Enantioselective Direct Vinylogous Allylic Alkylation of 4-Methylquinolones under Iridium Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b01934

The first enantioselective vinylogous allylic alkylation of 4-methylquinolones has been developed. This iridium-catalyzed reaction introduces an allyl group at the γ-position of 4-methyl-2-quinolones with exclusive branched selectivity and an excellent level of enantioselectivity. This in turn allows for the enantioselective synthesis of γ-allylquinolines and related nitrogenous heterocycles. This is the first application of 4-methylquinolones in an enantioselective transformation.

Full text of DOI:10.1021/acs.orglett.9b01934

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Direct Vinylogous Allylic Alkylation of
4‑Methylquinolones under Iridium Catalysis
Rahul Sarkar and Santanu Mukherjee*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, India
S
* Supporting Information
ABSTRACT: The first enantioselective vinylogous allylic
alkylation of 4-methylquinolones has been developed. This
iridium-catalyzed reaction introduces an allyl group at the γ-
position of 4-methyl-2-quinolones with exclusive branched
selectivity and an excellent level of enantioselectivity. This in
turn allows for the enantioselective synthesis of γ-allylquino-
lines and related nitrogenous heterocycles. This is the first
application of 4-methylquinolones in an enantioselective
transformation.
ver since the first reports by Takeuchi1 and Helmchen2 in
1997, iridium-catalyzed allylic substitution reactions have
Scheme 1. Ir-Catalyzed Enantioselective Vinylogous Allylic
Alkylation
E
been identified among the most versatile and reliable methods
for the enantioselective construction of carbon−carbon and
carbon−heteroatom bonds.3 Tremendous developments,
especially in the realm of catalyst design, took place during
the past two decades, primarily due to the works of Hartwig,4
Carreira,5 and You,6 and led to the invention of a plethora of
enantioselective transformations involving direct carbon- and
heteroatom-centered nucleophiles.3 In contrast, the application
of vinylogous nucleophiles in Ir-catalyzed allylic alkylation
remain rather subdued.
It was only in 2014 that Hartwig et al. developed the first Ir-
catalyzed vinylogous allylic alkylation using preformed silyl
dienolates as the nucleophile (Scheme 1A).7 Subsequent to
this report, Ir-catalyzed direct vinylogous allylic alkylation of
α,β-unsaturated carbonyl compounds was developed by the
Jørgensen8 and Stoltz groups.9 Very recently, our laboratory10
and subsequently Yin et al.11 developed the first Ir-catalyzed
enantioselective vinylogous allylic alkylation of 4-methylcou-
marins (Scheme 1B).
While contemplating the idea of exploring the aza-analogue
of 4-methylcoumarins as potential vinylogous nucleophiles, we
realized that 4-methylquinolones have never been used as
vinylogous nucleophiles in any enantioselective transforma-
tions. In fact, application of either 2-quinolones themselves or
their derivatives in enantioselective transformations remains
extremely rare. The only known catalytic enantioselective
transformations of 2-quinolone consist of [2 + 2]-photo-
cycloadditions with olefins, catalyzed by thioxanthone as chiral
sensitizer, pioneered by Bach et al.12,13 Apart from [2 + 2]-
photocycloadditions, no other enantioselective transformation
of 2-quinolones is reported to date.14
structural modification. In addition, the lack of literature
reports on the vinylogous reactivity of 4-methylquinolones
made us wonder about their electronic properties, despite
structural similarity with 4-methylcoumarins.
Following our recent works on the vinylogous allylic
alkylation of 4-methylcoumarins,10,16 we surmised that
iridium-catalyzed asymmetric allylic alkylation would be a
perfect platform to test the electronic properties of 4-
methylquinolones and at the same time to install a stereocenter
Considering the rich biomedical and pharmaceutical
importance of 2-quinolones,15 we envisioned that the
introduction of a chiral center around the 2-quinolone
framework would create an additional chemical space for its
Received: June 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
around 2-quinolone without disturbing its core structure
(Scheme 1C).
Table 2. Scope of the Enantioselective Allylic Alkylation
with Regard to Allylic Carbonates
a
Herein, we report the results of this investigation in the form
of the first catalytic enantioselective vinylogous allylic
alkylation of 4-methylquinolones.
