Organocatalytic Enantioselective Functionalization of Hydroxyquinolines through an Aza-Friedel-Crafts Alkylation with Isatin-derived Ketimines

Article abstract of DOI:10.1002/adsc.201701217

A highly enantioselective addition of hydroxyquinolines to isatin-derived ketimines has been realized using a quinine-derived thiourea organocatalyst. The reaction affords chiral 3-amino-2-oxindoles bearing a quinoline moiety with a quaternary stereocenter in high yields (up to 98%) and excellent enantioselectivities (up to 99%). Moreover, we can extend this methodology for the enantioselective functionalization of 5-hydroxyisoquinoline. This methodology represents, to the best of our knowledge, the first enantioselective addition of hydroxyquinolines to imines. (Figure presented.).

Full text of DOI:10.1002/adsc.201701217

Title: Organocatalytic Enantioselective Functionalization of
Hydroxyquinolines through an aza-Friedel-Crafts Alkylation with
Isatin-derived Ketimines
Authors: Carlos Vila, Alejandra Rendón-Patiño, Marc Montesinos-
Magraner, Gonzalo Blay, M. Carmen Muñoz, and José Pedro
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701217
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10.1002/adsc.201701217
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Organocatalytic Enantioselective Functionalization of
Hydroxyquinolines through an Aza-Friedel-Crafts Alkylation
with Isatin-derived Ketimines
Carlos Vila, a*Alejandra Rendón-Patiño,a Marc Montesinos-Magraner,a Gonzalo Blay,a
M. Carmen Muñozb and José R. Pedroa*
a
Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner 50, 46100 Burjassot,
València (Spain). E-mail: carlos.vila@uv.es, jose.r.pedro@uv.es
Departament de Física Aplicada, Universitat Politècnica de València, Camino de Vera s/n, 46022 València (Spain)
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
contrast to the nucleophilic functionalization of
quinoline ring broadly investigated in the literature.[5]
In order to accomplish the electrophilic
functionalization of the quinoline carbocyclic ring, we
planned to use the activating/directing effects of a
hydroxyl group in the carbocyclic ring.[6] This strategy
was used by the group of Jørgensen in 2006,[7] for the
diastereoselective atropoisomeric functionalization at
5’ position of the quinoline core of cupreine
derivatives by an amination reaction.
Abstract.
A
highly enantioselective addition of
hydroxyquinolines to isatin-derived ketimines has been
realized using a quinine-derived thiourea organocatalyst.
The reaction affords chiral 3-amino-2-oxindoles bearing a
quinoline moiety with a quaternary stereocenter in high
yields (up to 98%) and excellent enantioselectivities (up to
99%). Moreover, we can extend this methodology for the
enantioselective
functionalization
of
5-
hydroxyisoquinoline. This methodology represents, to the
best of our knowledge, the first enantioselective addition
of hydroxyquinolines to imines.
Keywords: asymmetric organocatalysis ; Friedel-Crafts
reaction; isatin-derived ketimines ; quinoline; thiourea
Nitrogen-containing aromatic heterocycles are
ubiquitous in agrochemicals, pharmaceuticals and
natural products.[1] Therefore, the synthesis of chiral
nitrogen heterocycles represents a hot topic in organic
chemistry due to the great synthetic and industrial
interest of such compounds. In this context,
quinoline[2] or 1-aza-naphthalene is one of the most
important aza-aromatic compounds because of the
wide range of biological activities of their derivatives.
The quinoline scaffold is present in numerous natural
products,[3] such as the alkaloid quinine used to treat
malaria and babesiosis, or its diastereoisomer
quinidine with antiarrhythmic activity; quinoline is
also present in synthetic drugs such as primaquine, an
alternative medication to treat and prevent malaria.
Figure 1. Examples of biologically active quinoline
compounds and 3-substituted 3-amino-2-oxindoles.
