N,N-Dialkylhydrazones as Versatile Umpolung Reagents in Enantioselective Anion-Binding Catalysis

Article abstract of DOI:10.1002/anie.202013380

An enantioselective anion-binding organocatalytic approach with versatile N,N-dialkylhydrazones (DAHs) as polarity-reversed (umpolung) nucleophiles is presented. For the application of this concept, a highly ordered hydrogen-bond (HB) network between a carefully selected CF₃-substituted triazole-based multidentate HB-donor catalyst, the ionic substrate and the hydrazone in a supramolecular chiral ion-pair complex was envisioned. The formation of such a network was further supported by both experimental and computational studies, which showed the crucial role of the anion as a template unit. The asymmetric Reissert-type reaction of quinolines as a model test reaction chemoselectively delivered highly enantiomerically enriched hydrazones (up 95:5 e.r.) that could be further derivatized to value-added compounds with up to three stereocenters.

Full text of DOI:10.1002/anie.202013380

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: N,N-Dialkylhydrazones as Versatile Umpolung Reagents in
Enantioselective Anion-Binding Catalysis
Authors: Melania Gómez-Martínez, María del Carmen Pérez-Aguilar,
Dariusz G. Piekarski, Constantin G. Daniliuc, and Olga García
Mancheño
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202013380
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10.1002/anie.202013380
Angewandte Chemie International Edition
COMMUNICATION
N,N-Dialkylhydrazones as Versatile Umpolung Reagents in
Enantioselective Anion-Binding Catalysis
Melania Gómez-Martínez,[a]‡ María del Carmen Pérez-Aguilar,[a]‡ Dariusz G. Piekarski,[a] Constantin G.
Daniliuc[a] and Olga García Mancheño*[a]
Dedication ((optional))
Abstract: A novel enantioselective anion-binding organocatalytic
approach with versatile N,N-dialkylhydrazones (DAHs) as
umpolung nucleophiles is presented. For the application of this
concept, a highly ordered hydrogen bond network between a
carefully selected CF3-substituted triazole-based multidentate
HB-donor catalyst, the ionic substrate and the hydrazone in the
supramolecular chiral ion pair complex was herein envisioned.
This was further supported by both experimental and
computational studies, showing the crucial role of the anion as
template unit. The asymmetric Reissert-type reaction of
quinolines has been selected as model test reaction, delivering
chemoselectively high enantiomerically enriched hydrazones (up
95:5 e.r.) that can easily be further derivatized to value-added
compounds with up to three stereocenters.
recently revealed an interesting role of the anion as bridging motif
between the catalyst and polarized nucleophiles to achieve an
effective orientation of the reactants.[10] This finding opens new
possibilities by the careful choice of appropriate nucleophiles able
to interact via H-bonding with the anions of the contact ion-pair
complex.
Inspired by the anion-binding properties of ammonium salts
via H-bonding with the C-H bonds alpha to the N-atom and its
reliable use in asymmetric catalysis,[11] we reasoned that N,N-
dialkylhydrazones (DAHs) could similarly interact with anions
(Figure 1a), providing a more rigid HB-network and an efficient
stereocontrol with such reagents. Moreover, hydrazones are
considered an important building block in organic synthesis since
they allow the introduction of a broad variety of functionalities in
complex molecules.[12] Particularly, DAHs have acquired
increasing interest in the past years due to their amphiphilic
behavior at the azomethine carbon.[13] However, despite the
versatility of these compounds as umpoled nucleophilic reagents,
until now only two different activation modes in organocatalysis,
H-bonding[4] and chiral counteranion catalysis[14] (Figure 1b),have
been efficiently employed.[15] In fact, the use of hydrazones as
nucleophiles through an anion-binding activation approach has
only been recently envisioned.[16] Hence, we herein report on the
first use of DAHs as suitable umpoled nucleophiles for anion-
binding catalysis by embracing an anion-bridging strategy to allow
for the facile and direct access to enantiomerically enriched
adducts (Figure 1c).
