Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2-Substituted 2,3-Dihydro-4-quinolones by a Protecting-Group-Free Approach

Article abstract of DOI:10.1021/acs.orglett.5b01654

Chiral 2-substituted 2,3-dihydro-4-quinolones were synthesized based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields with high enantioselectivities. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01654

Letter
pubs.acs.org/OrgLett
Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of
2‑Substituted 2,3-Dihydro-4-quinolones by a Protecting-Group-Free
Approach
Kodai Saito, Yuka Moriya, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
S
* Supporting Information
ABSTRACT: Chiral 2-substituted 2,3-dihydro-4-quinolones
were synthesized based on the chiral phosphoric acid catalyzed
intramolecular aza-Michael addition reaction using N-
unprotected 2-aminophenyl vinyl ketones as substrates in
good yields with high enantioselectivities.
tep economy is generally defined by the streamlining of
Sreaction steps by refraining from the use of protection−
deprotection reactions, redox, etc.,1 thereby enabling ready
access to target molecules. Protection and deprotection
reactions, although representing an important protocol in
synthetic organic chemistry, generally require much time and
cost, making the approach less step-economical.
The organocatalyzed aza-Michael addition was extensively
studied in recent years2 and is recognized as one of the most
powerful tools for the synthesis of enantioenriched nitrogen
heterocycles. The key issue is how to effect the cyclization in an
efficient and stereocontrolled manner. To achieve that goal, any
removable activating group on the nitrogen atom is frequently
required for stereocontrol and increasing the acidity of the
nitrogen. To that end, the development of a protecting-group-
free aza-Michael addition is highly desired to decrease the
number of reaction steps.3
The quinolone skeleton is found in many natural products and
is regarded as a “privileged” structure in medicinal chemistry
because it can be easily accessed with flexible synthetic
approaches that allow the production of large chemical libraries
having potential biological activities. Consequently, numerous
synthetic strategies have been developed to gain access to a range
of quinolone skeletons. 2-Substituted 2,3-dihydro-4-quinolone
derivatives represent a new class of antimitotic antitumor agents
(Figure 1).4 A highly enantioselective synthesis of those
structures is strongly desired because their enantiomers often
exhibit distinct properties. There are several reports of the
catalytic enantioselective synthesis of 2-aryl-2,3-dihydro-4-
quinolones.5 However, activating groups on the nitrogen atom
were required in those approaches. Pitchumani et al. developed a
cyclodextrin-mediated asymmetric synthesis in aqueous media
based on the sequential aldol-Michael reaction of o-amino-
acetophenone with various aldehydes in a one-pot manner.5f
This method requires more than a stoichiometric amount of
chiral reagent to realize a highly enantioselective addition.
Figure 1. Synthetic approaches to 2-substituted 2,3-dihydro-4-
quinolones.
Chiral phosphoric acid, a representative organocatalyst, has a
Brønsted acidic part (P−OH) and a Lewis basic part (PO) and
functions as a bifunctional catalyst.6 Although Rueping et al.
reported a chiral N-triflylphosphoramide catalyzed synthesis of
2-substituted 2,3-dihydro-4-quinolone derivatives using N-
protected 2-aminophenyl vinyl ketone, the enantioselectivity of
this reaction was unsatisfactory (49−63% ee).5h We report
herein a chiral phosphoric acid catalyzed intramolecular aza-
Michael addition of N-unprotected 2-aminophenyl vinyl ketone
to furnish 2-substituted 2,3-dihydro-4-quinolones in a highly
enantioselective manner.
At the outset, we selected 1a as the model substrate and treated
it with a range of phosphoric acids 3 bearing aryl groups at 3,3′-
Received: April 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01654
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
positions in benzene at 70 °C to give aza-Michael adduct 2a in
24% yield with 23% ee. Investigation of the 3,3′-substituents
revealed that the introduction of an electron-withdrawing group
has a beneficial effect on the enantioselectivity. Finally, we found
that 3g bearing a pentafluorophenyl C6F5 group was the catalyst
of choice for the aza-Michael addition reaction.7,8 Solvent
screening revealed that the mixed solvent of benzene and