However, this strategy has not been used for the
Quinoline-pyridone
hybrids,
both
natural
enantioselective
functionalization
of
(camptothecin) as synthetic derivatives (topotecan)
present cytotoxic activity and are used as
chemotherapeutic agents (Figure 1A).
The ubiquity of the quinoline scaffold has prompted
the development of several efficient methodologies for
the functionalization of quinolines.[4] In this context,
the electrophilic enantioselective functionalization of
the quinoline ring has been scarcely studied, in
hydroxyquinolines, to the best of our knowledge. In
view of this, we decided to study the enantioselective
aza-Friedel-Crafts reaction with imines, given the
importance of the development of the asymmetric
synthesis of chiral amines.[8] Recently, an aza-Friedel-
Crafts reaction with 8-hydroxyquinoline has been
described. However, this approach was reported for
the synthesis of racemic Betti bases.[9] In this
1
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10.1002/adsc.201701217
Advanced Synthesis & Catalysis
communication, we have chosen Boc-protected isatin-
derived ketimines as electrophiles,[10,11] which
Quinine (I) catalyzed the reaction to obtain the product
3aa with 66% yield after 6 days (Table 1, entry 1),
however the product was obtained with low
enantiomeric excess (15 % ee). When cupreine
derivative II was used as catalyst high
enantioselectivity (89% ee) was obtained, but the yield
was very low[17] (15%, Table 1, entry 2). To our delight,
when quinine-derived thiourea III was used (Table 1,
entry 3), the reaction proceeded smoothly with
excellent results. The chiral quinoline 3aa was
obtained with 96% yield and 98% ee, after 2 days.
When cinchonidine-derived thiourea IV was tested as
catalyst, product 3aa was afforded with the same
enantiomeric excess but lower yield (74%). The
reaction with quinine-derived squaramide V, gave
excellent enantioselectivity (99% ee), although with
provided
enantioenriched
tetrasubstituted
3-
aminooxindoles.[12] Remarkably, this motif is present
in several biologically active compounds such as those
shown in Figure 1B.[13,14] As a part of our ongoing
interest in the asymmetric synthesis of chiral
tetrasubstituted 3-aminooxindoles,[15] herein we
present the first enantioselective addition of
hydroxyquinolines to isatin-derived ketimines
catalyzed by a thiourea bifunctional organocatalyst.
We chose the reaction of 6-hydroxyquinoline 1a with
isatin-derived N-Boc ketimine 2a as a model reaction
to screen various bifunctional organocatalysts.
Bifunctional organocatalyst have been choosen
considering the significant advantages of this kind of
catalyst in asymmetric catalysis,[16] and we assume that
the double-activation mode of hydrogen bonding and
a Brønsted base could be essential to promote the aza-
Friedel-Crafts aminoalkylation of hydroxyquinolines.
moderate
yield
(56%).[17]
Other
thiourea
organocatalyst bearing a tertiary amine moiety, such
as Takemoto’s catalyst VI, proved to be an efficient
catalyst in terms of enantioselectivity (93% ee),
though with a decreased yield (Table 1, entry 6).
Therefore we chose catalyst III to continue further
optimization. Other solvents such as EtOAc, THF or
CH2Cl2, were also screened, but slightly lower
enantioselectivities were observed (entries 7-9). The
aza-Friedel-Crafts product 3aa could be also achieved
with good enantiomeric excess when only 2 or 1 mol%
of catalyst was used (entry 10 and 11, respectively),
although with lower yields. Furthermore, the opposite
enantiomer of 3aa, was achieved with excellent
enantioselectivity (97% ee, entry 12), when quinidine-
derived thiourea VII (5 mol%) was used as a catalyst.
Table 1. Optimization of the reaction conditions.a
Cat.
(x %)
I (10 %)
II (5 %)
III (5 %) 45 Tol.
IV (5 %) 29 Tol.
t(h) Solv.