The ability to efficiently synthesize enantioselective complex
molecules employing simple modes of activation has long been
considered an essential goal for asymmetric organocatalysis.[1]
Among different approaches, enantioselective anion-binding
catalysis,[2] which is based on the activation of an ionic substrate
towards nucleophilic attack upon binding the anion by a catalyst
and formation of a chiral contact ion pair, has recently emerged
as a powerful synthetic tool. Since the pioneering work by
Jacobsen et. al.[3] using chiral thioureas as hydrogen bond (HB)
donor catalysts,[4] many applications have been reported in this
field.[2] However, the implied non-covalent interactions for the
anion recognition are less directional and more difficult to control
than those implying covalent bonds.[5] For this reason, over the
last few years there have been tremendous efforts for the design
of new and original chiral catalysts[6] with the ability for multiple-
interactions to effectively spatially locate the reaction partners
and, hence, achieve high stereochemical control with challenging
reagents.[7] In this context, we have developed a novel family of
a) Hydrazones as anion binders b) Organocatalytic activation strategies
*
R
O
D
O
O
D
H
’R R’
N
D
H
R
H
R
A
P
H
R
R
Alk
N
O
Alk
Alk
E
N
H
E
N
N
H
H
Alk
N
R
N
A
H
H
R
H
R
H
ammonium
salts
neutral DAHs ?
HB-donor catalysis
chiral counteranion
chiral
triazole-based
organocatalysts,[8] which
present
multicoordination sites, great modulating capacity and the flexible
structure leading to a more effective fixation of the ionic
substrates. In consequence, a highly chirality transfer has been
achieved in a number of enantioselective reactions such as
nucleophilic dearomatization of N- and O-heteroarenes.[8-9] In fact,
computational studies on the action of these catalysts have
c)
Our hypothesis:
R
N
*
Multidentate fixation via HB
H
R
Alk
N
A
DAH α-C-H in anion-binding
E
N
Alk
Alk
Regio-, chemo- and highly
enantioselective
Versatile chiral hydrazones
N
Y
*E
H
H
contact ion pair
network
[a]
Dr. M. Gómez-Martínez, Dr. M. C. Pérez-Aguilar, Dr. D. G.
Piekarski, Dr. C. G. Daniliuc, Prof. Dr. Olga García Mancheño
Organic Chemistry Institute
anion-binding catalysis
Figure 1. Postulated anion-binding properties and asymmetric organocatalytic
approaches with umpoled N,N-dialkylhydrazones (DAHs).
Münster University
Corrensstraße 36
E-mail: olga.garcia@uni-muenster.de
These authors contributed equally
Supporting information for this article is given via a link at the end of
the document.
In order to evaluate our hypotheses, the enantioselective
Reissert-type dearomatization of quinolines was selected as
model test reaction (Table 1).[8],[17] We start our study by
‡
1
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10.1002/anie.202013380
Angewandte Chemie International Edition
COMMUNICATION
investigating the reaction of quinoline (2a), 2,2,2-
trichloroethoxycarbonyl chloride (TrocCl) as acylating agent and
the commercially available formaldehyde dimethylhydrazone 3a
as nucleophile,[18] in the presence of our most versatile triazole
catalyst 1a[8-10] (10 mol%) in toluene at -78 ºC (entry 1). Although
it proceeded with a complete regioselectivity to the desired 1,2-
addition product 4a, an unexpected low enantioselectivity was
observed. Bearing in mind the challenging stereocontrol with this
type of hydrazones, we further envisaged the need of an
additional fixation point of the nucleophile to the chiral catalyst.
