Enantio- and Diastereoselective Nucleophilic Addition of N-tert-Butylhydrazones to Isoquinolinium Ions through Anion-Binding Catalysis

Article abstract of DOI:10.1002/anie.202012861

A highly enantio- and diastereoselective thiourea-catalyzed dearomatization of isoquinolines employing N-tert-butylhydrazones as neutral α-azo carbanions and masked acyl anion equivalents has been developed. Experimental and computational data supports the generation of highly ordered complexes wherein the chloride behaves as a template for the catalyst, the hydrazone reagent, and the isoquinolinium cation, providing excellent stereocontrol in the formation of two contiguous stereogenic centers. The ensuing selective and high-yielding transformations provide appealing dihydroisoquinoline derivatives.

Full text of DOI:10.1002/anie.202012861

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Enantio- and Diastereoselective Nucleophilic Addition of N-tert-
Butylhydrazones to Isoquinolinium Ions through Anion-Binding
Catalysis
Authors: Esteban Matador, Javier Iglesias-Sigüenza, David Monge,
Pedro Merino, Rosario Fernández, and José M. Lassaletta
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202012861
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10.1002/anie.202012861
Angewandte Chemie International Edition
COMMUNICATION
Enantio- and Diastereoselective Nucleophilic Addition of N-tert-
Butylhydrazones to Isoquinolinium Ions through Anion-Binding
Catalysis
Esteban Matador,[b] Javier Iglesias-Sigüenza,[b] David Monge,*[b] Pedro Merino,*[c] Rosario
Fernández*[b] and José M. Lassaletta*[a]
Dedication ((optional))
Abstract:
A
highly enantio- and diastereoselective thiourea-
top) were used; the silyl group of the nucleophile behaves as a
halide scavenger, enabling catalyst turnover by formation of a
strong silicon–chlorine bond, which ultimately serves as the
driving force of the reaction. Conversely, the use of non-silylated
nucleophiles is rather limited in this context.[8] Over years, we
have exploited the nucleophilic character of hydrazones
(masked acyl anion equivalents) in asymmetric synthesis.[9] In
particular, the use of formaldehyde N-tert-butylhydrazone in
combination with bifunctional H-bonding organocatalysts
enabled efficient enantioselective functionalizations of neutral
electrophiles, mainly carbonyl compounds.[10] In parallel, other
groups used axially chiral Brønsted-acids in asymmetric
additions of hydrazones to aldimines[11] or 3-hydroxyisoindolin-1-
ones,[12] 6π-electrocyclizations with α,β-unsturated aldehydes,[13]
and addition of glyoxylate hydrazones to N-acyliminium salts.[14]
On the other hand, monosubstituted hydrazones behave as
bidentate H-bond donors, efficiently binding different anions,
including halides, in different contexts.[15] On this basis, we
envisaged that an additional interaction of the hydrazone with
chloride could be beneficial to generate highly ordered
intermediates in the dearomatization of heteroarenes (Scheme 1,
bottom), thus facilitating a good stereocontrol in the concomitant
formation of two contiguous stereogenic centers, a rare event in
the above-mentioned dearomatization processes.[16]
catalyzed dearomatization of isoquinolines employing N-tert-
butylhydrazones as neutral α-azo carbanion and masked acyl anion
equivalents has been developed. Experimental and computational
data supports the generation of highly ordered complexes wherein
the chloride behaves as a template for the catalyst, the hydrazone
reagent and the isoquinolinium cation, providing an excellent
stereocontrol in the formation of two contiguous stereogenic centers.
Ensuing selective and high-yielding transformations provide
appealing dihydroisoquinoline derivatives.
Asymmetric anion-binding catalysis has emerged as a powerful
tool in Organic Synthesis.[1] In this type of ion-pairing catalysis,
bi- and multidentate H-bond donors play a fundamental role by
binding the anionic counterions of the reactive cationic
electrophiles.[2] Notably, strategically positioned scaffolds in the
catalysts might facilitate additional cooperative noncovalent
interactions with at least one of the reacting partners, thereby
maximizing the stereochemical control of the process. For
example, extended aromatic systems which enable positioning
of electrophiles by π-π and cation-π interactions have played
this role in a handful of highly enantioselective transformations.[3]
This strategy proved to be suitable for asymmetric
dearomatizations of azaarenes via N-acyl pyridinium and
(iso)quinolinium intermediates,[4] making use of different types of
chiral X–H bond donor catalysts such as thioureas (N–H),[5]
silanediols (O–H)[6] and oligotriazoles (C–H)[7] to bind chloride
counteranions. In most cases, silylated nucleophiles such as
silyl ketene acetals[5a,6,7a,7b] and silyl phosphites[5b,7c] (Scheme 1,
Preliminary experiments were conducted employing
isoquinoline (1a) as
a model substrate, 2,2,2-trichloroethyl
chloroformate (TrocCl) as acylating reagent and 2,4-difluoro
benzaldehyde N-tert-butylhydrazone 2A as a nucleophile with
reduced reactivity.