Choice of a suitable N-protecting group which can be easily
removed after the γ-allylation was a prime concern at the
outset of our investigation. Following a few preliminary
experiments,17 p-Methoxybenzyl (PMB)-protected 3-cyano-4-
methylquinolin-2(1H)-one 1a was selected as the model
substrate for reaction with tert-butyl cinnamyl carbonate 2a
(Table 1). In the presence of DABCO as an external base to
a
Table 1. Optimization of Reaction Parameters
b
c
1a/2a
solvent
T (°C)
t (h)
yield (%)
er
1
2
3
4
5
1:1.2
1:1.2
1:1.2
1.2:1
1:1.2
(CH2Cl)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
50
50
25
50
50
72
21
72
6
35
90 (90)
15
78
94 (94)
98:2
98:2
97:3
98:2
98:2
a
Reaction conditions: 3 mol % of [Ir(COD)Cl]2, 6 mol % of L, 0.20
mmol of 1a, 0.24 mmol of 2, and 0.20 mmol of DABCO in 1.0 mL of
CH2Cl2. The catalyst was prepared via n-PrNH2 activation. Yields
correspond to the isolated product after chromatographic purification.
The er was determined by HPLC analysis on a chiral stationary phase.
d
24
a
Reaction conditions: 3 mol % of [Ir(COD)Cl]2, 6 mol % of L, 0.10
mmol of 1a, 0.12 mmol of 2a, and 0.10 mmol of DABCO in 0.5 mL of
b
The product 3af was obtained with 99.5:0.5 er after a single
b
solvent. The catalyst was prepared via n-PrNH2 activation. Yields
recrystallization. n.d. = not determined.
were determined by 1H NMR spectroscopy with mesitylene as
internal standard. Isolated yields are given in the parentheses.
c
Enantiomeric ratio (er) was determined by HPLC analysis on a
chiral stationary phase. 1.5 mol % of [Ir(COD)Cl]2, 3 mol % of
ligand, 0.20 mmol of 1a, 0.24 mmol of 2a, and 0.20 mmol of DABCO
in 1.0 mL of solvent.
d
having either electron-withdrawing or electron-donating
substituents at various positions of the aryl ring to generate
the products with good to high yield and uniformly high
enantioselectivity (entries 1−11). In the case of p-bromo-
phenyl-substituted allylic carbonate 2f, nearly enantiopure
product 3af could be obtained after a single recrystallization.
Single-crystal X-ray diffraction analysis of 3af revealed its
absolute configuration to be (S) (CCDC 1895445; Table 2).
The configurations of the other products were assigned by
analogy as the same. Pharmaceutically relevant heterocycles
were successfully incorporated into the products. Such
examples include dioxolane (3al), pyridine (3am), furan
(3an), and thiophene (3ao), which were formed with high
er (entries 12−15).
The efficacy of our protocol is not restricted to aryl- or
heteroaryl-substituted allylic carbonates. Alkyl- and alkenyl-
substituted allylic carbonates also effectively participated in the
reaction. Allylic carbonates bearing a linear alkyl group (2p)
and benzyl group (2q) provided the products with moderate to
good yield and high enantioselectivity (entries 16 and 17).
Product containing a branched alkyl group (3ar) was formed
in moderate yield and with good er (entry 18). Alkenyl-
substituted allylic carbonates (2s and 2t) resulted in γ-allylated
2-quinolones (3as and 3at) as a single regioisomer with high
yield and er (entries 19−20).
enolize 1a, a combination of 3 mol % of [Ir(COD)Cl]2 and 6
mol % of Feringa’s phosphoramidite ligand18 (Sa,S,S)-L was
first tested as precatalyst for the reaction in 1,2-dichloroethane
at 50 °C. To our delight, the reaction was found to proceed in
the expected fashion to generate the desired γ-allylated 2-
quinolone 3aa exclusively as a single regioisomer (>20:1 b/l)
with high enantioselectivity, albeit in only 35% yield (entry 1).
