Versatile and Enantioselective Preparation of Planar-Chiral Metallocene-Fused 4-Dialkylaminopyridines and Their Application in Asymmetric Organocatalysis

Article abstract of DOI:10.1021/acscatal.9b04438

A series of ferrocene-fused planar-chiral N-tosyl-4-pyridones (S)-2b-d were prepared in enantiomerically pure forms. Starting with the chiral ferrocenyl acetals, 1-[(2S,4S)-4-methoxymethyl-1,3-dioxan-2-yl]-1′,2′,3′,4′,5′-R₅-ferrocenes ((-)-3b,

Full text of DOI:10.1021/acscatal.9b04438

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Article
Versatile and Enantioselective Preparation of Planar-Chiral Metallocene-Fused
4-Dialkylaminopyridines and Their Application in Asymmetric Organocatalysis
Kazuhiro Yoshida, Qiang Liu, Risa Yasue, Shiro Wada,
Ryosuke Kimura, Takuma Konishi, and Masamichi Ogasawara
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04438 • Publication Date (Web): 21 Nov 2019
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Versatile and Enantioselective Preparation of Planar-
Chiral Metallocene-Fused 4-Dialkylaminopyridines
and Their Application in Asymmetric
Organocatalysis
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Kazuhiro Yoshida,*,† Qiang Liu,‡,§ Risa Yasue,† Shiro Wada,† Ryosuke Kimura,† Takuma
Konishi,‡ and Masamichi Ogasawara*,‡
† Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan
‡ Department of Natural Science, Graduate School of Science and Technology and Research
Cluster on "Innovative Chemical Sensing", Tokushima University, Tokushima 770-8506, Japan
§ Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo 001-0021, Japan
Abstract: A series of ferrocene-fused planar-chiral N-tosyl-4-pyridones (S)-2b-d were prepared
in enantiomerically pure forms. Starting with the chiral ferrocenyl acetals, 1-[(2S,4S)-4-
methoxymethyl-1,3-dioxan-2-yl]-1',2',3',4',5'-R5-ferrocenes ((–)-3b, R = Me; (–)-3c, R = Ph; (–)-
3d, R = Bn), N-tosylamino and formyl groups were introduced at the 1- and 2-positions of the
ferrocene cores in (S)-11b-d with control of the planar chirality. After the reaction with
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ethynylmagnesium bromide, generated propargyl alcohol derivatives (S)-17 were treated with
MnO2 and catalytic TBAI to give the planar-chiral pyridones by the iodide-catalyzed cyclization.
This method is highly practical with a shorter and higher-yield sequence without using noble
metal catalysts. Planar-chiral ferroco-pyridones (S)-2b-d were reacted with various Me3Si-NR'2
to give a library of ferrocene-fused 4-dialkylaminopyridines ((S)-1, DAAPs) in high yields as
single-enantiomers by the detosylative amination. The cymantrene-fused DAAPs were also
prepared in the same way. The library of the chiral DAAPs were examined in the two
asymmetric reactions as organocatalysts, and some newly prepared Fc-DAAPs showed better
enantioselectivity than the known species.
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Keywords: planar-chiral; ferrocene; cymantrene; enantioselective; 4-pyridone; 4-
dialkylaminopyridine; organocatalyst; cyclization
Introduction
Ferrocene is a cylindrical compound with unique three-dimensional properties.1,2 Introduction
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of two different substituents at the 1- and 2-positions of an Fe(II)-bound h -cyclopentadienyl
ligand breaks the symmetry to induce planar chirality in the molecule (Figure 1, left).3 The
ferrocene-based planar chirality has been proven to be useful chiral scaffolds in asymmetric
synthesis, and various such ferrocene derivatives have been utilized in a wide range of
asymmetric reactions as chiral ligands4 and chiral catalysts.5,6
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NR2
Y
Y
Fe
N
Fe
Fe
X
X
R'5
1
R2 = Me2, -(CH2)4-
R' = Me, Ph
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Figure 1. Enantiomeric pair of 1,2-disubstituted ferrocene (left) and Fu's ferrocene-fused planar-
chiral 4-dialkylaminopyridines 1 (right).
In 1990s, G. C. Fu employed this design concept for desymmetrizing flat-shaped N-
heteroarenes, and since then various ferrocene-fused 4-dialkylaminopyridines (Fc-DAAPs; 1;
Figure 1, right) were prepared and applied in asymmetric organocatalysis. Among many chiral 4-
dialkylaminopyridine derivatives reported so far,7,8 Fc-DAAPs are arguably the most successful
compounds.6 And indeed, 1 showed excellent enantioselectivity in a variety of asymmetric
transformations.9 In spite of the exceptional catalytic properties of 1, applications of these stylish
molecules have been rather limited9,10 probably due to their limited availability. The synthetic
sequence developed by Fu is shown in Scheme 1. Two major drawbacks in this synthetic
protocol are (i) necessity of the late stage chiral resolution of preformed racemic 1, and (ii)
limited diversity with respect to a substituent at the 4-position in the pyridine ring.9b,9c,11
A
dialkylamino group at the 4-pyridyl position, which plays important roles in controlling the
catalytic activity/selectivity of chiral DAAPs,12 was introduced in the middle stage of the
synthetic sequences. This means that each derivative of 1 with a different 4-substituent needs to
be prepared as a respective racemate through the independent reaction sequence, and, naturally,
the late stage chiral resolution of each compound is essential.
