Chiral Triazoles in Anion-Binding Catalysis: New Entry to Enantioselective Reissert-Type Reactions

Article abstract of DOI:10.1002/chem.201504094

Easily accessible and tunable chiral triazoles have been introduced as a novel class of C-H bond-based H-donors for anion-binding organocatalysis. They have proven to be effective catalysts for the dearomatization reaction of different N-heteroarenes. Although this dearomatization approach represents a powerful strategy to build chiral heterocycles, to date only a few catalytic methods to this end exist. In this work, the organocatalyzed enantioselective Reissert-type dearomatization of isoquinoline derivatives employing a number of structurally diverse chiral triazoles as anion-binding catalysts was realized. The here presented method was employed to synthesize a number of chiral 1,2-dihydroisoquinoline substrates with an enantioselectivity up to 86:14 e.r. Moreover, a thorough study of the determining parameters affecting the activity of this type of anion- binding catalysts was carried out.

Full text of DOI:10.1002/chem.201504094

DOI: 10.1002/chem.201504094
Full Paper
&
Organocatalysis
Chiral Triazoles in Anion-Binding Catalysis: New Entry to
Enantioselective Reissert-Type Reactions
Mercedes Zurro,[a, b] Sçren Asmus,[a] Julia Bamberger,[a] Stephan Beckendorf,[c] and
Olga García MancheÇo*[a, b]
Abstract: Easily accessible and tunable chiral triazoles have
been introduced as a novel class of CÀH bond-based H-
donors for anion-binding organocatalysis. They have proven
to be effective catalysts for the dearomatization reaction of
different N-heteroarenes. Although this dearomatization
approach represents a powerful strategy to build chiral
heterocycles, to date only a few catalytic methods to this
end exist. In this work, the organocatalyzed enantioselective
Reissert-type dearomatization of isoquinoline derivatives em-
ploying a number of structurally diverse chiral triazoles as
anion-binding catalysts was realized. The here presented
method was employed to synthesize a number of chiral 1,2-
dihydroisoquinoline substrates with an enantioselectivity up
to 86:14 e.r. Moreover, a thorough study of the determining
parameters affecting the activity of this type of anion-
binding catalysts was carried out.
Introduction
egy is based on the Reissert reaction. It consists of the activa-
tion of the N-heteroarene employing an acylating (such as acyl
chloride or chloroformate, RCOCl) or alkylating agent to gener-
ate the corresponding N-acyl or N-alkyl iminium species A. This
ionic intermediate is then susceptible to react with a nucleo-
phile, generating a new stereocenter with consequent loss of
the aromaticity (Scheme 1).[8] In early reports, the enantioselec-
tivity was achieved through the use of a chiral auxiliary.[9] The
first enantioselective catalytic Reissert reaction was reported in
2000 by Shibasaki et al.[10] A chiral aluminum Lewis acid was
employed as catalyst for the addition of cyanide to an N-acyl
In the last few years, asymmetric hydrogen-bonding
organocatalysis has emerged as a powerful synthetic tool.[1]
Hydrogen-bond donor catalysts, predominantly (thio)urea[2] or
squaramide[3] structures, can act as weak Lewis acids, activating
the basic sites of a neutral substrate such as carbonyl or imine
moieties by establishing intermolecular hydrogen bonds.[4]
Lately, this H-bonding activation approach has evolved into
a new class of process, the so-called anion-binding catalysis,
which allows the activation of electrophilic ionic substrates by
coordination to their counter anions.[5] Among the possible
target applications for developing enantioselective anion-bind-
ing catalysis, the dearomatization of N-heteroarenes consti-
tutes an interesting synthetic strategy.[6] Thus, chiral nitrogen-
containing heterocycles, widely present in pharmaceuticals
and biological natural products, can be built in one synthetic
step from abundant, economic and commercially available het-
eroarenes. To date, there are only a few catalytic asymmetric
methods for this purpose.[7] A very useful and common strat-
quinolinium or
isoquinolinium derivative (Scheme 1,
[Eq. (1)]).[10] More recently, the first enantioselective organo-
catalytic N-acyl Mannich reaction of isoquinolines (“Reissert-
type reaction”) was reported by the group of Jacobsen, em-
ploying thioureas as anion-binding organocatalysts (Scheme 1,
[Eq. (2)]).[11]
After this pioneering work in anion-binding catalysis with
thioureas, other types of compounds such as thiophosphor-
amides (also based on NÀH bonds),[12] silanediols (based on
OÀH bonds),[13] or the 1,2,3-triazole-based structures (based on
CÀH bonds) recently developed in our research group[14,15]
have been introduced as alternative potent anion-binding
organocatalysts.