Changing the reaction medium from 1,2-dichloroethane to
dichloromethane significantly improved the yield as well as the
rate of the reaction (entry 2). Performing the reaction at 25 °C
(entry 3) or increasing the amount of 1a (entry 4) adversely
affected the reaction efficacy. The loading of [Ir(COD)Cl]2
and ligand L could be reduced to 1.5 and 3 mol %, respectively,
without any negative influence on either yield or er (entry 5).
Having optimized the reaction conditions (Table 1, entry
2),19 we sought to test the scope and limitations of this
enantioselective γ-allylation reaction. As depicted in Table 2,
our protocol is quite general and can be applied to a wide
variety of allylic carbonates. 4-Methylquinolone 1a underwent
facile γ-allylic alkylation with cinnamyl carbonates (2a−k)
B
DOI: 10.1021/acs.orglett.9b01934
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Letter
After successfully showcasing the scope with respect to
allylic carbonates, we turned our attention to 2-quinolones
bearing substituents on the aryl ring for reaction with cinnamyl
carbonate 2a (Table 3A). N-Protected 3-cyano-4-methyl-2-
Attempted allylic alkylation of 3-cyano-4-ethyl-2-quinolone
under our optimized reaction conditions resulted in the
formation of a nearly equimolar mixture of branched/linear γ-
allylated products, and the brached product was formed as
1.1:1 dr.17
The applicability of the present catalytic system was tested
on other structurally related cyclic amides and even to
thioamide (Table 3B). 1,8-Naphthyridin-2-one derivative 1o
reacted efficiently to give the product 3oa with high yield and
er. A similar level of enantioselectivity was observed in the case
of cyclic thioamide 1p. In addition, our protocol could be
extended to 2-pyridone derivative 1q. Although the product
3qa was formed with only 30% yield, the reaction proceeded
with very high enantioselectivity.
Table 3. Scope of the Enantioselective Allylic Alkylation
with Respect to 2-Quinolones
a
To demonstrate the practicality of our protocol, a gram-scale
synthesis of 3aa was carried out with 1.5 mol % of
[Ir(COD)Cl]2 to obtain the product in 85% yield and 97:3
er (Scheme 2A). The enantiopurity of the product could be
improved to 98:2 er by a single recrystallization.
Scheme 2. (A) Gram-Scale Synthesis and (B) Synthetic
Elaboration of γ-Allyl-2-quinolone 3aa
a
Reaction conditions: 3 mol % of [Ir(COD)Cl]2, 6 mol % of L, 0.20
mmol of 1a, 0.24 mmol of 2a, and 0.20 mmol of DABCO in 1.0 mL of
CH2Cl2. The catalyst was prepared via n-PrNH2 activation. Yields
correspond to the isolated product after chromatographic purification.
The er was determined by HPLC analysis on a chiral stationary phase.
b
Reaction performed on a 0.10 mmol scale of 1c.
quinolones bearing substituents of diverse electronic demand
on the aromatic ring (1b−i) were well tolerated, furnishing the
products generally in high yield and with good to high
enantioselectivity (entries 1−8). Irrespective of the electronic
nature of the substituent on the 7-position of the quinolone
moiety, products (3ca and 3ha) were obtained only with
moderate enantioselectivity (entries 2 and 7).
The effect of the N-substituent on 2-quinolone was also
investigated (Table 3A). The p-methoxybenzyl group can be
replaced with simple alkyl (1j−1k), benzyl (1l), and even with
allyl (1m) groups without compromising either yield or
enantioselectivity (entries 9−12). However, the vinylogous
reactivity of quinolone was completely switched off when
unprotected 2-quinolone (1n) was employed (entry 13).
Instead of the desired γ-allylated product, this reaction resulted
in exclusive N-allylation.17 The above observations clearly
imply that the presence of a suitable N-protecting group is
necessary for 2-quinolones to exert its vinylogous reactivity. N-
Protected 4-methyl-2-quinolones with other electron-with-
drawing substituents such as ester, amide, or ketone at the 3-
position turned out to be completely unreactive under our
optimized reaction conditions.17
The synthetic utility of the γ-allylated 2-quinolones,
obtained through direct vinylogous allylic alkylation, was
displayed by converting the newly installed allylic unit into
various synthetically important functionalities (Scheme 2B).
Oxidative cleavage of olefin under OsO4−NaIO4 generated the
corresponding aldehyde from 3aa, which was isolated as the
alcohol 4 in 47% yield over two steps. Olefin cross-metathesis
of 3aa with methyl acrylate in the presence of Grubbs’ second-
C
DOI: 10.1021/acs.orglett.9b01934
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
generation catalyst furnished the ester 5 in 71% yield. Ir-
catalyzed hydroboration20 of the terminal double bond in 3aa
provided the alkyl borate 6 in 80% yield. Epoxidation of 3aa
using m-CPBA afforded the epoxide 7 in 59% yield, albeit with
poor diastereoselectivity (1.3:1 dr). Selective hydrogenation of
the terminal double bond could be achieved efficiently using
catalytic Pd/C as shown for 3ja and 3aa. Importantly, in the
case of 3aa, the PMB group survived under these conditions.
When subjected under Wacker oxidation conditions,21 3aa
surprisingly resulted in the formation of aldehyde 10 in 69%
yield. In all these cases, the products were isolated without any
erosion in enantiopurity.
The quinoline ring tethered with a chiral center is a very
important structural unit found in many chiral quinoline
alkaloids (including Cinchona alkaloids) with interesting
pharmacological as well as biological properties.22 However,
enantioselective synthesis of quinolines bearing a stereocenter
outside the aromatic ring is a challenging task.23 We realized
that this vinylogous allylic alkylation reaction could be applied
to address this issue.
93% yield. Compounds 11, 12, and 14 would be difficult to
synthesize by other means, thereby highlighting the power of
this protocol. As a proof of principle, formal γ-allylation of 4-
methylpyridine could also be achieved via a two-step sequence
starting from 3qa. Deprotection of the PMB group in 3qa
resulted in the formation of γ-allyl-2-pyridone 15 in 44% yield,
which was reacted with POCl3 under reflux to produce γ-allyl-
2-chloropyridine 16 in 72% yield (Scheme 3B). This reaction
sequence compliments the enantioselective Ir-catalyzed allylic
alkylation of 2-methylpyridines developed by You et al.24
The presence of the cyano group at the 3-position of
quinolones appears to be a prerequisite for its vinylogous
reactivity and at the same time marks a limitation of this
protocol. However, the cyano group in the product (3aa) can
be hydrolyzed to the corresponding amide (17) under aqueous
KOH in EtOH at 90 °C (Scheme 4). Subjecting 17 to
Scheme 4. Synthesis of α-Unsubstituted γ-Allylquinolone 18
Toward this goal, the PMB group in 3aa was successfully
removed using ceric ammonium nitrate (CAN) to give the
unprotected lactam (3na) in 78% yield (Scheme 3A). A single
Scheme 3. (A) Removal of Protecting Group and Synthesis
of Enantioenriched Quinolines. (B) Synthesis of γ-Allyl-2-
chloropyridine 16
refluxing aqueous NaOH in THF led to the decarboxylation
and furnished α-unsubstituted γ-allylquinolone 18. Enantio-
purity of 3aa was maintained during this reaction sequence.
In conclusion, we have developed the first enantioselective
vinylogous allylic alkylation of 4-methylquinolones. Using
easily accessible linear allylic carbonates as the allylic
electrophile, this Ir/phosphoramidite-catalyzed reaction deliv-
ers γ-allylated 2-quinolones generally in very high yield with
exclusive regioselectivity (b vs l) and excellent level of
enantioselectivity. This is the first time 4-methylquinolones
have been used in an enantioselective transformation.
Synthetic applicability of our protocol has been demonstrated
by converting the products into a number of useful structural
motifs containing diverse functional groups. Enantioselective
synthesis of chiral quinoline and pyridine derivatives achieved
through structural modification of the products also illustrates
the potential of this γ-allylic alkylation reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01934.
Experimental details and characterization data (PDF)
NMR spectra and HPLC chromatograms (PDF)
recrystallization led to enantiopure 3na, which was used for the
synthesis of quinoline derivatives. Treatment of 3na with
POCl3 under reflux generated γ-allyl-2-chloroquinoline 11 in
97% yield. Dechlorination as well as hydrogenation of the
terminal double bond took place when 11 was treated with
triethylammonium formate in the presence of Pd(PPh3)4 to
furnish γ-alkylquinoline 12 in 62% yield. Reaction of 3na with
P2S5 in basic medium furnished thiolactam 13 in 71% yield.
Methylation of 13 afforded γ-allyl-2-thiomethylquinoline 14 in
Accession Codes
CCDC 1895445 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
D
DOI: 10.1021/acs.orglett.9b01934
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Organic Letters
Letter
Aldehydes by Combined Organocatalysis and Transition-Metal
Catalysis. Angew. Chem., Int. Ed. 2015, 54, 10193−10197.
(9) Liu, W.-B.; Okamoto, N.; Alexy, E. J.; Hong, A. Y.; Tran, K.;
Stoltz, B. M. Enantioselective γ-Alkylation of α,β-Unsaturated
Malonates and Ketoesters by a Sequential Ir-Catalyzed Asymmetric
Allylic Alkylation/Cope Rearrangement. J. Am. Chem. Soc. 2016, 138,
5234−5237.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sm@iisc.ac.in.
ORCID
Rahul Sarkar: 0000-0003-3700-6580
Santanu Mukherjee: 0000-0001-9651-6228
Notes
(10) Sarkar, R.; Mitra, S.; Mukherjee, S. Iridium-Catalyzed
Enantioselective Direct Vinylogous Allylic Alkylation of Coumarins.
Chem. Sci. 2018, 9, 5767−5772.
The authors declare no competing financial interest.
(11) Shi, C.-Y.; Xiao, J.-Z.; Yin, L. Iridium-Catalyzed Direct
Asymmetric Vinylogous Allylic Alkylation. Chem. Commun. 2018,
54, 11957−11960.
ACKNOWLEDGMENTS
■
(12) For selected examples of intermolecular [2 + 2]-photo-
This work is funded by the Science and Engineering Research
Board (SERB) [Grant No. EMR/2016/005045]. R.S. thanks
the Council of Scientific and Industrial Research (CSIR), New
Delhi, for a doctoral fellowship. We thank Mr. Rupak Saha
(Department of Inorganic and Physical Chemistry, IISc,
Bangalore) for his help with the X-ray structure analysis. Mr.
Aditya Chakrabarty (Department of Organic Chemistry, IISc,
Bangalore) is gratefully acknowledged for his help with the
synthesis of some of the starting materials.
̈
cycloaddition of 2-quinolone, see: (a) Troster, A.; Alonso, R.; Bauer,
A.; Bach, T. Enantioselective Intermolecular [2 + 2] Photo-
cycloaddition Reactions of 2(1H)-Quinolones Induced by Visible
Light Irradiation. J. Am. Chem. Soc. 2016, 138, 7808−7811. (b) Bach,
T.; Bergmann, H. Enantioselective Intermolecular [2 + 2]-Photo-
cycloaddition Reactions of Alkenes and a 2-Quinolone in Solution. J.
Am. Chem. Soc. 2000, 122, 11525−11526. For examples of
intramolecular [2 + 2]-photocycloaddition of 2-quinolone, see:
(c) Alonso, R.; Bach, T. A Chiral Thioxanthone as an Organocatalyst
for Enantioselective [2 + 2] Photocycloaddition Reactions Induced by
Visible Light. Angew. Chem., Int. Ed. 2014, 53, 4368−4371. (d) Bach,
T.; Bergmann, H.; Grosch, B.; Harms, K. Highly Enantioselective
Intra- and Intermolecular [2 + 2] Photocycloaddition Reactions of 2-
Quinolones Mediated by a Chiral Lactam Host: Host−Guest
Interactions, Product Configuration, and the Origin of the Stereo-
selectivity in Solution. J. Am. Chem. Soc. 2002, 124, 7982−7990.
(13) For a different approach to similar enantioselective [2 + 2]-
photocycloaddition of 2-quinolones, see: (a) Yagishita, F.; Takagishi,
N.; Ishikawa, H.; Kasashima, Y.; Mino, T.; Sakamoto, M.
Deracemization of Quinolonecarboxamides by Dynamic Crystalline
Salt Formation and Asymmetric Photoreaction by Using the Frozen
Chirality. Eur. J. Org. Chem. 2014, 6366−6370. (b) Yagishita, F.;
Mino, T.; Fujita, T.; Sakamoto, M. Two-Step Asymmetric Reaction
Using the Frozen Chirality Generated by Spontaneous Crystallization.
Org. Lett. 2012, 14, 2638−2641. (c) Yagishita, F.; Sakamoto, M.;
Mino, T.; Fujita, T. Asymmetric Intramolecular Cyclobutane
Formation Via Photochemical Reaction of N,N-Diallyl-2-Quinolone-
3-Carboxamide Using a Chiral Crystalline Environment. Org. Lett.
2011, 13, 6168−6171.
REFERENCES
■
(1) Takeuchi, R.; Kashio, M. Highly Selective Allylic Alkylation with
a Carbon Nucleophile at the More Substituted Allylic Terminus
Catalyzed by an Iridium Complex: An Efficient Method for
Constructing Quaternary Carbon Centers. Angew. Chem., Int. Ed.
Engl. 1997, 36, 263−265.
(2) Janssen, J. P.; Helmchen, G. First Enantioselective Alkylations of
Monosubstituted Allylic Acetates Catalyzed by Chiral Iridium
Complexes. Tetrahedron Lett. 1997, 38, 8025−8026.
(3) Cheng, Q.; Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You,
S.-L. Iridium-Catalyzed Asymmetric Allylic Substitution Reactions.
Chem. Rev. 2019, 119, 1855. (b) Qu, J.; Helmchen, G. Applications of
Iridium-Catalyzed Asymmetric Allylic Substitution Reactions in
Target-Oriented Synthesis. Acc. Chem. Res. 2017, 50, 2539−2555.
(c) Hethcox, J. C.; Shockley, S. E.; Stoltz, B. M. Iridium-Catalyzed
Diastereo-, Enantio-, and Regioselective Allylic Alkylation with
Prochiral Enolates. ACS Catal. 2016, 6, 6207−6213. (d) Tosatti, P.;
Nelson, A.; Marsden, S. P. Recent Advances and Applications of
Iridium-Catalysed Asymmetric Allylic Substitution. Org. Biomol.
Chem. 2012, 10, 3147−3163. (e) Hartwig, J. F.; Stanley, L. M.
Mechanistically Driven Development of Iridium Catalysts for
Asymmetric Allylic Substitution. Acc. Chem. Res. 2010, 43, 1461−
1475. (f) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.;
Weihofen, R. Iridium-Catalysed Asymmetric Allylic Substitutions.
Chem. Commun. 2007, 675−691.
(4) Ohmura, T.; Hartwig, J. F. Regio- and Enantioselective Allylic
Amination of Achiral Allylic Esters Catalyzed by an Iridium−
Phosphoramidite Complex. J. Am. Chem. Soc. 2002, 124, 15164−
15165.
(5) Defieber, C.; Ariger, M.; Moriel, P.; Carreira, E. Iridium-
Catalyzed Synthesis of Primary Allylic Amines from Allylic Alcohols:
Sulfamic Acid as Ammonia Equivalent. Angew. Chem., Int. Ed. 2007,
46, 3139−3143.
(6) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L.
Iridium-Catalyzed Allylic Alkylation Reaction with N-Aryl Phosphor-
amidite Ligands: Scope and Mechanistic Studies. J. Am. Chem. Soc.
2012, 134, 4812−4821.
̈
(14) Troster, A.; Bauer, A.; Jandl, C.; Bach, T. Enantioselective
Visible Light-Mediated Formation of 3-Cyclopropylquinolones via
Triplet-Sensitized Deracemization. Angew. Chem., Int. Ed. 2019, 58,
3538−3541.
(15) (a) Hu, Z.; Banothu, J.; Beesu, M.; Gustafson, C. J.; Brush, M.
J. H.; Trautman, K. L.; Salyer, A. C. D.; Pathakumari, B.; David, S. A.
Identification of Human Toll-Like Receptor 2-Agonistic Activity in
Dihydropyridine−Quinolone Carboxamides. ACS Med. Chem. Lett.