Y.
ee
Entry
(%)b (%)c
1
95 Tol.
30 Tol.
66
15
96
74
55
56
15
89
98
98
99
93d
95
93
92
98
96
97d
2
3
4
5
V (5 %)
VI (5 %) 24 Tol.
22 Tol.
6
7
III (5 %) 45 EtOAc 94
III (5 %) 45 THF 58
III (5 %) 45 CH2Cl2 90
III (2 %) 45 Tol.
III (1 %) 45 Tol.
VII (5 %) 45 Tol.
8
9
10
11
12
57
25
65
a)
Reaction conditions: 0.1 mmol 1a, 0.1 mmol 2a, and
b)
Scheme 1. Scope of the aza-Friedel-Crafts reaction of 6-
hydroxyquinolines with 2. Reaction conditions: 1 (0.1
mmol), 2 (0.1 mmol), and catalyst III (5 mol%) in dry
toluene (1 mL) at rt for 45 h. Isolated yield after column
catalyst in dry solvent (1.5 mL) at rt. Isolated yield after
column chromatography, >20:1 regioselectivity determined
1
c)
by H NMR. Enantiomeric excess determined by chiral
HPLC. d) Opposite enantiomer.
1
chromatography, >20:1 regioselectivity determined by H
NMR.
2
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10.1002/adsc.201701217
Advanced Synthesis & Catalysis
With the optimized reaction conditions in hand (entry
3, Table 1), we proceeded to study the scope of the aza-
Friedel-Crafts reaction of 6-hydroxyquinolines with
ketimines 2 (Scheme 1). Initially, substitution at the
N1 of the oxindole was evaluated (Scheme 1, 3ꢀaa-
3ꢀad). Groups such as benzyl, phenyl, allyl or methyl
were well tolerated, providing the corresponding
products with high enantioselectivities (94-98ꢀ% ee).
Next, we evaluated different N-Boc ketimines derived
from various substituted N-benzylisatines. Electron-
donating (MeO or Me) or electron-withdrawing (NO2
or Cl) groups were tolerated at the 5-position of the
isatin-derived ketimine, affording the corresponding
products (3ae-3ah) with good yields and high
enantioselectivities. Moreover, ketimines with
substituents at 6- or 7-positions reacted smoothly,
providing the aminoalkylated hydroxyquinolines 3ai
and 3aj with good results. Moreover, the disubstituted
ketimine 2k could be used, obtaining the
corresponding product 3ak with excellent
enantiomeric excess (97%), but moderate yield (46%).
6-hydroxyquinaldine 1b could also be applied under
the optimized reaction conditions giving 3ba with
excellents results (96% yield, 98% ee).
8, with ketimines 2a and 2i, with moderate yields and
moderate enantiomeric excesses. Finally, when 8-
hydroxyquinoline was used as nucleophile, we could
not observed any reaction products. We attribute the
lack of the reactivity of 8-hydroxyquinoline to an
intramolecular hydrogen bonding between the
hydroxyl group and the nitrogen atom from the
quinoline.
Scheme 3. Aza-Friedel-Crafts reaction of 5-
hydroxyisoquinolines with 2a. Reaction conditions: 1f (0.1
mmol), 2a (0.1 mmol), and catalyst III (5 mol%) in dry
toluene (1 mL) at rt for 45 h. Isolated yield after column
1
chromatography, >20:1 regioselectivity determined by H
NMR.
Isoquinoline scaffold is also an important nitrogen
heterocycle that is present in a wide range of natural
products and pharmaceuticals.[18] In view of the
importance of isoquinoline structure, we decided to
explore our methodology with the aza-Friedel-Crafts
reaction of a hydroxyisoquinoline, in order to
enantioselectively functionalize the carbocylic ring.
Thus, 5-hydroxyisoquinoline 1f was used as a
nucleophile under the optimized reaction conditions
(Scheme 3), and the corresponding product 3fa,
regioselectively alkylated at C-6, was obtained with an
excellent 96% ee, but moderate yield (50%).
Scheme 2. Scope of the aza-Friedel-Crafts reaction of
hydroxyquinolines with 2. Reaction conditions: 1 (0.1
mmol), 2 (0.1 mmol), and catalyst III (5 mol%) in dry
toluene (1.5 mL) at rt for 45 h. Isolated yield after column
1
chromatography, >20:1 regioselectivity determined by H
NMR.
After have proved the efficiency of our methodology
for the enantioselective aza-Friedel-Crafts alkylation
of 6-hydroxyquinoline at the C-5 position of the
carbocyclic ring, we studied the scope of the reaction
with other hydroxyquinolines bearing a hydroxy group
in other positions of the carbocyclic ring (Scheme 2).
Our goal was to achieve the enantioselective
functionalization of every position in this ring by
simply changing the position of the directing group.
When 5-hydroxyquinoline (1c) was used as
nucleophile under the optimized reaction conditions,
with ketimine 2a and 2h, products 3ca and 3ch,
substituted at C-6 were obtained with good yields and
high enantiomeric excesses. 7-Hydroxyquinoline (1d)
was also applied, although we observed a diminished
Scheme 4. Plausible transition-state model and X-ray
crystal structure of 3ai.
The absolute configuration of the stereogenic centre in
compound 3ai was determined to be (R) on the basis
of X-ray crystallographic analysis (Scheme 4); the
configuration of the rest of the products 3 were
assigned on the assumption of a uniform mechanistic
pathway.[19] A plausible transition-state model is
depicted in Scheme 4. The thiourea catalyst is the
responsible for the preorientation and the activation of
reactivity
and
enantioselectivity.
The
7-
hydroxyquinoline was regioselectively alkylated at C-
3
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10.1002/adsc.201701217
Advanced Synthesis & Catalysis
In a 10 mL round bottom flask, hydroxyquinoline 1 (14.5
mg, 0.1 mmol), ketimine 2 (0.1 mmol), catalyst III (3.0 mg,
0.005 mmol, 0.05 eq) and a stir bar were placed. The flask
was purged with N2 and toluene (1 mL) was added via
syringe. The mixture was stirred at room temperature until
completion (TLC). Finally, the reaction mixture was
directly poured into a column for chromatography, using
hexane:EtOAc or CH2Cl2: MeOH as eluents to afford
product 3.
the substrates acting as bifunctional organocatalyst.
While the isatin-derived N-Boc-ketimine is activated
upon formation of hydrogen bonds between the N-Boc
group and the thiourea moiety of the catalyst, the
hydroxyquinoline undergoes nucleophilic activation
by hydrogen bonding with the quinuclidine moiety of
the catalyst, as Khan and Ganguly propose for the
addition of naphthols to the same ketimines.[20,21] The
quinoline will be directed to the Re-face of the
ketimine, thus accounting for the observed
enantioselectivity.
Additionally, different synthetic transformations were
conducted with compound 3aa, proving the utility of
the developed methodology (Scheme 5). Compound
3aa was transformed into triflate 4 with good yield
preserving the enantiomeric purity. Hydroxyquinoline
derivative 3aa was also easily transformed into N-
oxide 5 by oxidation with m-CPBA in CH2Cl2. Finally,
removal of the Boc group in 3aa was achieved by
heating in acetic acid at 60 ºC affording the free amine
6 in 95% yield without loss of the stereochemical
purity.
Synthesis and characterization data for compound 4
Compound 3aa (48.1 mg, 0.1 mmol) and 4-
dimethylaminopyridine (36.8 mg, 0.3 mmol, 3 eq) were
placed in a 10 mL round bottom flask. Then, the flask was
purged with N2 and CH2Cl2 (1 mL) was added. After 5
minutes, N-phenyl-bis(trifluoromethanesulfonimide (71.5
mg, 0.2 mmol, 2 eq) was added and the mixture was stirred
at room temperature. The reaction was monitored by TLC.
