the residue was purified by
flash chromatography on silica gel (hexane/ethyl acetate; gradient)
to yield 1e (8.1 mg, 46%) as a white foam. 1H NMR (400 MHz, CDCl3)
550.20391. C36H29N3OP requires [MþH]þ, 550.20483; [
(c 1.0, CHCl3).
a]
24 þ80.83
D
d
4.02 (t, J ¼ 5.8 Hz, 1H), 4.34 (dd, J ¼ 6.3, 17.5 Hz, 1H), 4.59 (dd,
4.2.6. (S)-N-((1H-imidazol-5-yl)methyl)-20-
J ¼ 5.3, 17.5 Hz, 1H), 6.41 (d, J ¼ 8.5 Hz, 1H), 6.79e6.90 (m, 3H),
6.92e7.00 (m, 3H), 7.02e7.10 (m, 3H), 7.11e7.17 (m, 1H), 7.23e7.38
(m, 7H), 7.40 (dd, J ¼ 3.2, 8.5 Hz, 1H), 7.50e7.57 (m, 1H), 7.65 (d,
J ¼ 8.1 Hz, 1H), 7.78 (d, J ¼ 9.0 Hz, 1H), 7.93 (d, J ¼ 8.4 Hz, 2H); 31P
(diphenylphosphaneyl)-[1,10-binaphthalen]- 2-amine (1d)
A solution of 10 (70.5 mg, 0.128 mmol) in neat phenylsilane
(80
m
L) was heated at 96 ꢁC for 19 hours. The volatiles were
removed via nitrogen blow down and the residue was purified by
flash chromatography on silica gel (hexane/ethyl acetate to ethyl
acetate/ethanol; gradient) to yield 1d (36.3 mg, 53%) as a white
NMR (162 MHz, CDCl3)
d
ꢀ12.79; 13C NMR (100 MHz, CDCl3)
d 42.01,
112.88, 116.38 (d, JCeP ¼ 8.6 Hz), 122.14, 124.18, 126.16 (d,
JCeP ¼ 2.2 Hz), 127.37, 127.30, 127.48, 127.51, 127.82, 128.30, 128.38,
128.40, 128.85, 128.94, 128.96, 129.03, 130.26, 133.13 (d,
JCeP ¼ 7.2 Hz), 133.33, 133.52, 133.92 (d, J ¼ 2.2 Hz), 133.97, 134.18,
134.434,135.00 (d, JCeP ¼ 7.3 Hz),136.68 (d, JCeP ¼ 6.7 Hz),136.88 (d,
JCeP ¼ 9.4 Hz), 140.87, 141.19, 141.84 (d, JCeP ¼ 2.2 Hz), 147.00; IR
foam. 1H NMR (400 MHz, CDCl3)
d 3.76 (bs, 1H), 4.21 (s, 2H), 6.53 (d,
J ¼ 8.4 Hz, 1H), 6.71e6.75 (m, 1H), 6.86e6.92 (m, 1H), 6.97e7.04 (m,
2H), 7.05e7.20 (m, 6H), 7.21e7.34 (m, 6H), 7.35e7.38 (m, 1H), 7.45
(dd, J ¼ 2.8, 8.6 Hz, 1H), 7.47e7.53 (m, 1H), 7.69 (d, J ¼ 8.0 Hz, 1H),
7.80 (d, J ¼ 8.9 Hz, 1H), 7.90 (d, J ¼ 8.5 Hz, 2H); 31P NMR (162 MHz,
(ATR, cmꢀ1
) n 3050, 1618, 1596, 1511, 1493, 1431, 1295, 1262, 1215,
CDCl3)
d
ꢀ13.61; 13C NMR (100 MHz, CDCl3)
d
40.47, 113.44, 116.43
1151,1091, 1023, 996, 914,852, 810, 773, 739, 694, 629; HRMS Found
23
(d, JCeP ¼ 8.7 Hz), 121.89, 124.22, 126.27, 126.40 (d, JCeP ¼ 2.9 Hz),
127.06, 127.29, 127.37, 127.89, 128.25, 128.32, 128.55, 128.60, 128.66,
128.71, 128.77, 129.84, 130.69, 133.08 (d, JCeP ¼ 7.0 Hz), 133.40,
133.59, 133.70, 133.90, 134.09 (d, JCeP ¼ 2.2 Hz), 134.39, 134.54,
136.62 (d, JCeP ¼ 11.5 Hz), 137.22 (d, JCeP ¼ 9.5 Hz), 137.79 (d,
JCeP ¼ 12.5 Hz), 141.43, 141.76, 142.97 (d, JCeP ¼ 2.2 Hz); IR (ATR,
[MþH]þ, 534.20915. C36H29N3P requires [MþH]þ, 534.20991; [
-55.16 (c 1.0, CH2Cl2).