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NR2
NR2
chiral
resolution
(R)-1
(S)-1
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Fe
N
N+
O–
N
R'5
rac-1
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Scheme 1. Fu's Original Synthesis of rac-1 and Enentiomeric Resolution.
In 2015, we reported an enantioselective synthesis of Fc-DAAPs and related compounds,
which partly overcame the drawbacks in the Fu's original synthesis of 1 (Scheme 2).13 The three
features of our synthetic strategy are: (i) introduction of proper substituents at the 1- and 2-
positions of a ferrocene platform with controlling its planar chirality utilizing a chiral ortho-
directing group (3 to 4 in Scheme 2),14 (ii) construction of the ferrocene-fused 4-pyridones by the
ring-closing metathesis reaction (8 to 2 in Scheme 2), and (iii) the late stage introduction of
various substituents at the 4-position of the ferrocene-fused pyridines (2 to 1, 9, and 10). The
chiral 1,3-dioxan-2-yl group in 3, developed by Kagan and his coworkers,15-17 is a powerful chiral
directing group for the highly diastereoselective lithiation of 3 (>99% de). Planar-chiral 4-
pyridones 2, obtained in essentially enantiomerically pure forms, are versatile synthetic
intermediates, and they could be converted to the various pyridine derivatives with retention of
the planar chirality in 2. An analogous synthetic strategy was applied to the synthesis of
metallocene-fused planar-chiral phospholes recently.18
Although the synthetic method in Scheme 2 provided a library of the planar-chiral pyridine-
based nucleophilic organocatalysts, including previously unknown species, without chiral
resolution, it still had room for further improvement. For example, the reaction sequence in
Scheme 2 is somewhat lengthy and some steps require the use of expensive noble metal catalysts,
such as the Hoveyda/Grubbs-II catalyst,19 with relatively high catalyst loading. Furthermore, this
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"first-generation synthesis" shows severe steric hindrance. The method can be used for the
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preparation of the Cp- and Cp*-derivatives (R' = H or Me), but the corresponding h -C5Ph5-
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analogues were not obtained in the same way (vide infra). It should be mentioned that the C5H5-
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derivatives of 1 are synthetically far less important due to the lower-enantioselectivity on their
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applications in asymmetric catalysis, and the sterically demanding h -C5Ph5-analogues show
much better performance in many reactions.9b,d,e,m
O
O
O
O
H
H
H
H
N
H
CHO
1) tBuLi
TsN3
TsCl
Et3N
TsOH
H2O
H
H
H
allyl-Br
K2CO3
O
O
O
O
Fe
Fe
Fe
Fe
Fe
OMe
NH2
OMe
NH
Ts
OMe
OMe
N
2) reduction
Ts
Ts
R'5
(–)-5a
(+)-5b (not isolated)
R'5
R'5
R'5
(–)-4a[17]
4b (not isolated)
R'5
(+)-6a
(+)-6b
(+)-7a
(–)-3a (R' = H)[15]
(+)-7b
single enantiomers
(–)-3b (R' = Me)[16]
single diastereomers
NR2
Me3Si-NR2
TiCl4
Fe
N
N
O
NR2 = NMe2 (w), pyrroridyl (x),
NEt2 (y), morpholyl (z),
NMeBn, isoindolyl
or HNR2,
DBU, TiCl4
O
R'5
(S)-1
H/G-II (cat.)
3 steps
Fe
Fe
N
N
Ts
Ts
Cl
Me
MeB(OH)2, K2CO3
Pd(PPh3)4 (cat.)
R'5
R'5
(S)-8a
(S)-8b
(S)-2a
(S)-2b
Fe
Fe
N
N
N
(COCl)2
[ref. 21]
Mes
Mes
Cl
R'5
Me5
Ru
O
(S)-9a
(S)-9b
(S)-10b
Cl
iPr
H/G-II
(Hoveyda/Grubbs-II)
Scheme 2. Enantioselective Synthesis of Ferrocene-Fused 4-Pyridones 2 and Pyridine
Derivatives 1, 9, and 1021: "First-Generation Synthesis" Using Ruthenium-Catalyzed Ring-
Closing Metathesis for Cyclization.13
With the background mentioned above, we started the present studies with intention to
overcome the limitations of the first generation synthesis of 1 (Scheme 2). The improved "second
generation synthesis" developed in this study is much shorter (i. e., more effective) and much
less costly without using the expensive noble metal catalysts. And more importantly, the newly
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developed synthesis can provide sterically demanding analogues of Fc-DAAPs which are with an
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(h -C5Ph5)Fe or (h -C5Bn5)Fe substructure. These bulky Fc-DAAP derivatives are synthetically
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more useful showing better enantioselectivity in many cases. It should be mentioned that the (h -
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C5Bn5)Fe derivatives are previously unknown and prepared for the first time through this study.