Thus, we replaced the alkyne substitution in 1a for a CF3 group in
1b, aiming at enhancing the catalyst polarization and anion-
binding affinity, as well as allowing a new F-H-bond between this
group at the catalyst and the carbonylic H-atom of the
formaldehyde hydrazone 3a. As predicted, the enantioselectivity
could be increased to 79:21 e.r. (entry 2).
solvent and, in consequence, an improvement in the
enantioselectivity of the process should be observed. In fact,
when a mixture of hexafluorobenzene (C6F6) and toluene was
employed, the enantiomeric ratio was slightly enhanced to 81:19
e.r., allowing to perform the reaction at 0 ºC (entry 3). Next,
tetrakistriazole catalysts 1c-f bearing different substituents at the
aryl moiety were tested, providing good yields but lower
enantioselectivities (entries 4-7), which supports the favorable
effect of the CF3 substitution at this position. In other to further
improve the enantioselectivity, other types of catalysts such as
thioureas 1h-i and squaramide 1j were tested (entries 8-10).
However, disappointing results were obtained with these stronger
HB-donors (<10% e.e.), which should bind more tightly the
chloride anion to form a chiral contact ion pair. Finally, the
regioisomeric CF3-tetrakistriazole 1g was investigated since
some reports on triazole anion-receptors showed higher anion
affinities with this type of isomers.[20] This structural change was
translated to a further improvement on the enantioinduction,
providing 4a in 88:12 e.r. (entry 11), and 92:8 e.r. when only C6F6
was used as r.t. (entry 12). Finally, the use of freshly distilled C6F6
at 4 ºC gave rise to the best enantiomeric ratio of 94:6 (entry 13).
With the optimized conditions in hand (see S.I. for a complete
optimization study), catalyst 1g (10 mol%) in C6F6 at 4 °C, the
substrate scope on the hydrazone 3 was explored (Scheme 1).
Symmetrically and non-symmetrically substituted N,N-dialkyl-
hydrazones provided good yields and moderate to good
enantioselectivities (4-7;9-11a), while a substantial drop in the
yield and a loss of enantioinduction was observed with an
aromatic substitution (8a). N-Monoalkyl and C1 substituted
hydrazones led to no reactivity or undesired products such as N-
Troc- and 1,4-addition adducts, respectively (see S.I.) Moreover,
as is shown in the Scheme 1, the substitution on the N-atom of
the hydrazone affected significantly to the enantioselectivity,
which is in line with our hypothesized participation of the N-alkyl
groups in the formation of the key chiral contact ion pair. Thus,
the replacement of the methyl group for longer linear alkyl chains
(6a) or benzyl (7a), and bulky groups such as i-Pr (5a) or t-Bu
(11a) led to lower enantioselectivities (70:30 – 85:15 vs. 94:6 e.r.).
Table 1. Optimization screening for the model reaction with 2a[a]
1) Troc-Cl, 0 °C
solvent, 1 h
*
N
N
NMe2
2) Catalyst 1
N
N-NMe2
Troc
3a
2a
4a
(2 equiv.)
H
H
OMe
1a, R' = H, R'' =
N
N
N
N
N
N
N
N
N
N
N
N
1b, R' = H, R'' = CF3
1c, R' = H, R'' =
1d, R' = H, R'' =
1e, R', R'' = H
N
R'
R'
tBu
Ph
H
H
H
H
H
R''
R''
CF3
CF3
H
R'
H
H
N
N
R'
N
N
N
1f, R'= F, R'' = H
N
N
Ar
N
Ar
N
N
N
Ar
Ar
Ar = 3,5-(CF3)2C6H3
1g
CF3
Ph
O
O
N
Me
tBu tBu
tBu
S
S
S
N
N
Me2N
NH HN
N
H
H
tBu
N
N
CF3
Ar NH
HN Ar
O
H
H
O
1h
1i
1j
Ent.