[a] M. Zurro, Dr. S. Asmus, J. Bamberger, Prof. Dr. O. García MancheÇo
Institute for Organic Chemistry, University of Regensburg
Universitätsstrasse 31, 93053 Regensburg (Germany)
E-mail: olga.garcia-mancheno@ur.de
We focused our attention on the use of triazoles for the
development of a new type of anion-binding catalysts due to
their unique structural features: i) 1,2,3-triazoles are easily ac-
cessible via click chemistry by the CuI-catalyzed azide–alkyne
cycloaddition (CuAAC) reaction,[16] and ii) the triazole unit
presents a highly polarized CÀH bond that allows the binding
of anions by hydrogen bonding.[17] The large dipole moment
(m=4.3–4.6 D), almost aligned with the C5ÀH bond,[18] in
combination with the relatively high acidity of this position
(pKa(DMSO) =27–28, for the 1H-tautomer)[19] makes 1,2,3-triazoles
[b] M. Zurro, Prof. Dr. O. García MancheÇo
Straubing Center of Science for Renewable Resources (WZS)
Schulgasse 16, 94315 Straubing (Germany)
[c] Dr. S. Beckendorf
Institute of Organic Chemistry, University of Münster
Corrensstrasse 40, 48149 Münster (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504094.
Part of a Special Issue “Women in Chemistry” to celebrate International
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Scheme 2. Reissert-type dearomatization of N-heretoarenes with triazole-
based anion-binding catalysts.
Results and Discussion
Synthesis of the triazole-based catalysts
Aiming at the development of a highly enantioselective
dearomatization of N-heteroarenes with CÀH-based H-donors,
a family of chiral triazole-based catalysts was initially devel-
oped. We designed the synthesis of the triazole catalysts by
iterative Sonogashira couplings, followed by CuAAC reactions
to incorporate the triazole moieties to the structure. To explore
the effect of the location of the chiral information in the cata-
lyst structure on the later chiral transfer to the products, vari-
ous catalysts bearing the chirality at the central backbone (1a–
e)[15] and at the end-chain (1 f–i) were synthesized (Scheme 3).
For the catalysts with chirality at the central backbone
(Scheme 3, top), the synthesis started from cheap and com-
mercially available 1,3,5-tribromobenzene, which was mono-al-
kynylated to form 6. Alternatively to the previous described
synthesis of 1a,[15] catalysts 1a–c could also be prepared by
a further double Sonogashira reaction with trimethylsilylacety-
lene, deprotection of the TMS group and desymmetrization via
CuAAC reaction with 3,5-ditrifluoromethylphenyl azide. A final
CuAAC reaction with the corresponding chiral 1,2-diamine de-
livered 1a–c in good yields (50–72%). Interestingly, 1a could
also be obtained from dialkyne 8 in a one-pot process imply-
ing two sequential click cycloaddition reactions. However, the
overall yield was significant lower (30%/2 steps from 8; 41 vs.
23% overall yield). On the other hand, the synthesis of the re-
gioisomer 1d required an initial desymmetrization of 6 to form
the amine 10. Next a Sonogashira coupling, following by a di-
azotization/substitution with NaN3 to generate the alkyne–
azide 12 was performed. Lastly, a CuAAC reaction, the depro-
tection of the alkyne group and a final click cycloaddition with
(1R,2R)-diazidocyclohexane provided 1d in good yield (41%
overall yield). The synthesis of the triazoles 1 f–i with chirality
at the end-chain was similarly carried out. Consequently, good
yields were obtained from the common alkyne 8 and azide 12
precursors as shown in Scheme 3 (bottom). From the same in-
Scheme 1. The Reissert-type approach for the catalytic asymmetric dearoma-
tization of isoquinolines as model N-heteroarenes and early reports.