In this article, we would like to report the details of the innovative second-generation
enantioselective synthesis of planar-chiral Fc-DAAPs and their application in asymmetric
organocatalysis.
Results and Discussion
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h
Unsuccessful Attempts to Prepare
-C5Ph5-Derivatives of Fc-DAAPs by First
Generation Synthesis. As mentioned in the introduction section, our original method of
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enantioselective synthesis of Fc-DAAPs, shown in Scheme 2, works only for the h -C5H5- and
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h -C5Me5-derivatives, and the corresponding h -C5Ph5-derivatives could not be prepared in the
same way.
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The results of the unsuccessful attempts at preparing the h -C5Ph5-derivatives are summarized
in Scheme 3. Chiral acetal (–)-3c was prepared from 1-formyl-1',2',3',4',5'-
pentaphenylferrocene20 and (S)-4-methoxybutane-1,3-diol in 76% yield. Chiral (2S,4S)-4-
methoxymethyl-1,3-dioxan-2-yl substituent in 3c is an excellent chiral directing group,15,16 and
deprotonation of 3c took place with high diastereoselectivity of >99.5% de. Lithiation of 3c
t
using BuLi at –78 °C in THF followed by a reaction with tosyl azide gave the corresponding
ferrocenyl azide, and subsequently the crude azide was reduced under a hydrogen atmosphere in
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the presence of catalytic Pd/C to give ferrocenylamine (–)-4c in 84% yield (for two steps). The
1H- and 13C-NMR analyses of (–)-4c clarified the compound to be essentially diastereomerically
pure. After N-tosylation of (–)-4c in >99%, N-allylation of (–)-5c was examined. To our
disappointment, however, the N-allylation did not proceed under the conditions in Scheme 3 and
desired 6c could not be obtained. It was suspected that the robustness of (–)-5c toward the N-
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allylation might be ascribed to the steric hindrance by the bulky h -C5Ph5 ligand. To diminish the
steric problems in (–)-5c as much as possible, the N-allylation was also examined after
deprotection of the chiral 1,3-dioxanyl moiety, but the reaction on aldehyde (S)-11c did not
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afford N-allylated species 7c. At this stage, we gave up to pursue the synthesis of the (h -
C5Ph5)Fe-derivatives by the method in Scheme 2.
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O
H
1) tBuLi, TsN3
2) H2 w/ Pd/C
CHO
H
OMe
O
OH OH
CSA
Fe
Fe
Fe
OMe
Ph5
Ph5
(–)-3c (76%)
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O
H
O
O
H
H
H
TsCl, Et3N
DABCO
O
Fe
NH
Ts
OMe
NH2
OMe
Ph5
Ph5
(–)-4c (84%)
(–)-5c (99%)
TsOH
H2O
allyl-Br
K2CO3
O
H
CHO
H
O
Fe
NH
Ts
Fe
OMe
N
Ts
Ph5
(S)-11c (99%)
Ph5
6c (0%)
allyl-Br
K2CO3
CHO
Fe
N
Ts
Ph5
7c (0%)
Scheme 3. Unsuccessful Attempts to Prepare Pentaphenylferrocene-Fused DAAP Derivatives by
First Generation Synthesis.
Development of Transition-Metal Free Iodide-Catalyzed Cyclization Producing 4-
Pyridones 2. During our investigations on the transformation of pyridone (S)-2a to pyridine (S)-
1ax,13,22 we encountered the formation of unexpected "ring-opening" product (S)-12 using an
equimolar mixture of pyrrolidine and titanium(IV) chloride under the unoptimized conditions.
The formation of (S)-12 was rationalized as depicted in Scheme 4. In the presence of Lewis-
acidic TiCl4, pyrrolidine attacks at the b-olefinic carbon in (S)-2a to give intermediate 13, which
subsequently eliminates the tosylamide anion to give the ring-opening product via a proton shift.
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N
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pyrrolidine
TiCl4
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N
Fe
N
Ts
Fe NH
Ts
N
toluene
0 °C
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(S)-2a
(S)-12
(S)-1ax
(S)-1ax/(S)-12 = 1/1
proton shift
O
Cl4Ti–
O
H
H
Fe N–
Ts
Fe
N
Ts
N+
N+
13
Scheme 4. Formation of Ring-Opening Product (S)-12 by Reaction of Pyridone (S)-2a with
Pyrrolidine in the Presence of Titanium(IV) Chloride.
On the assumption that the reaction steps between 13 and (S)-12 were reversible, a transition-
metal-free cyclization process producing 4-pyridones 2 was pursued (Scheme 5).23 We
envisioned that enone 15, which possesses a potential leaving group "LG" on the b-sp2-carbon,
might undergo a cyclization providing pyridone 2 as in Scheme 5. For the success of this
pyridone formation instead of the ring-opening as in Scheme 4, the LG substituent in 16 must be
a better leaving group than the tosylamide moiety. Cyclization precursor 15 could be generated
in situ by the conjugate addition of a nucleophilic LG– to ynone 14. Whereas LG– would be
regenerated at the transformation of 16 to 2, a substoichiometric (catalytic) amount of LG– might
be sufficient.