A significant background reaction was
observed in methyl tert-butyl ether (MTBE, 0.1 M), even at low
Previous work - Dearomatization by silylated nucleophiles
[a]
[b]
Prof. J. M. Lassaletta
R
R
Instituto Investigaciones Químicas (CSIC-US) and Centro de
Innovación en Química Avanzada (ORFEO-CINQA)
C/ Américo Vespucio 49, 41092 Sevilla, Spain
E-mail: jmlassa@iiq.csic.es
E. Matador, Dr. J. Iglesias-Sigüenza, Dr. D. Monge, Prof. R.
Fernández
OTBS
Nu
R
P
1) R'COCl
RO
OR
Cat*
OTBS
OR'
N
+
−
N
Nu
2) Cat*
then
Cl
N
R
R
SiR3Cl
O
R'
O
R'
(iso)quinolines
or pyridines
SiR3Nu
Departamento de Química Orgánica
Universidad de Sevilla and Centro de Innovación en Química
Avanzada (ORFEO-CINQA)
C/ Prof. García González 1, 41012 Sevilla, Spain
E-mail: dmonge@us.es, ffernan@us.es
Prof. P. Merino
Instituto de Biocomputación y Física de Sistemas Complejos (BIFI)
Universidad de Zaragoza-CSIC
50009 Zaragoza, Spain
Dearomatization by non-silylated nucleophiles
This work
S
R
*R
Ar
R
N
H
N
H
R
1) R'COCl
N
+
COR'
N
R'
[c]
N
Cl
2) Cat*
then
NuH
N
R'
tBu
N
O
HCl
H
H
N
Simultaneous
chloride binding?
tBu
R'
N
E-mail: pmerino@unizar.es
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Dearomatization of azaarenes.
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10.1002/anie.202012861
Angewandte Chemie International Edition
COMMUNICATION
temperatures: using an optimized gradient [−78 °C (20 hours) to
−20 °C (over 4 hours)], (rac)-dihydroisoquinoline 3aA was
obtained in 57% NMR-yield and 2.7/1 diastereomeric ratio
(Table 1, entry 1). In the presence of 10 mol% of several H-bond
donors (see the Supporting Information for details), the model
reaction was efficiently accelerated, reaching regularly higher
yields and dr’s. From the initial screening, tert-Leucine derived
thiourea Ia was identified as the most promising catalyst,
affording the desired product 3aA in 76% yield, a good 85% ee
and excellent dr (>20:1, entry 2). A marked decrease of
enantioinduction was observed for derivatives Ib and IIb
featuring squaramide units (entries 3 and 5), as well as for less
acidic catalyst IIa (entry 4).[17] The ee’s also dropped to 60% and
79% with alternative catalysts such as III, featuring an additional
(1R,2R)-(−)-1,2-diaminocyclohexane moiety, or p-brominated
derivative IV,[18] respectively (entries 6 and 7). Finally, we
evaluated the influence of the terminal dialkylamino fragment. N-
Benzyl-N-methyl derivative V (lacking one phenyl ring with
respect to Ia) provided a poor 48% ee (entry 8), suggesting that
a π−type interaction with the N-acyl quinolinium electrophile
might be involved.[3] Finally, catalyst VI,[19],[20] containing a more
rigid (R)-2-(diphenylmethyl)pyrrolidine group, afforded an
excellent 98% ee, while maintaining excellent dr (>20:1) and
good reactivity (72% NMR yield, entry 9). The urea analogue VII
was also used, showing a poorer catalytic activity and slightly
lower, but still excellent ee (entry 10). Further optimization of the
reaction with catalyst VI (entries 11-14) led to the use of a slight
excess (1.2 equiv) of hydrazone 2A in Et2O (0.1 M) as the
optimal solvent to obtain (S,S)-3aA in 75% isolated yield as a
single diastereoisomer (dr > 20:1) with excellent 99% ee (entry
14). Moreover, the catalyst loading could be reduced to 5 mol%
without compromising yield or stereoselectivity (entry 15).