a]
D
4.2.9. (S)-(20-(((1H-benzo[d]imidazol-2-yl)methyl)amino)-[1,10-
binaphthalen]-2-yl)diphenylphosphine oxide (12)
A
mixture of (S)-(þ)-2-(diphenylphosphine oxide)-1,10-
cmꢀ1
) n 3051, 1618, 1596, 1492, 1430, 1340, 1301, 1251, 1214, 1150,
binaphthyl-20-amine 6 (200 mg, 0.426 mmol) and 2-formyl-1H-
benzoimidazole (187 mg, 1.278 mmol) in the presence of 4 Å MS
(0.85 g) in dry toluene (8 mL) was stirred at 110 ꢁC for 14 h in a
pressure tube. The mixture was cooled down to room temperature
and then pre-cooled (ice/NaCl bath). After cooling, dry methanol
(3 mL) was added and then NaBH4 (54 mg,1.43 mmol) was added in
one portion and stirred at room temperature for 1 h. The mixture
was filtered through folded filter. The reaction mixture was treated
with water and the organic phase was extracted with ethyl acetate
(3 times). The combined organic phases were washed with brine,
dried over anhydrous magnesium sulfate and concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel (20e50% of hexane in ethyl acetate; gradient) to furnish 12
(212 mg, 83% yield) as yellow foam. The sample for analysis was
recrystallised from toluene/hexane. 1H NMR (400 MHz, CDCl3)
1088; HRMS Found [MþH]þ, 534.20872. C36H29N3P requires
23
[MþH]þ, 534.20991; [
a]
-2.68 (c 1.0, CH2Cl2).
D
4.2.7. (S)-(20-(((1H-imidazol-2-yl)methyl)amino)-[1,10-
binaphthalen]-2-yl)diphenylphosphine oxide (11)
The mixture of (S)-(þ)-2-(diphenylphosphine oxide)-1,10-
binaphthyl-20-amine
6
(200 mg,
0.426 mmol)
and
2-
formylimidazole (82 mg, 0.852 mmol) in the presence of 4 Å MS
(0.85 g) in dry toluene (8 mL) was stirred at 110 ꢁC for 70 h in a
pressure tube. The mixture was cooled down to room temperature
and then pre-cooled (ice/NaCl bath). After cooling, dry methanol
(2 mL) was added and then NaBH4 (80 mg, 2.13 mmol) was added in
one portion and stirred at room temperature for 3 h. The mixture
was filtered through folded filter. The reaction mixture was treated
with water and the organic phase was extracted with ethyl acetate
(3 times). The combined organic phases were washed with brine,
dried over anhydrous magnesium sulfate and concentrated under
vacuum. The residue was purified by flash chromatography on silica
gel (toluene/ethyl acetate to ethyl acetate; gradient) to furnish 11