When the starting material was consumed, H2O was added
(5 mL) and the mixture was extracted with EtOAc (3 x 20
mL). The combined organic layers were washed with brine
(30 mL) and dried under anhydrous Na2SO4. The organic
solvents were removed under reduced pressure and the
residue was purified by column chromatography being
eluted with hexane: AcOEt (90:10 to 60:40).
Synthesis and characterization data for compound 5
Compound 3aa (48.1 mg, 0.1 mmol) and meta-
chloroperoxybenzoic acid (17.3 mg, 0.2 mmol) were
dissolved in 1 mL of CH2Cl2 and the mixture was stirred at
room temperature. The reaction was monitored by thin layer
chromatography being eluted with hexane:AcOEt. When
the starting material was consumed, the solvent was
removed, and the crude mixture was dissolved in CH2Cl2
and poured directly to the column chromatograpy, using
hexane:AcOEt (90:10 to 60:40)as eluent to afford product 5.
Synthesis and characterization data for compound 6
Compound 3aa (40 mg, 0.08 mmol) was dissolved in AcOH
(2 mL). The solution was stirred at 60 ºC until completion.
Then, the reaction was quenched with a saturated aquous
NaHCO3 solution and extracted with CH2Cl2 (3x30 mL).
After drying the organic phase over MgSO4 and evaporation
of the solvent, the residue was purified by column
chromatography being eluted with CH2Cl2: MeOH (100:0 to
95:5).
Scheme 5. Synthetic transformations.
In conclusion, we have developed an enantioselective
aza-Friedel–Crafts reaction of hydroxyquinolines[22]
with isatin-derived ketimines,[23] using a quinine-
derived thiourea organocatalyst, obtaining the
corresponding chiral 3-aminooxindoles with good
yields and excellent enantioselectivities (up to 99% ee).
This approach enables the introduction of substituents
in positions C-5, C-6 or C-8 of the carbocyclic ring of
quinoline in a regioselective manner, by just switching
the position of the activating/directing hydroxy group.
Acknowledgements
Financial support from the MINECO (Gobierno de España;
CTQ2013-47494-P) is gratefully acknowledged. C.V. thanks
MINECO for a JdC contract and M.M-M. thanks Universitat de
València for a pre-doctoral grant. Access to NMR, MS and X-ray
facilities from the Servei central de suport a la investigació
experimental (SCSIE)-UV is also acknowledged.
Furthermore,
5-hydroxyisoquinoline
was
enantioselectively alkylated with good results.
Moreover, several transformations have been carried
out with the products obtained. We envision that this
procedure provides a successfully approach for the
enantioselective functionalization of the carbocyclic
ring of quinolines.
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5
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10.1002/adsc.201701217
Advanced Synthesis & Catalysis
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derived ketamine under the reaction conditions.
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essential for the activation of the nucleophile.
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[22] We have tried the reaction with a cuprein derivative as
nucleophile under the optimized reaction conditions.
However we did not observe conversion to aza-Friedel-
Crafts product. See Supporting Information for further
details.
[23] We have tried the reaction with other activated
ketimines under the optimized reaction conditions.
However we did not observed the aza-Friedel-Crafts
reaction. See Supporting Information for further details.
[19] CCDC 1557026 (3ai) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
6
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10.1002/adsc.201701217
Advanced Synthesis & Catalysis
COMMUNICATION
Organocatalytic Enantioselective Functionalization
of Hydroxyquinolines through an aza-Friedel-
Crafts Alkylation with Isatin-derived Ketimines
Adv. Synth. Catal. Year, Volume, Page – Page
Carlos Vila, a*Alejandra Rendón-Patiño,a Marc
Montesinos-Magraner,a Gonzalo Blay,a M. Carmen
Muñozb and José R. Pedroa*
7
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