The influence of the acylating reagent on reactivity and
selectivity was investigated maintaining 2A as the model
hydrazone. Surprisingly, protecting groups such as Cbz, alloc,
benzoyl, acetyl or benzyl completely suppressed the reactivity
(See the Supporting Information) but, interestingly enough, a 2-
chloropropionyl group was tolerated: the expected product (S,S)-
3aA’ was obtained in good yield, albeit in slightly lower 92% ee
(Scheme 2), suggesting the participation of the Troc or
CO2(CH2)2Cl moieties in noncovalent interactions.
Table 1. Screening of organocatalysts and optimization of the reaction.[a]
N
N
1) TrocCl (1.0 equiv), 0 °C, dry solvent (0.1 M), 1 h
H
Troc
N
N
2) Cat* (10 mol%),
then
N
tBu
tBu
N
1a
−78 °C ➝ −20 °C, 24 h
F
F
F
F
(1.1 equiv)
2A
3aA
Cat* =
O
O
S
S
N
N
N
H
Bzh
N
R
R
N
H
N
H
H
N
N
Bzh
N
O
N
H
H
Ph
Me
Bzh
O
O
Ia: R = ArF
Ib: R = ArF
IIb: R = CH2ArF
III
IIa: R = CH2ArF
CF3
X
Br
CF3
S
S
ArF
N
ArF
N
H
N
N
N
H
Bn
N
N
Bzh
O
N
N
Bzh
H
H
H
H
O
VI: X = S
VII: X = O
O
V
IV
Bzh = Benzhydryl, ArF = 3,5-bis(trifluoromethyl)phenyl
Cat*
[mol %]
ee
[%][c]
Entry
Solvent
Yield [%][b]
d.r.[c]
We next moved to explore the scope of the reaction
(Scheme 2). In general, dearomatization of isoquinoline (1a) with
differently substituted hydrazones (2A-K) afforded diazenes 3 in
good-to-high yields, excellent ee’s and nearly perfect dr’s (>20:1
in all cases). Within the electron-deficient aryl series,
dichlorinated analogue 2B furnished (S,S)-3aB in 75% yield and
97% ee, while 2C bearing a bulky bromine atom at ortho position
afforded the expected product (S,S)-3aC in 61% yield and 91%
ee. Importantly, hydrazones 2D and 2E, containing H-bond
acceptor functionalities (p-CN and m-NO2) were also well
tolerated, providing dearomatized products (S,S)-3aD and (S,S)-
3aE in high yields and 94% ee in both cases. Benzaldehyde
derived hydrazone 2F and derivatives 2G and 2H with diverse
electronic character also provided the corresponding products
(S,S)-3aF-aH in moderate-to-good yields (55-71%) and excellent
ee’s. Diazene (S)-3aI, derived from the simplest formaldehyde
N-tert-butylhydrazone 2I, was also obtained in good yield and ee.
Next, dearomatization of isoquinolines 1b-1k with representative
benzaldehyde derived hydrazone 2F were performed. 3-
Subtituted (3-methylisoquinoline and phenantridine) and 4-
1
-
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Et2O
57
-
2.7:1
>20:1
>20:1
>20:1
13:1
2
Ia (10)
Ib (10)
IIa (10)
IIb (10)
III (10)
IV (10)
V (10)
VI (10)
VII (10)
VI (10)
VI (10)
VI (10)
VI (10)
VI (5)
76
85
40
38
31
60
79
48
98
95
99
89
94
99
99
3
73
4
75
5
65
6
64
19:1
7
70
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
8
79
9
72
10
11
12
13
14[d]
15[d]
45
85
THF
70
toluene
Et2O
83
substituted
[4-bromoisoquinoline
and
4-
(phenylethynyl)isoquinoline] derivatives proved to be suitable
substrates, affording products (S,S)-3bF-eF in good yields and
high-to-excellent (93-98%) ee’s. Isoquinoline derivative 3f, which
contains a bulky phenyl group at 5-position, afforded diazene
(S,S)-3fF in a moderate 50% yield but high 90% ee. Similarly,
electron-deficient substrates (5-NO2 and 6-CN derivatives)
furnished the dearomatized products (S,S)-3gF and (S,S)-3hF in
88 (75)[e]
84 (70)[e]
Et2O
[a] Reactions at 0.1 mmol scale. [b] Estimated by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard. [c] Determined by HPLC. [d] Reaction
with 1.2 equiv of hydrazone. [e] In parenthesis, yield of isolated product.