Figure 1. 1,2,3-Triazoles as anion-binding motifs.
extremely good candidates as hydrogen bond donors
(Figure 1). Thus, strong hydrogen bonds, as for the inherently
more polarized NÀH and OÀH groups, can be reached by a co-
operative use of this type of CÀH bonds.[20]
Although the anion-binding ability of triazoles, especially
oligo-triazoles, has been well recognized,[21] we have recently
employed them for the first time as a new class of anion-
binding organocatalysts.[14,15] Thus, highly enantioselective
dearomatization of quinolines[15a] and pyridines[15b] has been
developed (up to 98:2 e.r., Scheme 2). The triazole-based orga-
nocatalysts showed an effective binding to a chloride counter
anion, generating a chiral chloride–catalyst complex. This spe-
cies, a chiral bulky anion, can form a contact ion-pair with the
N-acyl iminium substrate, allowing an efficient chiral transfer to
the final product. To get a deep insight into the reaction re-
quirements and the action of the organocatalysts, we decided
to further explore the activity of our triazole-based organocata-
lysts in a model dearomatization reaction. Herein, we report
the synthesis of novel triazole-based anion-binding catalysts
and an extensive study of their catalytic activity in the Reissert-
type dearomatization reaction of isoquinolines. (Scheme 2,
bottom).
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Scheme 3. Synthesis of the triazole organocatalysts bearing the chirality at the central backbone (top) and at the end-chain (bottom).
termediate 14, the tetrakistriazoles 1 f and 1h were generated
by a CuAAC reaction with the corresponding chiral azide, while
the hexakistriazoles 1g and 1i required a previous chain exten-
sion. Thus, an additional click cycloaddition with 12, alkyne
deprotection and final CuAAC was performed. In the case of
the BINOL-containing catalysts, the coupling reactions were
made with the MOM-protected derivatives, followed by a final
deprotection under acidic conditions.
screening conditions initially reported by Jacobsen for the
same substrate (2,2,2-trichloroethyl chloroformate (TrocCl) as
acylating agent, silyl ketene acetal 5a as nucleophile in Et2O at
À788C, and slow warming up to room temperature over 16 h).
Although in an earlier work a low rate background reaction
was reported (12% yield),[13] we surprisingly observed that in
the blank reaction under these conditions a relatively strong
background process was taking place (44%, entry 1). This
shows a remarkable difference between the N-acyl isoquinoline
substrates and the previous studies, especially with the N-acyl
Enantioselective N-acyl Mannich reaction of isoquinolines
pyridines. Thus, isoquinolines present
a
higher intrinsic
The performance of the triazole catalysts 1 was firstly explored
in the asymmetric dearomatization of isoquinoline (2a)
(Table 1). We started our study by employing the standard
reactivity towards the attack of
a nucleophile at the
a-position, making it more challenging to accomplish high
enantioselectivities.
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Being aware of the strong solvent effect in reactions pro-
ceeding through a charged intermediate, we considered inves-
tigating different solvent systems with the best two catalyst
structures, 1a and its triazole regioisomer 1d (Table 2). The use
of methyl tert-butylether (MTBE) instead of Et2O was beneficial,
Table 1. Screening of the triazole-catalysts.[a]
Table 2. Solvent and catalyst loading screening.[a]
Entry[a]
Catalyst
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
9
10
–
44
79
84
68
84
83
69
69
91
68
50:50
68:32
66:34
56:44
69:31
47:53
64:36
49:51
55:45
50:50
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Entry[a]
Catalyst (mol%)
Solvent
Yield [%][b]
e.r.[c]
1
2
3
4
5
6
7
8
1a (10)
1a (10)
1a (5)
1d (10)
1d (5)
1d (10)
1d (10)
1d (10)
MTBE
MTBE
MTBE
MTBE
MTBE
THF
79
75
76
74
64
38
61
77
75:25
75:25[d]
70:30
78:22
69:31
52:48
57:43
54:46
[a] Conditions: i) 2a (1.0 equiv) and TrocCl 4a (1.0 equiv) in Et2O at 08C,
30 min; then ii) at À788C, catalyst (10 mol%) and 5a (2.0 equiv) were
added and stirred for 16 h, while allowing warming up slowly to room
temperature. [b] Isolated yield. [c] Enantiomeric ratios determined by
chiral HPLC.
toluene
DCM
[a] Conditions: i) 2a (1.0 equiv) and TrocCl (1.0 equiv) in the correspond-
ing solvent at 08C, 30 min; then ii) at À788C, catalyst and 4 (2 equiv)
were added and stirred for 16–17 h, while allowing warming up slowly to
room temperature. [b] Isolated yield. [c] Enantiomeric ratios determined
by chiral HPLC. [d] Reaction at À788C for 24 h.