1
1 (mol%)
1a (10)
1b (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1h (10)
1i (10)
1j (10)
1g (10)
1g (10)
1g (10)
1g (5)
Solvent
Toluene
Toluene
T (°C)
Yield (%)[b]
e.r.[c]
-78
-78
0
74
87
79
76
88
87
69
79
79
92
90
75
84
72
80
65:35
79:21
81:19
63:37
72:28
74:26
51:49
50:50
52:48
51:49
88:12
2
3
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
Tol/C6F6 (3:1)
C6F6
1) Troc-Cl
C6F6, 0 °C
4
0
*
N
5
0
N
NR2
2) 1g (10 mol%)
N
N-NR2
6
0
3
Troc
4-11a
(2 equiv.)
2a
7
0
H
H
4 °C, 16 h
8
0
N
iPr
N
R
9
0
N
N
N
iPr
N
N
N
N
R
10
11
12
13
14
15
0
Troc
Troc
Troc
5a
4a
6a, R = nBu 86%, 83:17 e.r.
7a, R = Bn 68%, 80:20 e.r.
8a, R = Ph 11%, 51:49 e.r.
0
30%, 85:15 e.r.
84%, 94:6 e.r.
rt
92:8[d]
94:6[d]
C6F6
4
tBu
N
N
N
87:13[d]
92:8[d,e]
N
N
N
N
N
N
C6F6
4
Troc
9a
Troc
11a
Troc
10a
1g (10)
C6F6
4
65%, 95:5 e.r.
68%, 70:30 e.r.
90%, 91:9 e.r.
[a] Conditions: 2a (1 equiv.) and TrocCl (1 equiv.) were stirred in the
corresponding solvent (0.1 M) at 0 °C for 1 h; then the catalyst 1 and 3a (2
equiv.) were added at the appropriate temperature and reacted overnight. [b]
Isolated yields. [c] e.r. determined by chiral SFC. [d] Reaction using dried C6F6
over 4Å MS and freshly distilled 2a and 3a. [e] Reaction performed in 0.05 M.
Scheme 1. Screening of the substitution on the hydrazone 3.
Conversely, the employment of the freshly prepared 1-
piperidine and 1-pyrrolidine hydrazones, gave rise the products
9a and 10a with good to excellent enantioselectivities (up to 95:5
e.r.). However, for practical reasons the subsequent
investigations were mostly performed with the commercially
At this point, based on the work of MacMillan et al.,[19] we
predicted that the use of perfluoroarenes as solvents should
disfavor the possible cation π-interactions between the
corresponding quinolinium generated in the media and the
2
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10.1002/anie.202013380
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COMMUNICATION
available dimethyl hydrazone 3a. Thus, the scope on the quinoline
substrate 2 was carried out (Scheme 2). First of all, it is worthy to
mention that the reaction could be conducted in an up to 2 mmol
scale with no significant erosion in the activity or selectivity of the
process (4a; 79%, 93:7 e.r.). The substitution at different positions
of the quinoline was well tolerated, except for the C3- (4d) and
C8-positions (4e) that led to significant lower enantioselectivity or
no reaction, respectively. Moreover, the method showed a good
functional group compatibility, allowing many groups such as
halogens, methoxy, alkyl, alkenyl, alkynyl, nitro, amides or esters
to give the products 4f-s and 9b,g,l,n (R’2= (CH2)5) in good to high
enantioselectivities (up to 94:6 e.r.). Furthermore, the absolute
configuration of the new stereocenter could be determined as (S)
upon X-ray structure analysis of the crystalline product 4s.[21] It is
especially remarkable the excellent chemoselectivity observed
with quinolines substituted with an additional electrophilic species
such as an aldehyde or a nitro-Michael acceptor (4t, 9t and 4u).
In these cases, the reaction gave exclusively the 1,2-addition
product at the quinoline moiety within good enantioselectivities
(up to 92:8 e.r.). Remarkably, the reaction also proceeded in the
presence of a boronic ester, leading to the product 4v with an
80:20 e.r. Lastly, phenanthridine, a diazarene and less reactive,
more challenging pyridines could also be enrolled, leading to the
hydrazone products 12-14 in up to 90:10 e.r.