(80.4 mg, 34.3% yield) as yellow foam. 1H NMR (400 MHz, CDCl3)
d
4.38 (t, J ¼ 6.6 Hz, 1H), 4.63 (dd, J ¼ 6.3, 18.0 Hz, 1H), 4.88 (dd,
J ¼ 7.0, 18.0 Hz, 1H), 6.30 (d, J ¼ 8.4 Hz, 1H), 6.62e6.70 (m, 2H),
6.74e6.80 (m, 1H), 6.82e6.95 (m, 3H), 7.08e7.38 (m, 7H), 7.44 (d,
J ¼ 9.0 Hz, 1H), 7.50e7.67 (m, 6H), 7.76 (d, J ¼ 7.9 Hz, 1H), 7.93e8.06
(m, 4H), 13.99 (bs, 1H); 31P NMR (162 MHz, CDCl3)
d
ꢀ27.87; 13C
NMR (100 MHz, CDCl3)
d 42.60, 111.75, 112.54, 113.89 (d,
d
4.23 (t, J ¼ 6.5 Hz, 1H), 4.46 (dd, J ¼ 6.1, 17.5 Hz, 1H), 5.20 (dd,
JCeP ¼ 5.1 Hz), 118.72, 121.46, 121.89, 124.23, 125.44, 125.95, 126.65,
J ¼ 7.1, 17.5 Hz, 1H), 6.23 (d, J ¼ 8.4 Hz, 1H), 6.69e6.77 (m, 3H),
127.20, 127.43, 127.55, 127.80, 127.94, 128.35, 128.77, 128.89, 129.00,

S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
525
Chem. 6 (2008) 433e436;
j) H. Maeda, Y. Haketa, T. Nakanishi, J. Am. Chem. Soc. 129 (2007)
13661e13674.
129.09, 129.68, 129.78, 130.23 (d, JCeP ¼ 3.8 Hz), 130.72, 132.07 (d,
JCeP ¼ 2.2 Hz), 132.11, 132.20, 133.25, 133.48, 133.52, 133.59, 135.75
(d, JCeP ¼ 2.2 Hz),142.01,143.86,154.91; IR (ATR, cmꢀ1
) n 3052,1619,
[4] a) R. Yamakado, T. Sakurai, W. Matsuda, S. Seki, N. Yasuda, S. Akine, H. Maeda,
Chem. Eur. J. 22 (2016) 626e638;
1597, 1507, 1434, 1300, 1269, 1220, 1175, 1154, 1113; HRMS Found
[MþH]þ, 600.21910. C40H31N3OP requires [MþH]þ, 600.22048;
b) B. Dong, T. Sakurai, Y. Honsho, S. Seki, H. Maeda, J. Am. Chem. Soc. 135
(2013) 1284e1287;
23
[
a]
-117.44 (c 1.0, CHCl3).
D
c) B. Dong, T. Sakurai, Y. Bando, S. Seki, K. Takaishi, M. Uchiyama, A. Muranaka,
H. Maeda, J. Am. Chem. Soc. 135 (2013) 14797e14805;
d) Y. Haketa, Y. Honsho, S. Seki, H. Maeda, Chem. Eur. J. 18 (2012) 7016e7020;
e) Y. Haketa, S. Sasaki, N. Ohta, H. Masunaga, H. Ogawa, N. Mizuno, F. Araoka,
H. Takezoe, H. Maeda, Angew. Chem. Int. Ed. 49 (2010) 10079e10083.
[5] M. Nishio, Y. Umezawa, K. Honda, S. Tsuboyama, H. Suezawa, CrystEngComm
11 (2009) 1757e1788.
4.2.10. (S)-N-((1H-benzo[d]imidazol-2-yl)methyl)-20-
(diphenylphosphaneyl)-[1,10-binaphthalen]-2-amine (1f)
A solution of 12 (40 mg, 0.067 mmol) in neat phenylsilane
(300 m
L) was heated at 110 ꢁC for 14 hours. The volatiles were
[6] a) M. Roucan, M. Kielmann, S.J. Connon, S.S.R. Bernhard, M.O. Senge, Chem.