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10.1002/anie.202012861
Angewandte Chemie International Edition
COMMUNICATION
1) ClCO2R (1.0 equiv), 0 °C
dry Et2O (0.1 M), 1 h
R
S
N
R
ArF
CO2R
N
R
N
2) VI (5 mol%)
N
H
N
N
N
N
MMPP, MeOH
Troc
N
N
N
H
H
Troc
N
tBu
R'
N
Troc
tBu
2A-K
O
O
−
1a-k
R'
N
H
+
−
O
(S,S)-3, dr >20/1
N
N
+
N
tBu
R' = Ar, H
R'
VI
N
tBu
−78 °C ⟶ −20 °C, 24 h
tBu
F
F
(S,S)-3aA, (S,S)-3cF
(S,S)-4aA
61%, 99% ee, >20:1 d.r.
(S,S)-4cF
84%, 94% ee, >20:1 d.r.
Pd(OH)2 / H2
EtOAc
N
N
N
N
Troc
N
CO2(CH2)2Cl
Troc
N
N
tBu
N
tBu
tBu
N
Cl
Cl
(S,S)-3aB
F
F
F
F
(S,S)-3aA
(S,S)-3aA'
N
70%, 99% ee
73%, 92% ee
75%, 97% ee
Troc
NHtBu
PIFA
N
N
N
Troc
Troc
N
CH3CN/H2O
NHtBu
N
N
N
Troc
N
N
N
Troc
Troc
N
Troc
O
N
F
F
N
t
O2N
N
Bu
tBu
N
tBu
tBu
N
NC
(S)-6
70%, 94% ee
(S,Z)-5aA
76%, 97% ee
(S,Z)-5cF
88%, 94% ee
Br
(S,S)-3aC
(S,S)-3aD
(S,S)-3aE
(S,S)-3aF
61%, 91% ee
80%, 94% ee
72%, 94% ee
71%, 96% ee
Scheme 3. Transformations of adducts (S,S)-3.
Me
N
N
N
Troc
N
Troc
N
Troc
Troc
N
tBu
N
[Pd(OH)2/1 atm H2].[23] The synthetic usefulness of these
intermediates was demonstrated by accessing cyclic α-amino
ketones. Thus, employing [bis(trifluoroacetoxy)-iodo]benzene
(PIFA) as the oxidant, (S,Z)-5cF was transformed into α-amino
ketone (S)-6 in 70% isolated yield without racemization.
N
H
tBu
N
N
tBu
N
tBu
N
H
F
Me
OMe
(S,S)-3aH
59%, >99% ee
(S,S)-3aI
63%, 91% ee
81%, 88% eeb
(S,S)-3aG
55%, 98% ee
(S,S)-3bF
70%, 97% ee
R
Ph
Br
N
According to the predicted activation model, the geometry,
size and coordination ability of the counteranion should have a
marked effect in the reaction outcome. Hence, anion exchanges
(Cl➝TFA, BF4, BARF) were performed prior to the addition of
hydrazone 2A (Scheme 4A). As expected, poorer reactivities
and enantioselectivities were observed in all cases, highlighting
the importance of the spherical and small chloride anion to reach
optimal results. An additional experiment performed with
N
N
N
N
Troc
Troc
Troc
N
Troc
N
N
N
N
tBu
N
tBu
N
tBu
tBu
(S,S)-3cF
65%, 93% ee
(S,S)-3dF
69%, 98% ee
(S,S)-3eF
68%, 93% ee
(S,S)-3fF
50%, 90% ee
Ph
R =
NO2
NC
N
N
N
N
N
Me
Troc
N
Troc
N
Troc
tBu
N
N
tBu
tBu
pyrrolidine-derived hydrazone
7 was designed to indirectly
(S,S)-3gF
75%, 94% ee
(S,S)-3hF
78%, 90% ee
(S,S)-3iF
69%, 81% ee
assess the role of the N–H group in hydrazones 2. Under the
previously optimized conditions, the reaction with 1a yielded
adduct 8 in a modest 49% yield and in racemic form (Scheme
4B), confirming the essential role of the chloride binding ability of
the hydrazone.