The recyclability and stability of the catalysts was next
explored in the prototypical reaction of 2a, showing no
degradation of the enantioselectivity up to three runs (Scheme 3,
top). Afterwards, the synthetically value of the method and
versatile chemistry of the products were illustrated by
modifications of 4a (Scheme 3, bottom). Hence, the chiral
hydrazone could be easily transformed quantitatively upon acid
treatment into the corresponding aldehyde 15, maintaining the
enantiomeric purity, which was confirmed after reduction and
cyclization to the cyclic carbamate 16. Moreover, 4a was also
converted into the cyanide 17 by treatment with magnesium
monoperoxyphthalate (MMPP•6H2O). The adduct 17 was then
reduced to the tetrahydoquinoline 18, as well as further used as
common precursor for the preparation of the corresponding
aziridine 19 and epoxide 20 with complete diastereoselectivity
and same high e.r., which were opened in a completely
regioselective manner with MeOH in acid media to provide highly
decorated chiral tetrahydoquinolines (21 and 22) within three
stereocenters. Lastly, the possibility of N-Troc group deprotection
was demonstrated by treating 22 with Zn/AcOH, leading to the
desired NH-free derivative 23.
1) Troc-Cl
C6F6, 0 °C
run yield (%) e.r.
1
2
3
88
81
77
93:7
93:7
93:7
2a
N
N
NMe2
2) 1g (10 mol%)
3a (2 equiv.)
4 °C, 16 h
Troc
4a
1) Troc-Cl
C6F6, 0 °C, 1 h
R
(0.5 mmol scale)
R
NNR’2
2) 1g (10 mol%)
N
N
NR’2
N
Troc
3a (2 equiv.)
4, 12-14, R’ = Me
9, R’2 = -(CH2)5-
2
H
H
4 °C, 16 h
N
HCl
NaBH4
MeOH
N
N
Troc
CHO
N
NMe2
O
Troc
O
16, 63%, 92:8 e.r.
4a, 93:7 e.r.
15, quant.
N
N
R
N
N
MMPP.6H2O
MeOH, 0 °C
Troc NNMe2
Troc NNMe2
Troc NNR’2
Troc NNMe2
OMe
XH
X
4a
4d
4e
HCl
(1N Et2O)
4b, R = Me, 78%, 90:10 e.r.
9b, R = Me, 74%, 91:9 e.r.
4c, R = OMe, 68%, 85:15 e.r.
84%, 94:6 e.r.
no reaction
46%, 61:39 e.r.
A or B
79%, 93:7 e.r.[c]
R
MeOH
r.t.
N
CN
N
CN
N
CN
4f, R= Me, 78%, 91:9 e.r.
9f, R= Me, 34%, 92:8 e.r.
4g, R= OMe, 57%, 88:12 e.r.
4h, R= Ph, 84%, 84:16 e.r.
4i, R= nBu, 75%, 72:28 e.r.
Troc
X = NNs; 19, 92%, 93:7 e.r.
X = O; 20, 53%, 93:7 e.r.
Troc
21, 67%, 93:7 e.r.
22, 44%, 93:7 e.r.
Troc
R
N
17, 71%, 93:7 e.r.
Troc NNR’2
N
4l, R = OMe, 77%, 86:14 e.r.
9l, R = OMe, 32%, 88:12 e.r.
4m, R = Br, 48%, 85:15 e.r.
X = O
Zn, AcOH
Troc NNR’2
4j, R=
, 81%, 85:15 e.r.
Ph
Ph
Pd/C, Et3SiH
MeOH, 2 h, r.t.
4k R=
, 70%, 84:16 er
OMe
F
Cl
Br
O2N
OH
CN
N
CN
Troc
N
N
N
N
Troc NNMe2
4q
30%, 89:11 e.r.
N
H
18, 57%, 93:7 e.r.
Troc NNMe2
Troc NNR’2
Troc NNMe2
23, 67%, 95:5 e.r.
4o
4p
4n, 94%, 94:6 e.r.
9n, 77%, 94:6 e.r.