cyclohexane gave the best result (Table 1, entry 9). The loading
of (R)-3g could be reduced to 10 mol % without any deleterious
effect on the yield and enantioselectivity (entry 10).9
Scheme 1. Substrate Scope of Chiral Phosphoric Acid
Catalyzed Asymmetric Aza-Michael Addition
a
a
Table 1. Examination of Reaction Conditions
b
c
entry
catalyst
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
benzene
benzene
benzene
benzene
benzene
benzene
benzene
toluene
24
23
−13
52
84
3
48
70
34
67
quant
91
85
3g
3g
3g
3g
90
quant
quant
95
90
benzene/C6H12 (v/v = 1/1)
benzene/C6H12 (v/v = 1/1)
93
d
10
93
a
Reactions were carried out on a 0.1 mmol scale with starting material
1a (0.1 mmol) and (R)-3 (20 mol %) in benzene (0.1 M) at 70 °C
b
c
(details in Supporting Information). Isolated yields. Determined by
chiral HPLC analysis. (R)-3g (10 mol %) was used.
d
To extend the scope of the aza-Michael addition, substrates
1b−1o were subjected to the optimum reaction conditions
(Scheme 1). Substrates 1b−1e bearing ortho-substituted arene at
the β-position exhibited high reactivity and stereoselectivity.
Electron-withdrawing (1b−1d) and electron-donating (1e)
group substituted substrates were converted into the corre-
sponding products in 71−97% yield with 88−94% ee. Similar
efficient cyclization was observed in the reaction of substrates
1f−1h containing meta-substituted arenes to give 2f−2h in 73−
95% yield with 84−92% ee. para-Substituted aromatics on the
substrates were also robust to the conditions, furnishing 2i−2k in
good to high yields with high ee. 2-Naphthyl (1l), 2-thienyl
(1m), 2-furyl (1n), and tert-butyl (1o) group substituted
substrates participated in the reaction with good to high
efficiencies, and 2m could be further purified by a single
recrystallization.
a
Reactions were carried out on a 0.1 mmol scale with starting material
1 (0.1 mmol) and (R)-3g (10 mol %) in benzene (0.5 mL)/
cyclohexane (0.5 mL) at 70 °C (details in Supporting Information).
b
Isolated yields. Determined by chiral HPLC analysis. (R)-3g (20 mol
%) was used. After recrystallization.
c
Single-crystal X-ray analysis indicated that the absolute
configuration of 2d produced by the intramolecular aza-Michael
reaction was S (Figure 2). The absolute configuration of the
other products was surmised by analogy.
Further transformation of chiral 2,3-dihydroquinolones was
explored (Scheme 2). When (S)-2a was reduced with NaBH4, an
alcohol with 15:1 dr was obtained.10 This crude product was
converted into sulfide (S,S)-4a under Mitsunobu conditions in
89% yield without loss of optical purity.11 (S)-2a was efficiently
converted into tetrahydroquinoline (S)-5a using LiAlH4 and
AlCl3.
We investigated the reaction of N-protected substrates
(Scheme 3): when N-acetylated substrate 6a was subjected to
the same optimum reaction conditions as for 6a, 7a was obtained
B
DOI: 10.1021/acs.orglett.5b01654
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Organic Letters
Letter
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: takahiko.akiyama@gakushuin.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Transformation by
Organocatalysis” from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
Figure 2. ORTEP drawing of (S)-2d.
Scheme 2. Derivatization of Chiral 2,3-Dihydroquinolones
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In conclusion, we have developed a chiral phosphoric acid
catalyzed asymmetric synthesis of 2-substituted 2,3-dihydro-4-
quinolones using a protecting-group-free aza-Michael addition
reaction. This method could be applied to various substrates to
furnish the corresponding products in good to high yields with
high to excellent enantioselectivities.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, analytical data for all new compounds,
NMR spectra for the products, and HPLC charts. The
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01654.
C
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respectively).
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ee.
(10) The alcohol product of the reduction reaction was slightly
decomposed to 2-phenylquinoline during silica gel chromatography.
Therefore, the crude of the reduction reaction was used directly without
further purification.
(11) Mitsunobu reaction using a carboxylic acid as a nucleophile did
not work well. 2-Phenylquinoline was rapidly formed under the reaction
conditions.
D
DOI: 10.1021/acs.orglett.5b01654
Org. Lett. XXXX, XXX, XXX−XXX