Commun. 54 (2018) 26e29;
removed by nitrogen flow and the residue was purified by flash
chromatography on silica gel (20e40% of hexane in ethyl acetate;
gradient) to yield 1f (32.8 mg, 84% yield) as white foam. 1H NMR
b) G. Cafeo, M. De Rosa, F.H. Kohnke, P. Neri, A. Soriente, L. Valenti, Tetrahe-
dron Lett. 49 (2008) 153e155;
c) G. Hirata, H. Maeda, Org. Lett. 20 (2018) 2853e2856;
d) M. Kielmann, M.O. Senge, Angew. Chem. Int. Ed. 57 (2018) 2e26, in press;
e) D.S. Kim, J.L. Sessler, Chem. Soc. Rev. 44 (2015) 532e546;
(400 MHz, CDCl3)
d
4.18 (t, J ¼ 5.9 Hz, 1H), 4.55 (dd, J ¼ 6.5, 18.0 Hz,
1H), 4.77 (dd, J ¼ 5.4, 18.0 Hz, 1H), 6.40 (d, J ¼ 8.5 Hz, 1H), 6.76e6.84
(m, 1H), 6.96e7.08 (m, 6H), 7.10e7.20 (m, 3H), 7.28e7.40 (m, 9H),
7.45 (dd, J ¼ 3.4, 8.5 Hz, 1H), 7.51e7.57 (m, 1H), 7.61 (d, J ¼ 8.0 Hz,
1H), 7.73 (d, J ¼ 9.0 Hz, 1H), 7.94 (d, J ¼ 8.2 Hz, 1H), 7.95 (d,
ꢀ
ꢀ
f) G. Aragay, D. Hernandez, B. Verdejo, E. Escudero-Adan, M. Martínez,
P. Ballester, Molecules 20 (2015) 16672;
g) L. Adriaenssens, C. Estarellas, A. Vargas Jentzsch, M. Martinez Belmonte,
S. Matile, P. Ballester, J. Am. Chem. Soc. 135 (2013) 8324e8330;
J ¼ 8.6 Hz, 1H), 10.52 (bs, 1H); 31P NMR (162 MHz, CDCl3)
d
ꢀ12.52;
ꢀ
ꢀ
h) J.R. Blas, J.M. Lopez-Bes, M. Marquez, J.L. Sessler, F.J. Luque, M. Orozco,
Chem. Eur. J. 13 (2007) 1108e1116;
13C NMR (100 MHz, CDCl3)
d
42.02, 112.61, 116.54 (d, JCeP ¼ 8.2 Hz),
i) J.S. Park, C. Bejger, K.R. Larsen, K.A. Nielsen, A. Jana, V.M. Lynch,
J.O. Jeppesen, D. Kim, J.L. Sessler, Chem. Sci. 3 (2012) 2685e2689.
[7] a) U. Lüning, Angew. Chem. Int. Ed. 51 (2012) 8163e8165;
b) J. Choudhury, S. Semwal, Synlett 29 (2018) 141e147;
c) E. Peris, Chem. Rev. 11 (8) (2018) 9988e10031;
d) A.J.M. Miller, Dalton Trans. 46 (2017) 11987e12000;
e) V. Blanco, D.A. Leigh, V. Marcos, Chem. Soc. Rev. 44 (2015) 5341e5370;
f) D. Troegel, J. Stohrer, Coord. Chem. Rev. 255 (2011) 1440e1459.
[8] a) N.J. Zondlo, Acc. Chem. Res. 46 (2013) 1039e1049;
b) M. Nishio, Tetrahedron 61 (2005) 6923e6950.
122.30, 122.95, 124.27, 126.08 (d, JCeP ¼ 2.2 Hz), 126.43, 127.40,
127.58, 127.62, 127.78, 128.34, 128.42, 128.99, 129.09, 129.15, 129.94,
130.52, 133.17, 133.26, 133.44, 133.87 (d, JCeP ¼ 1.5 Hz), 134.06,
134.12, 134.33, 134.44, 136.25 (d, JCeP ¼ 6.6 Hz), 136.67 (d,
JCeP ¼ 5.1 Hz), 140.55, 140.86, 141.13 (d, JCeP ¼ 2.2 Hz), 153.71 (d,
JCeP ¼ 1.5 Hz); IR (ATR, cmꢀ1
) n 3051, 1618, 1596, 1511, 1492, 1452,
1428, 1323, 1293, 1266, 1216, 1151, 1092, 1023, 998, 951, 917, 845,
809, 737, 694, 628. HRMS Found [MþH]þ, 584.22415. C40H31N3P
[9] J.-M. Garnier, C. Anstiss, F. Liu, Adv. Synth. Catal. 351 (2009) 331e338.