A: Cu(acac)2, PhI=NNs, MeCN, r.t. B: mCPBA, DCM, r.t.
84%, 94:6 e.r.
79%, 92:8 e.r.
Scheme 3. Recycling of the catalyst 1g and synthetic applications.
Me2N
MeO2C
N
=
N
Lastly, aiming at gaining insight into the key interactions within
the catalyst 1g and the mechanism of the reaction, the standard
reaction of 2a and TrocCl with hydrazone 3a was investigated in
more detail (Figure 2). The monitoring of the reaction course was
performed at room temperature in an NMR tube in C6F6/toluene-
d8 (4:1) due to solubility issues (Figure 2a, see S.I.). This revealed
a fast transformation, requiring just 1 h to reach 4a in ~60% yield
(6 h, 76%) and ≤5 min for the final enantioselectivity of 92:8 e.r.
Moreover, the chloride anion affinity of the catalyst 1g was
determined by NMR titration with tetrabutylammonium chloride
(TBACl) as chloride source in a constant [2 mM] of 1g (see S.I.
for details). As predicted, the central CF3 groups boosted the
affinity to ~3100 M-1 (and ~1875 M-1 for its regioisomer 1b vs.
~500 M-1 for 1a).[10] Based on that, a plausible mechanism
considering the formation of a tight catalyst:substrate contact ion
Troc NNMe2
4r
97%, 77:23 e.r.
Troc NNMe2
4s
84%, 90:10 e.r.
Troc
Me2NN
PinB
OHC
O2N
N
N
N
N
Troc NNMe2
4v
97%, 80:20 e.r.
Troc NNMe2
Troc NNR’2
4u
12a
4t, 79%, 92:8 e.r.
9t, 41%, 89:11 e.r.
71%, 71:29 e.r.
18%, 90:10 e.r.
Ph
N
N
N
N
Troc NNMe2
Troc NNMe2
Troc NNMe2
13a
79%, 77:23 e.r.
14a
14b
30%, 90:10 e.r.[d]
18%, 85:15 e.r.[d]
[a] Standard conditions. [b] Isolated yields. [c] Result of both 1 and 2 mmol scale reactions.
[d] Reaction in Et2O at -78 °C for 2 days.
Scheme 2. Substrate scope.[a,b]
3
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10.1002/anie.202013380
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COMMUNICATION
a)
b)
Reaction monitoring (in C6F6/Tol-d8, r.t.). First hour zoom-in
TrocCl
2a
N
90
80
70
60
50
40
N
N
N
N
N
N
N
N
N
Cl
Troc
Troc
4a
I
*
CF3
CF3
catalyst 1a
Cl
N
N
N
N
*
Cl
N
N
3a HCl
N
CF3
CF3
CF3
II
Troc
chiral contact
ion-pair
CF3
30
Yield (%)
20
3a (or 4a)
1g:Cl⎻ complex
N
B
CH3
N
ee (%)
N
N
10
H
Troc H
III
*
Ka = 3089 ± 9% M-1
CH3
N
Cl
0
(NMR-titration with TBACl
in acetone-d6, 2 mM)
B = Cl- or 3a
0,0
0.0
0,2
0.2
0,4
0.4
0,6
0.6
00
.
,8
8
1,0
1.0
H
H
3a
t (h)
c)
F—H bond
H—Cl bond
Cl—p bond
p
Cl—
CH—Cl
New C—C bond
F—H
zoom-in
TS
2.7
0.0
II + 3a
III
-13.5
B3LYP-GD3BJ/def2tzvp//AM1
in C6H6 with
COSMO-RS at BP86/def2tzvp
Figure 2. a) Reaction monitoring and binding constant for 1g:Cl-,[22] b) proposed mechanism, and c) computed TS for the model reaction
of 2a with 3a in C6F6 at r.t.. Zoom-in: F–H (red), CH–Cl (black), and Cl–p interactions (blue); new C–C bond (grey). See S.I. for details.
pair complex is shown in Figure 2b. Hence, the real substrate
quinolinium salt I is formed in situ by treatment of 2a with TroCl.
This species forms a chiral contact ion pair II with the catalyst 1g.
Then, the nucleophilic attack of the hydrazone 3a delivers the
intermediate III, which provides the final product upon
deprotonation by Cl- or another molecule of 3a, with concomitant
formal elimination of HCl and regeneration of the catalyst 1g.[18]
Finally, the transition state (TS) of the reaction was computed at
DFT-B3LYP[23]-GD3BJ[24]/def2tzvp[25]//AM1[26] level of theory
including the solvent effect (C6F6) with COSMOS-RS[27] at
BP86[28]/def2tzvp (Figure 2c, see S.I. for more details). The 1g:Cl-
complex in I is stabilized by four HBs between Cl- and the C-H
bonds of the central triazoles and arenes. Moreover, the approach
of the nucleophile 3a is directed by a F–H bond between a CF3
group of 1g and a carbonyl H of 3a (see weakly bounded II...3a).
In the TS, however, only one arms of the catalyst participates in
the HB-interactions with Cl-, while additional stabilization via F–H
bonds with the CF3 group and both the substrate and 3a, as well
as a Cl–p interaction between the Troc-group and the other arm
of the catalyst, takes place. The nucleophilic addition involves a
small barrier of 2.7 kcal mol-1, leading to the more stable
intermediate III (-13.5 kcal mol-1) that further evolves to the final
product 4a. Moreover, the H-bonding network and pre-orientation
in the TS explained a more favorable Si-face attack and the
observed absolute configuration (S) of the product.
chloride salts embracing a novel catalytic anion-binding approach
has been developed. The synthetic versatility of the method was
also demonstrated by derivatization of the obtained chiral
hydrazones into value-added heterocyclic compounds with up to
three stereocenters. The use of a multidentate triazole-based H-
donor as catalyst bearing CF3 groups in the central aromatic units
allows for the formation of a supramolecular tight chiral contact
ion pair complex by a highly ordered HB-network between the
catalyst, ionic substrate and nucleophilic hydrazone to ensure a
high enantioselectivity even at room temperature. Based on
experimental and computational observations, the chloride anion
has an important role as it acts as junction between all
components of the reaction. Moreover, the nature of N-alkyl group
on the hydrazone is also crucial, since it participates in the HB-
network in the TS to fix the reagent. Further catalytic strategies
based on such anion-templated HB-assemblies are currently
being investigated in our group.
Acknowledgements
The European Research Council (ERC-CG 724695) and the
Deutsche Forschungsgemeinschaft (DFG) within the SFB858 are
gratefully acknowledged for generous support. L. Schifferer is
thanked for providing some catalysts precursors.
In conclusion, an enantioselective nucleophilic addition of
umpoled formaldehyde N,N-dialkylhydrazones to quinolinium
Keywords: Hydrazones • Umpolung • Anion-binding catalysis •
Enantioselective catalysis • Heterocycles
4
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10.1002/anie.202013380
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5
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Entry for the Table of Contents
anion-binding catalysis approach
1) Troc-Cl
R
R
*
H
R
*
2) catalyst
(10 mol%)
R
*
Cl
N
Alk
N
E
N
N
Alk
N
Alk
N
H
F
N
Troc
H
Alk
F
N
H-Cl
F
H
H
29 examples
up to 95:5 e.r.
versatile chiral hydrazones
Alk
H
contact ion pair
anion-templated (TS) assembly
C6F6, 4 °C
Networking for success! Umpoled N,N-dialkylhydrazones have been identify for the first time as versatile nucleophiles with multiple-
networking ability for self-assembled chiral contact ion pair complexation in enantioselective anion-binding catalysis, leading to a highly
ordered non-covalent interactions network with the anion as central template motif that allows high enantiomeric inductions in a model
Reissert-type reaction with quinolines.
6
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