The binding of catalyst VI to the chloride anion in the
presence of hydrazone 2D was also analyzed by 1H-NMR
titration with tetrabutylammonium chloride (TBACl) in 9:1
toluene-d8/CD2Cl2 under catalytically relevant conditions: [VI] =
0.01 M, [2D] = 0.12 M).[24] As shown in Figure 1, the thiourea N–
H protons and the ortho C–H protons of the 3,5-bis-(trifluoro-
a
b
Scheme 2. Substrate scope. Reactions performed at 0.2 mmol scale.
Reaction performed with 2.5 equiv of hydrazone.
high yields and ee’s (up to 94%). The introduction of a methyl
substituent at C7, however, led to the expected adduct with
lower ee [(S,S)-3iF, 81% ee]. Unfortunately, pyridinium salts
showed no reactivity under the optimized conditions. Not
surprisingly, poor conversion or no reaction were also observed
with crowded substrates such as 8-bromoisoquinoline (1j) or 1-
methylisoquinoline (1k), respectively, while aliphatic aldehyde
hydrazones afforded products in poor conversions (see the
Supporting Information for details). Importantly, the synthesis of
(S,S)-3aA (64%, 99% ee, dr >20:1) and (S,S)-3cF (64%, 94%
ee, d.r. >20:1) were also efficiently performed at 1.0 mmol scale
under slightly different reaction conditions [VI (7.5 mol%), 26 h].
Crystals of (S,S)-3aA suitable for X-ray diffraction analysis[20]
were used to assign its absolute S,S configuration.
A: Assessment of counteranion effect
2) Anion exchange
1) TrocCl (1.0 equiv), 0 °C
Et2O (0.1 M), 1 h
3) VI (5 mol%), 2A (1.2 eq)
−78 °C ⟶ −20 °C, 24 h
(S,S)-3aA
1a
ArF
F
−
O
O
−
−
Cl
−
ArF
B
B
ArF
ArF
F
F
CF3
No reaction
Reference
F
84% NMR yield
99% ee, dr >20:1
14% NMR yield
rac, dr 15:1
Considering the growing interest in azoxy compounds as
therapeutic agents,[21] the selective oxidation of representative
adducts (S,S)-3aA and (S,S)-3cF was targeted as an interesting
transformation (Scheme 3). Magnesium monoperoxyphthalate
22% NMR yield
74% ee, dr 19:1
B: Influence of the hydrazone structure
1) TrocCl (1.0 equiv), 0 °C, Et2O (0.1 M), 1 h
N
N
1a
hexahydrate
compounds (S,S)-4 in good yields, as single regioisomers and
without compromising the stereochemical
integrity.[22]
(MMPP·6H2O)
efficiently
afforded
azoxy
Troc
N
2) VI (5 mol%),
(1.2 equiv)
Ph
N
N
Ph
7
8: 49%, racemic
−78 °C ⟶ −20 °C, 24 h
Additionally, adducts (S,S)-3 underwent a fast tautomerization to
hydrazones (S)-5 under standard hydrogenation conditions
Scheme 4. Control experiments.
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10.1002/anie.202012861
Angewandte Chemie International Edition
COMMUNICATION
CF3
A: Transition structure
H
H
N
S
N
N
N
H
N
H
CF3
O
H
Cl
NC
H
Cl
CF3
Cl
Me
N
F3C
Me
O
N
Me
O
Ph
H
H
+
H
N
N
N
O
N
H
S
−
Cl
H
H
H
tBu
B: NCI analysis
Cltroc···π
Forming bond
C–Hisoquinoline···Cl
C–Hhydrazone···Cl
−
π···π
Figure 1. Simultaneous 1H NMR titration experiment of VI and 2D with TBACl
(9:1 toluene-d8/CD2Cl2, [VI] = 0.01 M; [2D] = 0.12 M).
Cl
−
Cl
C–HtBu···π
methyl)phenyl group[25] are strongly shifted downfield upon the
stepwise addition of TBACl. Interestingly, the hydrazone
azomethine and N–H protons are also perturbated, even at high
hydrazone/chloride ratios,[26] suggesting a concurrent chloride
binding of both catalyst and hydrazone. Additionally, the
absence of a significant non-linear effect suggests that a 2:1
[VI]2/Cl− complex might not be operating in this case.[27]
Moreover, the method of continuous variation[28] was used to
determine the binding stoichiometry between catalyst VI and
TBACl and, as expected, the collected data fits with a 1:1
complex (see Supporting Information).