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O
O–
O
5
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•
LG
H
LG–
Fe N–
Ts
Fe
Fe
NH
Ts
NH
Ts
LG
8
9
R'5
R'5
O–
R'5
14
15
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O
Fe
N
Ts
Fe
N
Ts
LG
LG–
R'5
R'5
16
2
Scheme 5. Strategy for Nucleophile-Catalyzed Cyclization of 1-Propynoyl-2-N-
tosylaminoferrocene 14.
At the outset, this idea was examined in the synthesis of pentaphenylferroco-pyridone 2c,
which could not be prepared by our first generation synthesis as mentioned in the previous
section. The results are summarized in Scheme 6. Treatment of aldehyde (S)-11c, which was
prepared as in Scheme 3, with ethynylmagnesium bromide afforded propargylic alcohol (–)-17c
in 95% yield as a diastereomeric mixture. Ynone (S)-14c could be prepared by the MnO2-
oxidation of (–)-17c in dichloromethane, but the compound was easily polymerized into
uncharacterized gummy materials and was not isolable. Due to the susceptibility of (S)-14c, a
direct conversion of (–)-17c into (S)-2c "in one pot" was tested. That is, propargylic alcohol (–)-
17c was reacted with manganese(IV) oxide in the presence of a catalytic nucleophile. After an
extensive survey of various nucleophiles, which include pyridine, DMAP, DABCO,
triethylamine, copper(I) iodide, etc., it was found that a reaction using tetrabutylammonium
iodide (TBAI; 0.5 equiv. to 17c) proceeded cleanly to produce (S)-2c in 99% yield (see the
Supporting Information for details).
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OH
CHO
MnO2
TBAI (0.5 equiv)
MgBr
Fe
Fe
NH
Ts
NH
Ts
7
8
9
Ph5
Ph5
(–)-17c (95%)
(S)-11c
O
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O
MnO2
Fe
N
Ts
Fe
NH
Ts
Ph5
Ph5
(S)-2c (99%)
(S)-14c
(not isolable)
Scheme 6. Iodide-Catalyzed Synthesis of Ferrocene-Fused 4-Pyridone 2c.
Deep red crystals of (–)-2c was grown by slow diffusion of pentane into the concentrated
dichloromethane solution of (–)-2c. The single-crystal X-ray crystallography revealed that the
compound was a single enantiomer. The unit cell contains two independent molecules, having
slightly different conformations, and the structure of one of the two crystallographically
independent molecules is shown in Figure 2.24 The absolute configuration of levorotatory 2c was
determined to be (S), which is consistent with the stereochemistry deduced from the
diastereoselective lithiation of (–)-3c.15,16 The tosyl group on N(1) takes the position opposite to
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the bulky h -C5Ph5 ligand avoiding steric interactions with the phenyl groups. On the other hand,
the space above the carbonyl moiety of the pyridone ring remains relatively open, which may be
an important issue for the conversion of 2c to dialkylaminopyridine derivatives 1 by the reactions
with trimethylsilylamines (vide infra).
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60
Figure 2. Ball-and-stick drawing of the single-crystal X-ray structure of (S)-(–)-2c with selected
atom numbering.24
Scheme 7 shows a plausible reaction mechanism for the iodide-catalyzed cyclization of 1-
propynoyl-2-N-tosylaminoferrocenes producing the ferrocene-fused N-tosyl-4-pyridones. The
iodide anion attacks the alkynyl terminal in ynone (S)-14, which is generated in situ by the
oxidation of propargylic alcohol (S)-17 with manganese(IV) oxide, to give intermediate A. After
the isomerization of allenol A into enone B, the intramolecular conjugate addition of the anionic
tosylamide to the enone moiety affords intermediate C. Subsequent elimination of the iodide
anion from C gives pyridone (S)-2 to complete the catalytic cycle. For the effective synthesis of
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(S)-2, the undesirable self-polymerization of (S)-14 should be avoided. Ynone (S)-14, generated
by the oxidation of (S)-17, needs to react with iodide anion faster than the self-polymerization.
This may be a reason why relatively high catalyst-loading (i.e., 50% TBAI) is required to realize
the high yields in this process. Although Scheme 7 could explain the formation of (S)-2,
involvement other processes, such as a radical mechanism, could not be ruled out.
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MnO2
(S)-17
O
O
Fe N H
Ts
I–
Fe
N
Ts
(S)-14
R'5
(S)-2
R'5
H
I
O–
•
H
O
I
Fe N–
Ts
Fe
N
Ts
H
A
C
R'5
R'5
O
H
Fe N–
Ts
I
R'5
B
Scheme 7. Plausible Reaction Mechanism for Iodide-Catalyzed Cyclization Producing
Ferrocene-Fused 4-Pyridones.
Optimization of Reaction Conditions for More Efficient Synthesis of Planar-Chiral
Ferrocene-Fused 4-Pyridones 2. With the iodide-catalyzed cyclization reaction in our hands,
the enantioselective synthesis of (S)-2c was finally accomplished. The synthetic sequence
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4
developed in this study is versatile and applicable to the synthesis of other ferrocene-fused
5
6
5
5
pyridones, such as 2b and 2d containing the (h -C5Me5)Fe and (h -C5Bn5)Fe moieties,
7
8
9
respectively.
