Transition-Metal-Free Cascade Synthesis of 4-Quinolones: Umpolung of Michael Acceptors via Ene Reaction with Arynes

Article abstract of DOI:10.1021/acs.orglett.6b01830

A novel "one-pot" aryne transformation is described that affords various 4-quinolone derivatives without recourse to transition-metal catalysis. Arynes react with aza-Morita-Baylis-Hillman (AMBH) adducts through a cascade sequence involving an insertion/c

Full text of DOI:10.1021/acs.orglett.6b01830

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Cascade Synthesis of 4‑Quinolones: Umpolung
of Michael Acceptors via Ene Reaction with Arynes
R. Santhosh Reddy,† Chandraiah Lagishetti,† I. N. Chaithanya Kiran, Hengyao You, and Yun He*
School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road,
Shapingba, Chongqing 401331, P. R. China
S
* Supporting Information
ABSTRACT: A novel “one-pot” aryne transformation is described that affords various 4-quinolone derivatives without recourse
to transition-metal catalysis. Arynes react with aza-Morita−Baylis−Hillman (AMBH) adducts through a cascade sequence
involving an insertion/cyclization/ene reaction process to afford 4-quinolones in high yields with a broad substrate scope under
mild reaction conditions. Essentially, an umpolung of reactivity at the β carbon of α,β-unsaturated ketone has been achieved by
an inverse electron demand aryne−ene reaction to provide a C-arylated product.
Scheme 1. Reaction of Aryne with AMBH Adduct
4-Quinolones are structural components of many bioactive
natural products and pharmaceutically important substances,
including a large number of marketed antibiotics such as
Ciprofloxacin, Levofloxacin, and Moxifloxacin.1 In addition, 4-
quinolones have been studied as potential treatments for a
range of diseases, as they exhibit antidiabetic,2 anticancer,3
antiviral,4 antimitotic,5 antimalarial,6 and HIV-1 integrase
inhibitory activities.7 Therefore, various synthetic methods
have been developed for the synthesis of this valuable scaffold.8
Unfortunately, these methods often require multistep sequen-
ces, laborious isolation of the intermediates, a longer reaction
time, or harsh reaction conditions and are also limited by
unsatisfactory yields, narrow substrate scope, and poor
regioselectivities. All these methods involve one C−C bond
formation as a key step starting with an appropriately
functionalized aryl group (Supporting Information, Scheme
1). For flexible and rapid synthesis of 4-quinolone libraries for
high-throughput screening and further drug discovery research,
a one-pot synthesis with multiple bond-forming transforma-
tions (MBFTs) and aryl group incorporation would be more
practical and desirable.
subsequently underwent an inverse electron demand ene
reaction with an excess of the aryne, to furnish 2,3-substituted
4-quinolones (6) exclusively under mild reaction conditions.
Notably, the present novel one-pot reaction with MBFTs
provides an efficient method for the flexible and rapid synthesis
of highly functionalized 4-quinolones.
This metal-free aryne−ene reaction attracted our attention
and aroused curiosity, as intermolecular aryne−ene reactions14
(with electron-rich ene component) have received only scant
attention in the realm of ene reactions (Supporting
Information, Scheme 2), and the inverse electron demand15
aryne−ene reaction with electron deficient ene component
remains elusive.14c Herein we report a mild and novel “one-pot”
aryne transformation for the construction of various substituted
As part of our continuing efforts9 on the transition-metal-free
synthesis of valuable bioactive scaffolds using arynes,10 we
envisioned that the zwitterionic intermediate A from an in situ
generated aryne11 and aza-Morita−Baylis−Hillman (AMBH)
adduct (2)12 could undergo favorable intramolecular Michael
addition (Path a, 6-endo-trig cyclization) to afford bioactive
tetrahydroquinolines 3 (Scheme 1).13 In addition, intermediate
A could also undergo an ene reaction (Path b) with an excess of
the aryne to provide C-arylated compound 4. Surprisingly, the
reaction took a different course during our studies, where aryl
anion A smoothly added onto the less reactive ester moiety
(Path c, 6-exo-trig cyclization) to afford enone 5, which
Received: June 22, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01830
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Organic Letters
Letter
4-quinolones through a cascade insertion−cyclization followed
by a rare inverse electron demand ene reaction.
Our exploration was commenced by treating AMBH adduct
2a with the aryne generated in situ from 2-(trimethylsilyl)aryl
triflate 1a using KF and 18-crown-6 at ambient temperature
(Scheme 2). Either enone 5a or 4-quinolone 6a could be
inverse electron demand ene reaction, as electron-rich arynes
reacted faster and gave higher yields than the electron-deficient
aryne.
The scope and generality of the cascade reaction was then
explored under the optimized reaction conditions (AMBH
adduct (1 equiv), aryne (2.5 equiv), KF (5.0 equiv), 18-crown-6
(5.0 equiv), CH3CN, 25 °C, 4 h), and the results are
summarized in Schemes 4, 5, and 6. Initially, to test the effect of
Scheme 2. Cascade Reaction of Aryne and AMBH Adduct
Scheme 4. Substrate Scope of the Cascade Reaction:
Variation of Aryl Amines of Aza MBH Adducts
obtained by varying the equivalents of 1a in the cascade
reaction. The reaction afforded 5a (49%) as the major product
when 1.2 equiv of 1a was used, whereas the use of 2.5 equiv of
1a resulted in the formation of 6a (84%) (Supporting
Information, Table 1).16
Encouraged by these results, the versatility of an aryne−ene
reaction as an effective strategy in C−C bond formation was
examined by treating a wide range of β-trimethylsilyl triflates 1
with electron-deficient alkene intermediate 5a, and the results
are summarized in Scheme 3. Initially, the reaction was
Scheme 5. Substrate Scope of the Cascade Reaction:
Variation of AMBH Adducts
a
Scheme 3. Substrate Scope of the Inverse Electron Demand
a b
,
Ene Reaction
a
Reaction conditions: 5a (0.15 mmol), 1 (0.18 mmol), KF (0.36
mmol), 18-crown-6 (0.36 mmol), CH3CN (3.0 mL), 25 °C, and 1 h.
b
Yields of the isolated products with respect to 5a. 12 h.
a
Reaction conditions: 1a (0.50 mmol), 2 (0.20 mmol), KF (1.00
mmol), 18-crown-6 (1.00 mmol), CH3CN (4.0 mL), 25 °C, and 4 h.
Yields of the isolated products with respect to 2.
conducted with the parent aryne derived from 1a (1.2 equiv) in
CH3CN, where the β-carbon of α,β-unsaturated cyclic ketone
5a reacted with “polarity inversion” (via ene reaction) and
provided C-arylated umpolung product 6a in 91% yield. To
further demonstrate the potential expandability and flexibility of
this method in the formation of molecularly diverse 4-
quinolone derivatives, different 4,5-disubstituted symmetrical
aryne precursors, including benzodioxole, dimethoxy, Indane,
and dimethyl derivatives were examined. In all the cases
studied, the corresponding umpolung products (6b−e) were
obtained in excellent yields. Most notably, the extended π
conjugate naphthalene derived benzyne also afforded the
desired 4-quinolone 6f in high yield. Gratifyingly, the 4,5-
difluoro aryne reacted under the optimized reaction conditions
to provide 4-quinolone 6g in 75% yield, albeit at a slower rate.
These results suggest that the reaction proceeds through an
an aryl group on amines in the formation of 4-quinolone
derivatives, various arylamine adducts 2 were examined
(Scheme 4). N-Arylamines bearing a Br, Cl, F, ethyl, or
methoxy group on an aromatic nucleus were well tolerated to
furnish 4-quinolone derivatives (6h−o) in high yields. Benzyl
capped amine with an unsubstituted and p-Cl aryl ring also
underwent an efficient cascade reaction with arynes, leading to
the formation of 4-quinolone derivatives (6p and 6q) in
moderate yields. It is noteworthy that various halo quinolones
could allow further functionalization to afford libraries of 4-
quinolones.
Prompted by these interesting results, a range of differently
substituted AMBH adducts (2) were examined to afford
substituted 4-quinolones (Scheme 5). Various aryl moieties
B
DOI: 10.1021/acs.orglett.6b01830
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Letter
interestingly, the reaction can be easily scaled up without losing
the reaction yield (Supporting Information).
Scheme 6. Substrate Scope of the Cascade Reaction:
Variation of Aryne Precursors
a
To probe the mechanism of this reaction, the following
control experiments were carried out (Scheme 7): (a) when 2a,
Scheme 7. Control and Crossover Experiments
a
Reaction conditions: 1 (0.50 mmol), 2 (0.20 mmol), KF (1.00
mmol), 18-crown-6 (1.00 mmol), CH3CN (4.0 mL), 25 °C, and 4 h.
b
Yields of the isolated products with respect to 2. Reaction time 12 h.
c
1
Inseparable mixture of regioisomers (1:1:1:1) as determined by H
NMR.
with electronically dissimilar groups at the 4-position of the
aromatic ring were well tolerated, and their reactions furnished
4-quinolone derivatives (6r−w) in high yields. Moreover,
substitution of a halo or an alkoxy is tolerated at the 2-, 3-, and
5-position of the aromatic ring in 2, resulting in the desired
products (6x−ab). Intriguingly, 3,4-fluorobromo and penta-
fluoro substituents on the aromatic ring also afforded 4-
quinolones 6ac and 6ad. Systems containing thiophene and
naphthalene moieties furnished the desired products (6ae and
6af), thereby further expanding the scope of this cascade
reaction. In a similar fashion, a substrate lacking an aromatic
ring afforded 3-substituted 4-quinolone 6ag in 74% yield. In
general, AMBH adduct 2 bearing an electron-withdrawing
group on the aromatic ring usually afforded slightly higher
yields, suggesting that an electron-deficient aromatic ring favors
the labile proton transfer in the inverse electron demand ene
reaction.
In an attempt to further widen the scope and generality,
various substituted 2-(trimethylsilyl)aryl triflates 1 were
examined. Scheme 6 summarizes the result of this investigation,
further demonstrating the power of this method to construct
molecular diversity and complexity from simple building blocks.
Symmetrical aryne precursor 4,5-benzodioxolebenzyne reacted
with AMBH adducts to give the corresponding 4-quinolones
6ah−aj in high yields. Electronically diverse 4,5 disubstituted
symmetrical aryne precursors including dimethoxy, Indane,
dimethyl, and difluoro derivatives all reacted smoothly to
provide the corresponding products (6ak−an) in good to high
yields. Notably, fluorinated 4-quinolones are known to have
potential applications in the synthesis of analogues for drug
discovery.17 Remarkably, the reaction of unsymmetrical 4-
methylbenzyne furnished almost equal amounts of all four
possible regioisomeric products (6ao) in 78% yield, suggesting
that steric effects of aryne in this reaction are negligible.
Significantly, electron-rich arynes gave higher yields than the
electron-deficient arynes, which may be attributed to the fact
that electron-rich arynes favor cyclization onto ester. More
7, and 5a were treated separately with 1a in CD3CN, the
corresponding protonated product 6a was obtained smoothly
(eqs 1 and 2), and no deuterium incorporation product was
observed, which sheds light on a concerted ene reaction; (b) in
the absence of an aryne, intermediate 5a remained unchanged
under the optimized reaction conditions, and olefin isomer-
ization was not observed (eq 3). These results support that the
second aryne addition preferentially follows the ene reaction
rather than base mediated deprotonation/nucleophilic addition.
Further, the reaction of aryne 1a with deuterated AMBH
adduct 2a-d under the optimized conditions led to deuterated
quinolone 6a-d. The complete transfer of deuterium onto an
aromatic moiety was observed as expected, which confirms the
concerted ene reaction (eq 4). To substantiate the inverse
electron demand aryne−ene reaction, ene-intermediate 5a was
treated with a mixture of electron-rich and -deficient aryne
precursors 1c and 1g (1:1 molar ratio) (eq 5), and the study
suggests that electron-rich aryne-enophile 1c reacts almost 10
times faster than the electron-deficient aryne 1g, providing 4-
quinolone 6c in excellent yield.
Based on the aforementioned results and literature
precedence,10 a probable mechanism for the synthesis of 4-
quinolone derivatives is outlined in Scheme 8. The reaction of
the AMBH adduct with an aryne leads to the generation of
intermediate 5a through a cascade insertion−cyclization
process.18 Intermediate 5a subsequently adds to another
molecule of electrophilic aryne in a concerted manner
proceeding via an inverse electron demand ene reaction to
provide product 6a.
In summary, we have developed a transition-metal-free, mild,
general, and efficient method for the flexible synthesis of
functionalized 4-quinolones in high yields via a unique cascade
reaction of arynes with an AMBH adduct. This one-pot cascade
sequence features insertion, cyclization, and an inverse electron
demand aryne−ene reaction, involving one C−N and two C−C
bond formations. The methodology presented herein is
C
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Scheme 8. Proposed Mechanism of the Cascade Reaction
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01830.
Experimental procedures and spectral data for all new
compounds (PDF)
(9) Guo, J.; Kiran, I. N. C.; Reddy, R. S.; Gao, J.; Tang, M.; Liu, Y.;
He, Y. Org. Lett. 2016, 18, 2499.
AUTHOR INFORMATION
Corresponding Author
■
(10) (a) Wright, A. C.; Haley, C. K.; Lapointe, G.; Stoltz, B. M. Org.
Lett. 2016, 18, 2793. (b) García-Lopez, J.-A.; Cetin, M.; Greaney, M. F.
Org. Lett. 2015, 17, 2649. For selected reviews on aryne chemistry,
see: (c) Yoshida, S.; Hosoya, T. Chem. Lett. 2015, 44, 1450. (d) Goetz,
A. E.; Shah, T. K.; Garg, N. K. Chem. Commun. 2015, 51, 34.
(e) Yoshida, H. Nucleophilic Coupling with Arynes. In Comprehensive
Organic Synthesis, 2nd ed.; Knochel, P., Molander, G. A., Eds.; Elsevier:
Amsterdam, 2014; Vol. 4, p 517. (f) Dubrovskiy, A. V.; Markina, N. A.;
*E-mail: yun.he@cqu.edu.cn.
Author Contributions
†R.S.R. and C.L. contributed equally.
Notes
The authors declare no competing financial interest.
Larock, R. C. Org. Biomol. Chem. 2013, 11, 191. (g) Perez, D.; Pena,
̃
ACKNOWLEDGMENTS
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D.; Guitian, E. Eur. J. Org. Chem. 2013, 2013, 5981. (h) Tadross, P.
M.; Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (i) Bhunia, A.; Yetra, S.
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■
We are grateful for the financial support from the National
Science Foundation of China (Nos. 21572027 and 21372267)
and the Postdoctoral Research Grant (2014M562278).
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