Computational studies for the synthesis of compounds 3aF
and 3aI were performed to corroborate the presence of a highly
ordered supramolecular transition structure involving the
chloride ion. In the most favored transition structure the
azomethine carbon approaches to the Si face of the
isoquinolinium C(1)=N bond (Figure 2, top). Differences of 17.3
and 10.5 kcal mol–1 (for 3aI and 3aF, respectively) were found
with respect to the most stable transition structure leading to the
(R)-enantiomer, accounting for a complete enantioselectivity.
The formation of minor amounts of the latter in some cases is
attributed to a residual background reaction. Notably, NCI
analysis[29] of the lowest energy transition structure showed the
presence of stabilizing Cl-π, CH-π and π-π interactions (Figure
2, bottom). Moreover, a recently developed tool for quantitative
NCI analysis[30] confirmed that noncovalent interactions of the
chloride ion with the NH’s of the thiourea moiety and hydrazone
as well as with the azomethine hydrogen atom are stronger in
the preferred TS (Figure 2, bottom square). These interactions
are responsible for fixing the orientation of the reagents in a
highly ordered [VI]‒Cl‒hydrazone complex as the key
intermediate, from which the preferential approach of the
azomethine carbon to the Si face of the isoquinolinium C(1)=N
bond accounts for the high enantio- and diastereoselectivity
reached and the observed (S,S) absolute configuration.
N–Hhydrazone···Cl
C2–HArF···Cl
N–Hthiourea···Cl
Figure 2. Lowest-energy transition structure leading to the (S,S)-enantiomer of
3aF. Top: Optimized geometry at the wb97xd/def2svp/pcm=diethyl ether level
of theory. Bottom: NCI analysis showing main noncovalent interactions.
Detailed interactions of the chloride ion are indicated in the square.
to catalyze
a
three-component dearomatization reaction
employing isoquinolines, 2,2,2-trichloroethyl chloroformate
(TrocCl) and N-tert-butyl hydrazones as neutral π-nucleophiles
to obtain functionalized dihydroisoquinolines bearing two
contiguous stereogenic centers with excellent enantio- and
diastereoselectivities.
Experimental
and
computational
evidences support the key role of the chloride anion as a
template for the formation of highly ordered transition structures
stabilized by a set of cooperative noncovalent interactions that
explain the exquisite stereocontrol of the reaction. The extension
of this multiple anion binding strategy to other substrates and/or
reagents is currently object of study in our laboratory.
Acknowledgements
We thank the Spanish MICINN (grants PID2019-106358GB-C21,
PID2019-106358GB-C22,
PID2019-104090RB-100,
and
predoctoral fellowship to E. M.), Aragon Government (Grupos
E34_20R), European FEDER funds and the Junta de Andalucía
(Grants P18-FR-3531, P18-FR-644 and US-1262867) for
financial support. We also thank general NMR/MS services of
the University of Sevilla and resources from the super-
computers "Memento" and “Cierzo” provided by BIFI-ZCAM
(University of Zaragoza, Spain). Prof. J. Contreras-García
(Université Sorbonne, France) and Dr. R. A. Boto (University of
In summary, a tert-Leucine derived thiourea has been shown
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10.1002/anie.202012861
Angewandte Chemie International Edition
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the Basque Country, Spain) are gratefully acknowledged for
fruitful discussions on NCI analyses.
Keywords: • Asymmetric catalysis • Hydrazones •
Dearomatization • Organocatalysis • Acylation
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10.1002/anie.202012861
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
S
Esteban Matador, Javier Iglesias-
R
*R
Ar
R
R
TS =
N
H
N
H
Sigüenza, David Monge,* Pedro
Merino,* Rosario Fernández* and José
M. Lassaletta*
1) TrocCl
N
N
+
Troc
N
N
N
−
2) Cat* (5 mol%),
then
S
Cl
Troc
R'
S
HCl
tBu
H
H
N
NHtBu
R'
N
good yields
dr >20:1
up to >99% ee
tBu
R'
N
R´ = Ar, H
Page No. – Page No.
Two is better than one! The ability of the chloride anion to simultaneously bind a
thiourea catalyst and a hydrazone nucleophile results in a highly ordered
termolecular transition structure stabilized by a cooperative set on noncovalent
interactions, ultimately resulting in an exquisite stereocontrol in the dearomatization
of isoquinolines
Enantio- and Diastereoselective
Nucleophilic Addition of N-tert-
Butylhydrazones to Isoquinolinium
Ions through Anion-Binding Catalysis
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