Considering this key issue and the excellent performance of
1a with the other N-heteroarenes (quinolines, up to 98:2 e.r.;
pyridines, up to 99:1 e.r.), we next studied our triazole catalysts
possessing the chirality at the central backbone (1a–e) (en-
tries 2–6). The tetrakistriazole catalysts derived from 1,2-cyclo-
hexanediamine 1a and 1d led to good enantioselectivities,
68:32 e.r. and 69:31 e.r., respectively (entries 2 and 5). Further-
more, the catalyst derived from the 1,2-diphenyldiamine 1b
provided an inferior chiral induction (66:34 e.r., entry 3), where-
as the BINAM derivative 1c led to an almost racemic product
(56:44 e.r., entry 4). Moreover, the bistriazole 1e was also stud-
ied (entry 6), leading to a poor inverse enantioselectivity of
47:53 e.r. These results indicate that the central chirality at the
backbone is not the only and principal element involved in the
chirality transfer, showing that four triazoles are required to
have a cooperative effect for the effective chloride anion
binding and enantioinduction.
providing the product 3a in higher enantiomeric ratios (en-
tries 1 and 4). Additionally, the use of THF, DCM, or toluene as
solvents led to a drastic drop of the enantioinduction. It could
also be observed that the reaction at À788C gave the same
enantiomeric excess obtained as when, after the addition of
the catalyst and nucleophile, the reaction was allowed to
warm up to room temperature (entry 2 vs. 1). Therefore, for
practical reasons only the addition of the catalyst and nucleo-
phile was conducted at À788C. As expected, a reduction of
the catalyst loading from 10 to 5 mol% led to a decrease of
the enantioselectivity (entries 3 and 5).
Afterwards, the reaction with the triazole structures present-
ing the chiral unit at the end-chain derived from (S)-methyl-
naphthyl azide or 2-azido BINOL was conducted. However,
these catalysts led to lower enantioselectivities compared to
the previous ones. Thus, the tetrakistriazoles (1 f and 1h) pro-
vided low to moderate enantioselectivities (entries 7 and 9),
whereas the hexakistriazoles (1g, 1i) led to no appreciable
enantioinduction (entries 8 and 10). Despite the disappointing
results, these experiments provided valuable information, con-
firming that four is the optimal number of triazoles in the cata-
lyst. This could be explained by a less localized and effective
binding of the chloride anion by the more flexible hexakistria-
zoles, which might allocate more anions in a non-specific
manner.
From the previous screenings, catalysts 1a and 1d provided
3a with a similar enantioselectivity (75:25 and 78:22 e.r., en-
tries 1 and 4, respectively). Although 1d showed a slightly
better enantioselectivity in MTBE, 1a was chosen as the cata-
lyst for the optimization of the nucleophile and acylating
agent. Thus, the effect of the nucleophile substitution on the
enantioselectivity of the reaction was then studied by varying
the initial isopropyl group at the oxygen in the silyl ketene
acetals 5 (Table 3). An increase of the steric hindrance with
a tert-butyl substituent (5b) did not improve the initial enan-
tioselectivity, providing a similar result (73:27 vs. 75:25 e.r.). On
the other hand, the use of a less demanding methyl group in
5c led to the corresponding addition product 3c in a
significantly lower enantioinduction (67:33 e.r.).
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phenyl substituent was placed slightly further away (3g), like
for the CCl3 group in the Troc, the enantioselectivity improved.
However, the reactivity was almost suppressed (67:33 e.r.,
<5% yield). A variety of acyl chlorides were also tested, but
they gave poor enantioselectivities. All these observations
showed the great influence of the acylating agent on both the
reactivity and the enantioselectivity of the process. Thus, the
use of TrocCl appears to be key for inducing a high enantiose-
lectivity. It seems that a carbamoyl group with a bulky group
at the b position is required. Moreover, the unique behavior of
the Troc group could also be attributed to possible additional
positive weak interactions, such as Cl–p or halogen–halogen,[22]
with the isoquinolinium intermediate and the catalyst–chloride
complex. This might then assist in the fixation and orientation
of the substrate in the chiral contact ion-pair prior attack of
the nucleophile.
Table 3. Screening of the nucleophile 5.[a–c]
[a] Conditions: i) 2a (1.0 equiv) and TrocCl 4a (1.0 equiv) in MTBE at 08C,
30 min; then ii) at À788C, 1a (10 mol%) and 5 (2.0 equiv) were added
and stirred for 16 h, while allowing warming up slowly to room tempera-
ture. [b] Isolated yields. [c] Enantiomeric ratios determined by chiral HPLC.