€
[10] a) D. Salinger, R. Brückner, Synlett 2009 (2009) 109e111;
requires [MþH]þ, 584.22556; [
a]
23 -126.95 (c 1.0, CH2Cl2).
D
b) T. Ooi, K. Ohmatsu, K. Maruoka, J. Am. Chem. Soc. 129 (2007) 2410e2411;
ꢁ
ꢁ
ꢁ
ꢁ
ꢀꢁ
ꢁ
c) S. Vyskocil, M. Smrcina, V. Hanus, M. Polasek, P. Kocovský, J. Org. Chem. 63
(1998) 7738e7748;
Acknowledgements
d) Y.-L. Yang, C.-K. Pei, M. Shi, Org. Biomol. Chem. 9 (2011) 3349e3358;
e) P.N.M. Botman, O. David, A. Amore, J. Dinkelaar, M.T. Vlaar, K. Goubitz,
J. Fraanje, H. Schenk, H. Hiemstra, J.H. van Maarseveen, Angew. Chem. Int. Ed.
43 (2004) 3471e3473.
We are grateful to Macquarie University for an iMQRES schol-
arship to SE.
[11] C. Anstiss, F. Liu, Tetrahedron 66 (2010) 5486e5491.
[12] a) D. Cantillo, C.O. Kappe, J. Org. Chem. 75 (2010) 8615e8626;
b) I.T. Raheem, E.N. Jacobsen, Adv. Synth. Catal. 347 (2005) 1701e1708;
c) K.E. Price, S.J. Broadwater, B.J. Walker, D.T. McQuade, J. Org. Chem. 70
(2005) 3980e3987;
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2018.12.016.
d) P. Buskens, J. Klankermayer, W. Leitner, J. Am. Chem. Soc. 127 (2005)
16762e16763;
e) V.K. Aggarwal, S.Y. Fulford, G.C. Lloyd-Jones, Angew. Chem. Int. Ed. 44
(2005) 1706e1708;
References
f) R. Kenny, F. Liu, Chem. Rec. 17 (2017) 535e553.
[13] a) R. Kenny, F. Liu, Eur. J. Org. Chem. (2015) 5304e5319;
b) C. Anstiss, J.-M. Garnier, F. Liu, Org. Biomol. Chem. 8 (2010) 4400e4407;
c) J.-M. Garnier, F. Liu, Org. Biomol. Chem. 7 (2009) 1272e1275.
[14] K. Junge, G. Oehme, A. Monsees, T. Riermeier, U. Dingerdissen, M. Beller,
J. Organomet. Chem. 675 (2003) 91e96.
[1] a) A. Domagala, T. Jarosz, M. Lapkowski, Eur. J. Med. Chem. 100 (2015)
176e187;
b) S. Said Fatahala, S. Hasabelnaby, A. Goudah, G. Mahmoud, R. Helmy Abd-El
Hameed, Molecules 22 (2017) 461;
[15] a) A.D. Burrows, M.F. Mahon, M. Varrone, Dalton Trans. (2003) 4718e4730;
b) X. Shu, H. Liang, Q. Wu, F. Zhou, X. Zheng, H. Fu, B. Xu, R. Li, C. Zhang,
H. Chen, RSC Adv. 7 (2017) 14816e14823;
c) E. Yasui, M. Wada, N. Takamura, Tetrahedron Lett. 50 (2009) 4762e4765;
ꢀ
d) A. Aiello, E. Fattorusso, A. Giordano, M. Menna, W.E.G. Müller, S. Perovic-
€
Ottstadt, H.C. Schroder, Bioorg. Med. Chem. 15 (2007) 5877e5887.
c) X.-L. Zheng, C.-Y. Zheng, F.-D. Zhou, H.-Y. Fu, M.-L. Yuan, R.-X. Li, B. Xu,
H. Chen, Chin. Chem. Lett. 27 (2016) 678e680;
d) R. Luo, H.-r. Liang, X.-l. Zheng, H.-y. Fu, M.-l. Yuan, R.-x. Li, H. Chen, Catal.
Commun. 50 (2014) 29e33.
[2] a) N. Grüger, H. Wadepohl, L.H. Gade, Dalton Trans. 41 (2012) 14028e14030;
b) A. Gualandi, L. Cerisoli, H. Stoeckli-Evans, D. Savoia, J. Org. Chem. 76 (2011)
3399e3408;
c) C.A. Caputo, N.D. Jones, Dalton Trans. (2007) 4627e4640;
d) C. Mazet, L.H. Gade, Chem. Eur. J. 8 (2002) 4308e4318.
[3] a) H. Maeda, Y. Kusunose, Chem. Eur. J. 11 (2005) 5661e5666;
b) R. Yamakado, Y. Ashida, R. Sato, Y. Shigeta, N. Yasuda, H. Maeda, Chem. Eur.
J. 23 (2017) 4160e4168;
[16] A.M. Brosnahan, A. Talbot, B.A. McKeown, S.E. Kalman, T.B. Gunnoe, D.H. Ess,
M. Sabat, J. Organomet. Chem. 793 (2015) 248e255.
€
[17] H.-U. Blaser, H.-P. Buser, R. Hausel, H.-P. Jalett, F. Spindler, J. Organomet.
Chem. 621 (2001) 34e38.
[18] a) M.M. Siddiqui, L. Radhakrishna, J.T. Mague, M.S. Balakrishna, J. Organomet.
Chem. 824 (2016) 15e24;
c) A. Kuno, N. Tohnai, N. Yasuda, H. Maeda, Chem. Eur. J. 23 (2017)
11357e11365;
d) Y. Haketa, Y. Bando, K. Takaishi, M. Uchiyama, A. Muranaka, M. Naito,
H. Shibaguchi, T. Kawai, H. Maeda, Angew. Chem. Int. Ed. 51 (2012)
7967e7971;
e) H. Maeda, Y. Bando, K. Shimomura, I. Yamada, M. Naito, K. Nobusawa,
H. Tsumatori, T. Kawai, J. Am. Chem. Soc. 133 (2011) 9266e9269;
f) H. Maeda, Y. Kusunose, Y. Mihashi, T. Mizoguchi, J. Org. Chem. 72 (2007)
2612e2616;
g) H. Maeda, T. Shirai, Y. Bando, K. Takaishi, M. Uchiyama, A. Muranaka,
T. Kawai, M. Naito, Org. Lett. 15 (2013) 6006e6009;
b) M.F. Semmelhack, A. Chlenov, D.M. Ho, J. Am. Chem. Soc. 127 (2005)
7759e7773.
[19] a) J. Liu, H. Li, R. Dühren, J. Liu, A. Spannenberg, R. Franke, R. Jackstell,
M. Beller, Angew. Chem. Int. Ed. 56 (2017) 11976e11980;
b) K. Dong, R. Sang, X. Fang, R. Franke, A. Spannenberg, H. Neumann,
R. Jackstell, M. Beller, Angew. Chem. Int. Ed. 56 (2017) 5267e5271;
c) H. Li, H. Neumann, M. Beller, Chem. Eur. J. 22 (2016) 10050e10056;
d) R. Jennerjahn, I. Piras, R. Jackstell, R. Franke, K.-D. Wiese, M. Beller, Chem.
Eur. J. 15 (2009) 6383e6388;
e) C.M. So, Z. Zhou, C.P. Lau, F.Y. Kwong, Angew. Chem. Int. Ed. 47 (2008)
6402e6406;
h) Y. Haketa, H. Maeda, Chem. Eur. J. 17 (2011) 1485e1492;
i) H. Maeda, M. Terasaki, Y. Haketa, Y. Mihashi, Y. Kusunose, Org. Biomol.

526
S.S. Eliseenko, F. Liu / Tetrahedron 75 (2019) 518e526
f) W.C. Fu, Z. Zhou, F.Y. Kwong, Organometallics 35 (2016) 1553e1558;
b) M. Shi, Y.-M. Xu, Angew. Chem. Int. Ed. 41 (2002) 4507e4510.
[27] M. Shi, J.-K. Jiang, Tetrahedron: Asymmetry 13 (2002) 1941e1947.
[28] a) F. Zhong, G.-Y. Chen, Y. Lu, Org. Lett. 13 (2011) 82e85;
b) X.-Y. Guan, Y. Wei, M. Shi, Chem. Eur. J. 16 (2010) 13617e13621.
[29] a) A. Nakano, S. Kawahara, S. Akamatsu, K. Morokuma, M. Nakatani,
Y. Iwabuchi, K. Takahashi, J. Ishihara, S. Hatakeyama, Tetrahedron 62 (2006)
381e389;
b) Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama, J. Am. Chem. Soc.
121 (1999) 10219e10220.
[30] a) M. Shi, Y.-H. Liu, L.-H. Chen, Chirality 19 (2007) 124e128;
b) Y.-H. Liu, L.-H. Chen, M. Shi, Adv. Synth. Catal. 348 (2006) 973e979.
[31] C. Wang, L. Wang, S. Zeng, S. Xu, Z. He, Phosphorus Sulfur Silicon Relat. Elem.
188 (2013) 1548e1554.
[32] N. Utsumi, H. Zhang, F. Tanaka, C.F. Barbas, Angew. Chem. Int. Ed. 46 (2007)
1878e1880.
[33] S.-H. Chen, B.-C. Hong, C.-F. Su, S. Sarshar, Tetrahedron Lett. 46 (2005)
8899e8903.
[34] W.L.F. Armarego, C.L.L. Chai, Purification of Laboratory Chemicals, sixth ed.,
Butterworth-Heinemann, 2009, 6 ed.
[35] S.T. Handy, J.J. Sabatini, Org. Lett. 8 (2006) 1537e1539.
g) O.Y. Yuen, M. Charoensak, C.M. So, C. Kuhakarn, F.Y. Kwong, Chem. Asian J.
10 (2015) 857e861;
h) J.V. Suarez-Meneses, E. Bonilla-Reyes, E.A. Ble-Gonzalez, M.C. Ortega-Alfaro,
R.A. Toscano, A. Cordero-Vargas, J.G. Lopez-Cortes, Tetrahedron 70 (2014)
1422e1430;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
i) A. Zapf, R. Jackstell, F. Rataboul, T. Riermeier, A. Monsees, C. Fuhrmann,
N. Shaikh, U. Dingerdissen, M. Beller, Chem. Commun. (2004) 38e39.
[20] D. Pingen, C. Müller, D. Vogt, Angew. Chem. Int. Ed. 49 (2010) 8130e8133.
[21] G.T. Venkanna, H.D. Arman, Z.J. Tonzetich, ASC Catal. 4 (2014) 2941e2950.
[22] X. Liu, H. Nan, W. Sun, Q. Zhang, M. Zhan, L. Zou, Z. Xie, X. Li, C. Lu, Y. Cheng,
Dalton Trans. 41 (2012) 10199e10210.
[23] K. Moonen, I. Laureyn, C.V. Stevens, Chem. Rev. 104 (2004) 6177e6216.
[24] C. Anstiss, P. Karuso, M. Richardson, F. Liu, Molecules 18 (2013) 2788.
[25] Catalysts 1aef bind to solvent molecules that cannot be removed without
significant catalyst decomposition. All catalysts demonstrated partial
decomposition over long-term high vacuum exposure. The attempts to
replace solvent molecules with dichloromethane or deuterated chloroform
via co-evaporation by nitrogen flow led to partial decomposition of catalysts
as well.
[26] a) M. Shi, M.-J. Qi, X.-G. Liu, Chem. Commun. (2008) 6025e6027;