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To enhance the practicality of this "second-generation synthesis", the reaction conditions for
each steps were thoroughly optimized to simplify the synthetic operations. The results are
summarized in Scheme 8. The improved enantioselective synthesis of planar-chiral ferrocene-
fused pyridones (S)-2 starts from respective chiral acetals (–)-3 and needs only three
t
isolation/purification steps to (S)-2. The diastereoselective lithiation of (–)-3 using BuLi
followed by a reaction with tosyl azide afforded the corresponding ferrocenyl azide, and the
subsequent palladium-catalyzed reduction of the crude azide under a hydrogen atmosphere gave
the ferrocenylamine, which was immediately tosylated without purification to provide N-
tosylaminoferrocenyl acetal (–)-5 in high yield ranging 58-84%. Acetal (–)-5, purified by silica
1
13
gel column chromatography, was confirmed to be diastereomerically pure by the H- and C-
NMR analyses. The acid-catalyzed hydrolysis of (–)-5 gave the corresponding aldehyde (S)-11 in
>92% yield in enantiomerically pure form. The purification/isolation of (S)-11 may be skipped,
but we checked the enantiomeric homogeneity of (S)-11 at this stage. Aldehyde (S)-11 was
treated with ethynylmagnesium bromide, and the crude propargylic alcohols, which were
obtained by simple extraction, was applied to the iodide-catalyzed cyclization as in Schemes 6/7
to give planar-chiral 4-pyridone (S)-2 in high yield ranging from 66% to 95% (Scheme 8).
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O
O
O
H
H
CHO
H
1) tBuLi, TsN3
2) H2 with Pd/C
H
O
O
MgBr
2) MnO2, TBAI
1)
TsOH
OMe
H2O
Fe
N
Ts
Fe
Fe
Fe
NH
Ts
OMe
NH
Ts
3) TsCl, Et3N
DABCO
R'5
R'5
R'5
R'5
(–)-3b-d
(–)-5b-d
(S)-11b-d
(S)-2b-d
3b: R' = Me
3c: R' = Ph
3d: R' = Bn
5b: 70%
5c: 84%
5d: 58%
11b: >99%
11c: 99%
11d: 92%
2b: 72%
2c: 95%
2d: 66%
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57
58
59
60
Scheme 8. Optimized Synthetic Sequence for Enantioselective Construction of Ferrocene-Fused
4-Pyridones 2: "Second-Generation Synthesis" Using Iodide-Catalyzed Cyclization of
Propynoyl-N-tosylaminoferrocenes.
The second-generation synthesis of pyridones 2 developed here is much shorter with the
simpler operations and higher yields compared to the first-generation synthesis. Furthermore, the
second-generation synthesis can afford the sterically demanding ferroco-pyridones such as 2c
and 2d, which are not accessible by the first-generation synthesis. While the total yield from (–)-
3b to (S)-2b was 35% in nine-steps by the first-generation synthesis, the second-generation
synthesis according to Scheme 8 provided (S)-2b in 50% total yield starting with (–)-3b in six-
steps. The synthesis of (S)-2c was more effective in 71% total yield from (–)-3c. The chiral
source of the chiral directing group in (–)-3 is commercially available (S)-1,2,4-butanetriol, of
which optical antipode, (R)-1,2,4-butanetriol, is also commercially available for the synthesis of
(R)-enantiomers of planar-chiral ferroco-pyridones (R)-3.
Preparation of Planar-Chiral Ferroco-Pyridines 1 from 4-Pyridones 2. In the previous
report, we demonstrated that planar-chiral N-tosyl-4-pyridones (S)-2a and (S)-2b were versatile
precursors to various pyridine derivatives.13 The direct conversion of (S)-2b into a series of 4-
dialkylaminopyridine derivatives (S)-1bw-bz was achieved by the reaction with an appropriate
N-trimethylsilylamine in the presence of titanium(IV) chloride in good to excellent yields (see,
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8
9
Schemes 2 and 9). This detosylative amination reaction was found to be operative for the
sterically demanding ferroco-pyridones such as (S)-2c and (S)-2d as well, and the results are
summarized in Scheme 9. The reactions introducing dimethylamino, pyrrolidinyl, or morpholyl
groups at the 4-position of the pyridine rings proceeded very cleanly and the corresponding Fc-
DAAPs were obtained in excellent yields ranging 82-99%. On the other hand, the reaction with
diethyl(trimethylsilyl)amine was somewhat slow and the yields of the 4-diethylaminopyridine
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60
5
derivatives are relatively low (47-80%). Steric influence of the h -C5R'5 ligands on the
detosylative amination reaction is minimal and three pyridones 2b-d showed similar reactivity.
5
The isolated yields of the h -C5Me5 derivatives are somewhat lower, which can be ascribed to
their sensitivity toward air-oxidation, since the chromatographic purification was conducted
under air.
It should be emphasized that all the transformations shown in Schemes 8 and 9 are
stereoretentive. Whereas (S)-2b-d obtained by our method are enantiomerically pure, planar-
chiral ferroco-DAAP derivatives are also single enantiomers. Namely, we have established the
divergent process preparing a library of various planar-chiral pyridine-based nucleophilic
organocatalysts in enantiomerically pure forms without optical resolution. Our second-generation
synthesis is fairly versatile and various substituents can be introduced both at the 4-pyridyl
5
5
position as well as in the h -C5R'5 moiety. The h -pentabenzylcyclopentadienyl derivatives (1dw-
dy) and 4-diethylamino-/4-morpholyl-ferroco-pyridines (1by, 1cy, 1dy, 1bz, and 1cz) are new
compounds and prepared for the first time by our synthetic method.
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O
NR2
Me3Si-NR2, TiCl4
Fe
N
Ts
Fe
N
7
8
9
R'5
R'5
(S)-2b-d
(S)-1
2b: R' = Me
2c: R' = Ph
2d: R' = Bn
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NR2 = NMe2 (w), pyrroridinyl (x),
NEt2 (y), morpholyl (z)
NMe2
N
(S)-1bw (87%)
(S)-1cw (99%)
(S)-1dw (94%)
(S)-1bx (88%)
(S)-1cx (91%)
(S)-1dx (88%)
Fe
Fe
N
N
Fe
Fe
N
N
R'5
R'5
O
N
NEt2
(S)-1by (47%)
(S)-1cy (71%)
(S)-1dy (80%)
(S)-1bz (82%)
(S)-1cz (85%)
R'5
R'5
Scheme 9. Conversion of (S)-Ferroco-N-tosyl-4-pyridones 2 to Ferroco-DAAP Derivatives 1.
Single crystals of (S)-(–)-1dw were grown from pentane/dichloromethane and isolated as deep
red prisms. The X-ray crystallography revealed that the compound was single enantiomeric.24
The absolute configuration of levorotatory 2c was determined to be (S), which is consistent with
the stereochemistry deduced from the reported diastereoselective lithiation of the closely related
(–)-3b.15,16 All five phenyl groups in the h -C5Bn5 ligand point away from Fe(1) avoiding the
5
5
steric interaction with the (h -pyrido-Cp)Fe moiety. The ferrocene core in (–)-3b shows
5
essentially no distortion with the dihedral angle between the two h -ligand being 3.08°.
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60
Figure 3. Ball-and-stick drawing of the single-crystal X-ray structure of (S)-(–)-1dw with
selected atom numbering.24
A plausible reaction mechanism for the detosylative amination reaction is shown in Scheme
10. A reaction of a trimethylsilylamine with titanium(IV) chloride generates a titanium amide,
Cl3Ti-NR2, that attacks the carbonyl moiety in (S)-2 to form intermediate D. Elimination of
titanium(IV) oxodichloride gives iminium species E, that also exists in different resonance form
F. The subsequent reaction of N-tosylpyridinium intermediate F with Me3Si-NR2 affords the
corresponding (S)-1 together with tosylamide TsNR2, which was indeed isolated from the
reaction mixture.
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O
NR2
7
8
9
Me3Si-NR2 (2 equiv), TiCl4
– Me3SiCl
Fe
N
Ts
Fe
N
R'5
R'5
(S)-2
(S)-1
10
11
12
13
14
15
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Cl3Ti-NR2
+ Me3Si-NR2
– Ts-NR2
– Me3SiCl
Cl3Ti
O
N+R2
NR2
NR2
– [TiOCl2]n
Fe
N
Ts
Fe
N
Fe
N+
Ts
Ts
• Cl–
• Cl–
R'5
R'5
R'5
D
E
F
Scheme 10. Plausible Reaction Pathway of Detosylative Amination of (S)-2 Producing (S)-1.
Enantioselective Synthesis of Planar-Chiral Cymantrene-Fused DMAP (S)-1ew and PPY
(S)-1ex. The generality of the synthetic method developed in this study was tested on preparation
5
of DAAP derivatives fused with a metallocene other than ferrocenes. Cymantrene, (h -
cyclopentadienyl)manganese(I) tricarbonyl, was chosen as a platform for this purpose, and the
results are shown in Scheme 11. The synthesis began with known chiral cymantrenyl acetal (+)-
3e,25 of which sequential diastereoselective lithiation, azidation, and NaBH4 reduction gave
aminocymantrene (+)-4e in 70% yield as a single-diastereomer. After the N-tosylation of (+)-4e,
the hydrolysis of the chiral acetal moiety using aqueous hydrochloric acid provided aldehyde (S)-
11e in enantiomerically pure form in 48% yield. Treatment of (S)-11e in the same way as the
ferrocene derivatives provided the corresponding cymantrene-fused 4-pyridone (S)-2e in 68%
yield. Pyridone (S)-2e could be converted to cymantrene-fused DMAP (S)-1ew and PPY (S)-1ex
in 49% and 46% yields, respectively.
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9
O
O
H
H
H
H
O
O
1) tBuLi, TsN3
2) NaBH4
OMe
OMe
NH2
Mn
CO
Mn
OC
OC
OC
OC
CO
(+)-3e
(+)-4e (70%)
O
CHO
1)
10
11
12
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1) TsCl, Et3N
DABCO
MgBr
N
Ts
CO
NHTs
Mn
2) HClaq
2) MnO2, TBAI
Mn
OC
OC
(S)-11e (48%)
OC
OC
CO
(S)-2e (68%)
Me3Si-NR2
TiCl4
N
NMe2
N
N
Mn
OC
OC
Mn
OC
OC
CO
CO
(S)-1ew (49%)
(S)-1ex (46%)
Scheme 11. Enantioselective Synthesis of Planar-Chiral Cymantro-pyridines (S)-1ew and (S)-
1ex.
Although the yields of the cymantrene derivatives were lower than those of the ferrocene
derivatives, probably due to the air sensitivity of the manganese complexes, the reaction
sequence in Scheme 11 demonstrated the versatility and generality of the second-generation
synthesis of the planar-chiral DAAP species.
Application of (S)-1 in Asymmetric Organocatalysis. The library of the nucleophilic
organocatalysts, (S)-1, obtained in this study was applied in the two prototypical asymmetric
reactions and their catalytic performance was evaluated.
The first asymmetric reaction catalyzed by (S)-1 is an addition reaction of 2-tBu-phenol (19)
to ethyl(p-tolyl)ketene (18), which was suggested to take place by the Brønsted acid-catalyzed
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mechanism (Table 1).9i The h -C5Me5 derivatives, (S)-1bw-bz, were prepared by our first-
generation synthesis and their catalytic applications in this reaction were already examined in the
previous report.13 The reported results are included in the table for comparison (entries 1-4).
Among them, ferroco-PPY (S)-1bx, which is Fu's original, showed good catalytic activity in the
10
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addition reaction to give ester 20 in 90% yield with 92% ee (entry 2). The h -C5Ph5-derivatives,
(S)-1cw-cz, were poor catalysts for this transformation, and 20 was obtained in less than 8%
yields with low enantioselectivities of 32% ee at best (entries 5-8). The poor performance of (S)-
1cw-cz, which contain the electron-withdrawing h -C5Ph5 ligand,26 could be attributed to their
5
lower basicity compared to (S)-1bw-bz. And indeed, cymantro-pyridines (S)-1ew-ex, which
were also weakly basic due to the electron-withdrawing nature of the cymantrene framework,
showed similar poor catalytic activities and enantioselectivities in the reaction (entries 12-13).
5
On the other hand, h -C5Bn5-derivatives (S)-1dw-dy, which contain a bulkier and electron-
5
5
donating h -pentaalkylcyclopentadienide, could be regarded as refined variants of h -C5Me5-
derivatives (S)-1bw-bz and showed excellent catalytic activities (entries 9-11). Pyridine catalysts
(S)-1dw-dy provided (R)-20 in excellent yields with better enantioselectivities compared to the
products obtained by homologous (S)-1bw-by (entries 5-7 vs entries 9-11). Notably, newly
developed (S)-1dx displayed the highest enantioselectivity of 94% ee in the present reaction and
outperformed the other ferroco-/cymantro-pyridines.
Table 1. Enantioselective Addition of o-tBu-Phenol (19) to Ethyl(p-tolyl)ketene (18) Catalyzed
by (S)-1a
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tBu
tBu
(S)-1
(3 mol %)
H
HO
O
+
•
toluene
23 °C, 2 h
O
O
18
19
(R)-20
9
entry
1d
2d
3d
4d
5
(S)-1
1bw
1bx
1by
1bz
1cw
1cx
yield (%)b
% ee of 20c
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92
90
90
84
8
79
92
90
79
9
6
7
15
-
7
1cy
0
8
1cz
4
32
90
94
90
40
15
9
1dw
1dx
1dy
1ew
1ex
92
91
92
5
10
11
12
13
16
a The reaction was carried out in toluene at 23 °C in the presence of catalyst (S)-1 (3 mol %).
The absolute configuration of 20 was deduced by comparison with the reported results [ref. 9i]. b
Isolated yield by silica gel chromatography. c Determined by HPLC analysis on a chiral
stationary phase (see the Supporting Information for details). d Taken from ref. 13.
The second reaction examined was the kinetic resolution of racemic secondary alcohol rac-21.
The acetylation of rac-21 with acetic anhydride proceeds in an enantioselective fashion in the
presence of (S)-1 (4 mol %) to give ester (S)-22 and recovered (R)-21 (Table 2). The catalytic
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properties of the h -C5Me5 derivatives (S)-1bw-bz were already examined in the previous
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report13 and the reported results are included in Table 2 for comparison (entries 1-4). Among the
7
8
5
h -C5Me5 derivatives, (S)-1by having a 4-diethylamino substituent showed the highest
9
10
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enantioselectivity with s-factor27 of 6.7 (entry 3). It was reported, however, that h -C5Me5
derivative 1bw was not an appropriate catalyst for the analogous kinetic resolution of secondary
alcohols and the corresponding h -C5Ph5-derivative 1cw showed much better enantioselectivity.9b
5
5
With our second-generation synthesis of the planar-chiral DAAPs, a series of h -C5Ph5-
derivatives (S)-1cw-cz were available for this study. As we expected, indeed, (S)-1cw-cz showed
excellent enantioselectivities with s-factors ranging 13 to 69 (entries 5-8). The best selectivity (s
= 69) was recorded using (S)-1cz, which was prepared for the first time in this study, but its
catalytic activity was decreased due to the less electron-donating ability of the 4-morpholyl
5
substituent (entry 8). The performance of h -C5Bn5 derivatives (S)-1dw-dy was somewhat
similar to that of (S)-1bw-by, but the former showed slightly better selectivities than the latter
(entries 9-11). Once again, (S)-1dw-dy can be seen as improved variants of (S)-1bw-by.
Cymantrene-fused DMAP (S)-1ew and PPY (S)-1ex were also applied to the kinetic resolution of
rac-21. The results were, however, unsatisfactory in terms of both catalytic activity and
enantioselectivity, which can be ascribed to the less electron-donating and the sterically compact
character of the cymantrene platform in (S)-1ew-ex (entries 12 and 13).
Table 2. Enantioselective Acetylation of rac-21 Catalyzed by (S)-1a
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(S)-1 (4 mol %)
Ac2O (0.8 equiv)
NEt3 (0.8 equiv)
OH
tBu
OAc
tBu
OH
tBu
+
Et2O
20 °C, 72 h
7
8
rac-21
(S)-22
(R)-21
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entry
(S)-1
conv (%)b
65
% ee of 22c % ee of 21c s-factord
1e
2e
3e
4e
5
1bw
1bx
1by
1bz
1cw
1cx
1cy
1cz
41
43
39
41
89
91
75
97
47
43
45
50
54
75
70
92
78
62
76
60
8
5.0
5.0
6.7
5.3
33
62
70
66
41
46
45
7
6
48
7
13
8
69
9
1dw
1dx
1dy
1ew
1ex
62
66
68
31
27
78
83
98
23
19
6.3
6.0
11
10
11
12
13
3.7
4.0
a The reaction was carried out in diethyl ether at 20 °C in the presence of catalyst (S)-1 (4
mol %). b Determined by 1H NMR analysis. c Determined by HPLC analysis on a chiral
stationary phase (see the Supporting Information for details). The absolute configurations of 22
and recovered 21 were determined by comparison with the reported results [ref. 9b]. d Calculated
based on a first-order equation [ref. 27]. e Taken from ref. 13.
Conclusions
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In summary, we have developed a substantially improved method of preparing various
metallocene-fused planar-chiral 4-pyridones 2/4-dialkylaminopyridines 1 in enantiomerically
pure forms. The renewed method, "second-generation synthesis of Fc-DAAPs", is much more
practical and advantageous than our previous enantioselective synthesis of 2/1, because it is (i)
with shorter and more efficient synthetic sequence, (ii) results in higher yields of 2/1, (iii) no
need for expensive noble metal catalysts, and (iv) accessible to sterically demanding Fc-DAAPs
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having an (h -C5Ph5)Fe or (h -C5Bn5)Fe moiety. Whereas the bulky Fc-DAAP derivatives are
synthetically more useful showing better enantioselectivity in general, the last point is
particularly important innovation in the present protocol. These bulky Fc-DAAPs could not be
5
prepared by our first-generation synthesis. The h -C5Bn5-DAAP derivatives are previously
unknown and prepared for the first time in the present studies. The success of the second-
generation synthesis depends in large part on the discovery of the iodide-catalyzed cyclization of
1-propynoyl-2-N-tosylaminoferrocenes 14 giving the corresponding 4-pyridones 2 in excellent
yields. One unique feature of our synthesis of Fc-DAAPs is the late stage introduction of various
dialkylamino-substituents at the 4-position of Fc-DAAPs by the detosylative amination of 2.
Since the detosylative amination worked efficiently even on the bulky pyridones such as 2c and
2d, our method is divergent and could provide a library of planar-chiral pyridine-based
nucleophilic organocatalysts. Due to the versatility of the second-generation synthesis, a new
family of planar-chiral DAAP derivatives, cymantrene-fused DAAPs 1e, were also prepared in
the same way.
Finally, the library of the planar-chiral DAAPs were examined in the two prototypical
asymmetric reactions as organocatalysts. Some newly prepared Fc-DAAP derivatives showed
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better performance than the known species in these reactions. This is a clear-cut advantage of
having the library of Fc-DAAPs.
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Since the development of Fc-DAAPs 1 in 1990s by Fu, these compounds have been
recognized as one of the most attractive and versatile chiral nucleophilic catalysts showing
applicability to a wide range of asymmetric reactions. We believe that present study should
contribute further development of these unique molecules.
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AUTHOR INFORMATION
Corresponding Authors
kyoshida@faculty.chiba-u.jp
ogasawar@tokushima-u.ac.jp
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is available free of charge on the ACS
Publications website at DOI: *********.
The following files are available free of charge.
Experimental procedures and compound characterization data (PDF)
Crystallographic data for (S)-(–)-2c and (S)-(–)-1dw (CIF)
ACKNOWLEDGMENT
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This work was supported by JSPS KAKENHI "Precisely Designed Catalysts with Customized
Scaffolding" to K.Y. (Grant #18H04236) and a Grant-in-Aid for Scientific Research (B) to M.O.
(Grant #18H01979) from MEXT, Japan.
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