Having identified the optimal reaction conditions, (use of
TrocCl as acylating reagent, 5a as nucleophile, and 10 mol% of
the catalyst in MTBE as solvent at À788C to room tempera-
ture), a number of isoquinolines with various substitution pat-
terns were explored in the presence of the most efficient cata-
lyst 1d (Table 5). Different bromo-substituted isoquinolines
were initially examined. Good enantioselectivity values were
obtained with the 4-bromo (3l) and 5-bromo derivatives (3m)
(81:19 and 82:18 e.r., respectively), whereas a slightly lower se-
Considering the better performance of the isopropyl silyl
ketene acetal 5a, this nucleophile was employed for the rest
of the study. Then, different acylating agents were subsequent-
ly tested (Table 4). First, several chloroformates were investigat-
Table 4. Screening of the acylating reagent 4.[a–c]
Table 5. Screening of the substrate scope.[a–c]
[a] Conditions: i) 2a (1.0 equiv) and 4 (1.0 equiv) in MTBE at 08C, 30 min;
then ii) at À788C, 1a (10 mol%) and 5a (2.0 equiv) were added and
stirred for 16 h, while allowing warming up slowly to room temperature.
[b] Isolated yields. [c] Enantiomeric ratios determined by chiral HPLC.
ed to determine the importance of the 2,2,2-trichloroethyl
group of the Troc moiety. Low enantioselectivities were ob-
served with the related 2-chloroethyl carbonochloridate (3d),
presenting only one chlorine, or the trichloromethyl carbono-
chloridate (3e), in which the CCl3 group is directly bonded to
the oxygen atom. A similar disappointing result was obtained
with benzoyl chloride (3 f). On the other hand, when the
[a] Conditions: i) 2a (1.0 equiv) and TrocCl 4a (1.0 equiv) in MTBE at 08C,
30 min; then ii) at À788C, 1d (10 mol%) and 5 (2 equiv) were added and
stirred for 16–17 h, while allowing warming up slowly to room tempera-
ture. [b] Isolated yields. [c] Enantiomeric ratios determined by chiral HPLC.
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lectivity was observed for the 8-bromo-substituted isoquino-
line (3o, 72:28 e.r.). The use of the bulkier tert-butyl ketene
acetal 5b led to a slight increase of the enantiomeric ratio,
giving 3n with 86:14 e.r. The introduction in the 5-position of
an electron-donating group such as methoxy or a bulkier aryl
group, as well as a strong electron-withdrawing group such as
nitro was well tolerated. However, the more electron-rich deriv-
ative (3p, 75:25 e.r.) led to a significantly better level of enan-
tioselectivity compared to the more sterically hindered p-tolyl-
substituted (3r) or the electron-poor derivatives (3q). Methyl
substitution at the 3-position led to a notable decrease of the
enantioselectivity, (3s, 65:35 e.r.), most probably due to steric
reasons. Interestingly, at this position a less sterically demand-
ing fused ring system provided high levels of enantioselectivity
(3t, 84:16 e.r.), whereas a deactivating ester group led to no
conversion (3u). Finally, 1-chloro- or 1-methyl-substituted iso-
quinolines did not participate in this reaction. This also
showed an important steric effect on the reactivity, a non-sub-
stituted C1-isoquinoline being required to allow the approach
of the nucleophile to this position in the contact ion-pair
system. In summary, the reaction can be employed in a wide
substrate scope, high substitution tolerance of functional
groups in almost all positions with exception of the substitu-
tion at the C1, and the presence of deactivating groups at the
C3.
Lastly, and assuming similar behavior for all the substrates,
the absolute configuration of the dihydroisoquinoline products
3 was assigned as (R) by comparison of the sign of the
observed optical rotation for 3a with the one reported in the
literature (Figure 2).[11]
Reaction course and anion-binding studies
A comparative study of the course of the reaction with quino-
line and isoquinoline as substrates with the silyl ketene acetal
5a in the presence and absence of catalyst 1a in MTBE at
À788C for 22 h was next carried out (Figure 3). The evolution
of the enantiomeric excess and yield was monitored by HPLC
and GC,[23] respectively. As previously reported,[15a] the reaction
with quinoline using catalyst 1a provided the addition product
in a high enantioselectivity of 97:3 e.r. (Figure 3, left). Although
a moderate 82:18 e.r. was observed after 15 min, an almost
constant high enantiomeric excess was recorded after a reac-
tion time of 4 h. Despite the less efficient background reaction
(52% vs. 83%, 22 h), a slight inhibition of the reaction rate
could be detected in the presence of the catalyst in the first
hours. Similarly, the reaction course with isoquinoline was
studied (Figure 3, right). Although there was a considerable
background reaction (65%, 22 h), the catalyzed process was
more efficient (98%) showing no initial inhibition. However, in
this case a significantly lower enantioinduction was reached
and the enantiomeric excess remained constant after 30 min
(70:30 e.r.).