2019, 10, 132−136. (b) Jain, S.; Chandra, V.; Kumar Jain, P.; Pathak,
K.; Pathak, D.; Vaidya, A. Comprehensive Review on Current
Developments of Quinoline-Based Anticancer Agents. Arabian J.
Chem. 2016, DOI: 10.1016/j.arabjc.2016.10.009. (c) Kumar, N.; Raj,
V. P.; Jayshree, B. S.; Kar, S. S.; Anandam, A.; Thomas, S.; Jain, P.;
Rai, A.; Rao, C. M. Elucidation of Structure-Activity Relationship of 2-
Quinolone Derivatives and Exploration of their Antitumor Potential
through Bax-Induced Apoptotic Pathway. Chem. Biol. Drug Des. 2012,
80, 291−299.
(16) Kayal, S.; Mukherjee, S. Catalytic Enantioselective Vinylogous
Allylic Alkylation of Coumarins. Org. Lett. 2017, 19, 4944−4947.
(17) For details, see the Supporting Information.
(18) Teichert, J. F.; Feringa, B. L. Phosphoramidites: Privileged
Ligands in Asymmetric Catalysis. Angew. Chem., Int. Ed. 2010, 49,
2486−2528.
(19) To study the substrate scope, 3 mol % of [Ir(COD)Cl]2 was
used over 1.5 mol % as the former led to uniformly high yield and er.
(7) (a) Chen, M.; Hartwig, J. F. Iridium-Catalyzed Regio- and
Enantioselective Allylic Substitution of Silyl Dienolates Derived from
Dioxinones. Angew. Chem., Int. Ed. 2014, 53, 12172−12176. Also see:
(b) Chen, M.; Hartwig, J. F. Iridium-Catalyzed Regio- and
Enantioselective Allylic Substitution of Trisubstituted Allylic Electro-
philes. Angew. Chem., Int. Ed. 2016, 55, 11651−11655.
(8) Næsborg, L.; Halskov, K. S.; Tur, F.; Mønsted, S. M. N.;
Jørgensen, K. A. Asymmetric γ-Allylation of α,β-Unsaturated
E
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Organic Letters
Letter
(20) Yamamoto, Y.; Fujikawa, R.; Umemoto, T.; Miyaura, N.
Iridium-Catalyzed Hydroboration of Alkenes with Pinacolborane.
Tetrahedron 2004, 60, 10695−10700.
(21) Tsuji, J.; Shimizu, I.; Yamamoto, K. Convenient General
Synthetic Method for 1,4- and 1,5-Diketones by Palladium Catalyzed
Oxidation of α-Allyl and α-3-Butenyl Ketones. Tetrahedron Lett. 1976,
17, 2975−2976.
(22) (a) O’Donnell, F.; Smyth, T. J. P.; Ramachandran, V. N.;
Smyth, W. F. A Study of the Antimicrobial Activity of Selected
Synthetic and Naturally Occurring Quinolines. Int. J. Antimicrob.
Agents 2010, 35, 30−38. (b) Michael, J. P. Quinoline, Quinazoline
and Acridone Alkaloids. Nat. Prod. Rep. 2008, 25, 166−187. (c) Boyd,
D. R.; Sharma, N. D.; Loke, P. L.; Malone, J. F.; McRoberts, W. C.;
Hamilton, J. T. G. Synthesis, Structure and Stereochemistry of
Quinoline Alkaloids from Choisya Ternata. Org. Biomol. Chem. 2007,
5, 2983−2991.
(23) For an example, see: Meazza, M.; Hammer, F. T. N.; Jørgensen,
K. A. Synergistic Diastereo- and Enantioselective Functionalization of
Unactivated Alkyl Quinolines with α,β-Unsaturated Aldehydes.
Angew. Chem., Int. Ed. 2017, 56, 1634−1638.
(24) Liu, X. J.; You, S. L. Enantioselective Iridium-Catalyzed Allylic
Substitution with 2-Methylpyridines. Angew. Chem., Int. Ed. 2017, 56,
4002−4005.
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DOI: 10.1021/acs.orglett.9b01934
Org. Lett. XXXX, XXX, XXX−XXX