Figure 2. Assignment of the absolute configuration by comparison of the re-
ported [a]D for 3a.
The reaction profile of the catalyzed reaction with the regio-
isomeric catalyst 1d showed unexpected behavior (Figure 4,
Figure 3. Kinetic study of the dearomatization reaction of quinoline (left) and isoquinoline (right) in the presence and absence of catalyst 1a in MTBE at
À788C.
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Figure 4. Study of the reaction course for the dearomatization of isoquinoline with catalyst 1d in MTBE at À788C without (left) and after 3 h incubation of
1d with the pre-formed isoquinolium substrate (right).
left). Although a good yield of 75% was obtained in the
presence of the catalyst 1d after 22 h, a remarkable retarded
reaction was observed in the first few hours. However, from
a critical point (around 3 h) the reaction rate suddenly in-
creased, so that the catalyzed reaction became faster than the
non-catalyzed process. This fact might indicate an induction
time for the formation of a more active catalytic species. In
order to shed some light on the observed induction period,
a further kinetic study was carried out (Figure 4, right). Prior to
its use, the catalyst 1d was incubated for 3 h at À788C with
Scheme 4. Comparison between Cl and Br counter anions.
the pre-formed isoquinolinium chloride salt II’, which is in
equilibrium with the neutral chloride derivative I’.[24] The reac-
tion was then monitored after the addition of the nucleophile
5a. There was no positive influence on the final enantioselec-
tivity (73:27 vs. 75:25 e.r.). However, the induction period was
not observed on this occasion. This observation reinforces the
postulated induction period required for 1d to form the active
catalytic species. Since for 1a a sigmoidal curve was also not
observed, the induction time might be extremely fast (<5 min)
or does not occur with this catalyst. Furthermore, the main
structural difference between 1a and 1d is the presence of re-
gioisomeric triazole units at the end-chain. This indicates a pre-
orientation requirement of the rotational flexible tetrakis
triazole catalysts 1, which seems to be more critical for 1d, to
effectively bind the chloride anion and coordinate with the
substrate to form the active 1-II’ complex. A plausible pre-
orientation with 1d is depicted in Figure 4 (top-right).
ratio could be achieved when employing the regioisomer cata-
lyst 1a (5 mol%). These results showed that a bromide anion
can also be accommodated inside the chiral cavity of this type
of tetrakistriazole catalysts and efficiently transfer the chirality
to the N-acyl iminium substrate.
A final comparison between the typical NÀH-based hydro-
gen bond donor organocatalysts thioureas and squaramides,
and the tetrakistriazole 1d was made (Figure 5). Although the
thiourea 1j employed in the early work by Jacobsen and
co-workers provided 3a in a high 90:10 enantiomeric ratio
(reported 93:7 e.r.),[11] squaramide 1k[26] (67:33 e.r.) proved to
be slightly less efficient than 1d (78:22 e.r.). This shows the
competitive good performance of the tetrakistriazole
structures as a new type of H-donor catalysts.
Additionally, the effect of the counter anion, chloride versus
bromide, on the enantioselectivity was investigated
(Scheme 4). A notably higher enantioselectivity using TrocCl
compared to the result with TrocBr[25] in the presence of cata-
lyst 1d was obtained (78:22 e.r. vs. 66:34 e.r., respectively).
However, with the Br anion a similar good 72:28 enantiomeric
Conclusion
A family of chiral triazoles has been developed as a new type
of anion-binding organocatalysts based on CÀH bonds as
H-donors. We have introduced these structures as effective
and competitive catalysts for the Reissert-type dearomatization
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Acknowledgements
The Deutsche Forschungsgemeinschaft (DFG) is gratefully
acknowledged for generous support.
Keywords: anion-binding
·
enantioselective reactions
·
isoquinolines · organocatalysis · triazoles
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Figure 5. Comparison with other H-donors.
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Experimental Section
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In a dried Schlenk tube, isoquinoline derivative 2 (0.1 mmol) was
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Received: October 12, 2015
Published online on January 7, 2016
Chem. Eur. J. 2016, 22, 3785 – 3793
www.chemeurj.org
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim