Domino Synthesis of 3-Alkyliden-2,3-Dihydro-4-Quinolones

Article abstract of DOI:10.1002/adsc.201801490

The synthesis of 3-alkyliden-2,3-dihydro-4-quinolones has been accomplished in a domino fashion through a three-step sequence that comprised an initial aza-Baylis-Hillman reaction, followed by a 1,3-rearrangement and an intramolecular amination. Starting from readily available aryl vinyl ketones and N-tosyl imines, the reaction with PPh₃, CsOAc and CuI in CH₃CN gave rise, in good overall yields, to final 3-alkyliden-4-quinolone derivatives, valuable scaffolds in medicinal chemistry. The simultaneous addition of two bases, PPh₃ and CsOAc, was found to be crucial for the success of the process. While PPh₃ promoted the reversible aza-Baylis-Hillman reaction, CsOAc triggered the subsequent 1,3-rearrangement, which shifted the initial equilibrium and allowed to complete the synthetic sequence upon the addition of CuI. (Figure presented.).

Full text of DOI:10.1002/adsc.201801490

Title: Domino Synthesis of 3-Alkyliden-2,3-Dihydro-4-Quinolone
Authors: Esther Raga, Marcos Escolano, Javier Torres Fernández,
Fernando Rabasa Alcañiz, Maria Sanchez-Rosello, and
Carlos del Pozo
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801490
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Domino Synthesis of 3-Alkyliden-2,3-Dihydro-4-Quinolones
Esther Raga,a Marcos Escolano,a Javier Torres,a Fernando Rabasa-Alcañiz,a María
Sánchez-Rosellóa and Carlos del Pozoa,*
a
Departamento de Química Orgánica, Universidad de Valencia, E-46100 Burjassot, Spain
E-mail: carlos.pozo@uv.es
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the W3, WW under
http://dx.doi.org/10.1002/adsc.201######.((Please delete if not appropriate))
Abstract. The synthesis of 3-alkyliden-2,3-dihydro-4- While PPh3 promoted the reversible aza-Baylis-Hillman
quinolones has been accomplished in a domino fashion reaction, CsOAc triggered the subsequent 1,3-
through a three-step sequence that comprised an initial aza- rearrangement, which shifted the initial equilibrium and
Baylis-Hillman reaction, followed by a 1,3-rearrangement allowed to complete the synthetic sequence upon the
and an intramolecular amination.
addition of CuI.
Starting from readily available aryl vinyl ketones and N-tosyl
imines, the reaction with PPh3, CsOAc and CuI in CH3CN
gave rise, in good overall yields, to final 3-alkyliden-4-
quinolone derivatives, valuable scaffolds in medicinal
chemistry. The simultaneous addition of two bases, PPh3 and
CsOAc, was found to be crucial for the success of the
process.
Keywords:
4-quinolones,
aza-Baylis
Hillman,
intramolecular amination, 1,3-rearrangement, domino
reactions
Introduction
4-Quinolones are privileged structures in drug
discovery due to their ubiquitous presence in natural
products and biologically active substances.[1] These
scaffolds are present in a large number of marketed
antibiotics such as ciprofloxacin and levofloxacin.[2]
In addition, suitable functionalization of these
nitrogen heterocycles has allowed the shift towards
other therapeutic areas, being also present in a wide
variety of biologically active molecules with
antiviral,[3] anticancer,[4] antimalarial,[5] antimitotic[6]
or antidiabetic[7] properties, among others. For this
reason, several synthetic methodologies have been
devised to access the valuable 4-quinolone skeleton.[8]
However, the preparation of 3-alkyliden-2,3-dihydro-
4-quinolone derivatives, that contain an exocyclic
double bond, is much less common. These
Scheme 1. Synthetic strategies to access 3-alkyliden-2,3-
compounds have been shown to possess interesting dihydro-4-quinolones.
biological activities such as antifertility, antiasmathic
or antiarthritic properties.[9] The strategies currently
The generation of the C-C bond between the
known for their synthesis can be categorized
depending on the formation of which bond leads to
ring closure. Closure of bond a (Scheme 1) was
accomplished by means of an intramolecular Friedel-
Crafts type acylation, that created the C-C bond
connecting the aromatic ring and the carbonyl
functionality (Scheme 1, via a).[10]
carbonyl and the exocyclic double bond (bond b,
Scheme 1) involved the use of a Stetter type reaction
catalyzed by an NHC ligand (Scheme 1, via b),[11]
while the N-C bond c was assembled by a palladium
catalyzed tandem carbonylation/allene insertion of
ortho-iodo N-tosyl anilines (Scheme 1, via c).[12]
1
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
Table 1. Optimization conditions for the aza-Baylis-
Hillman reaction (ABH).a)
Finally, the construction of both bonds a and d was
recently described through the reaction of Baylis-
Hillman adducts with arynes generated from ortho-
trimethylsilyl triflates with potassium fluoride
(Scheme 1, via d).[13]
Herein we report a new strategy for the synthesis of
3-alkyliden-2,3-dihydro-4-quinolone
derivatives
starting from ortho-bromo aryl vinyl ketones and N-
tosyl imines. It involves a three-step sequence
consisting of an initial aza-Baylis-Hillman reaction
3
Entry
Ar
Ph
Ph
Ph
Solvent
THF
Base
PPh3
PPh3
PPh3
t [h]
24
24
4
2
[%]b)
followed by
a
1,3-rearrangement and an
3a
[20]
intramolecular amination (Scheme 1, via e). This new
methodology, that generates the aromatic C-N bond d
(Scheme 1) in the final closure, was achieved in a
domino fashion, rendering 3-alkyliden-2,3-dihydro-4-
quinolones in a very simple manner from readily
available starting materials.
1
2
3
2a
2a
2a
3a
[20]
CH3CN
Et2O
3a
[57]c)
4
5
6
7
PMP
PMP
PMP
PMP
Et2O
THF
THF
THF
PPh3
PPh3
24
24
24
24
---
---
---
---
2b
2b
2b
2b
Results and Discussion
PPh2Me
PPhMe2
The initial aza-Baylis-Hillman reaction was
evaluated employing aryl vinyl ketone 1a as a model
substrate.[14] The results obtained in the optimization
process are compiled in Table 1. The first attempt to
perform the reaction of compound 1a and the N-tosyl
imine derived from benzaldehyde 2a was carried out
using PPh3 as a base in THF. After 24h at room
temperature, a small amount of the Baylis-Hillman
3b
[20]
8
PMP
THF
P(PMP)3
24
2b
3b
[20]
9
PMP
CH3CN P(PMP)3
24
2b
PMP= p-methoxyphenyl. a) Reactions were carried out with
1a (1 equiv) and 2 (1.2 equiv), base (10 mol%) in the
b)
corresponding solvent (0.095M) at room temperature.
Yields were determined by H-NMR. Yield of isolated
1
c)
adduct 3a was detected by 1H-NMR (Table 1, entry 1). compound 3a after precipitation in diethyl ether.
Similar result was achieved when CH3CN was used as
With compound 3a in hand, we decided to explore
the feasibility of the intramolecular amination in order
to access 3-alkyliden-4-quinolone derivatives in a
sequential manner. Thus, the reaction was initially
tested with PdCl2(PPh3)2 and t-BuOK or Cs2CO3 as
bases in refluxing toluene.[16] Unfortunately, very low
yields of product 5a were obtained (Table 2, entries 1,
2). It is important to point out that, before the
intramolecular amination, a base-promoted 1,3-
rearrangement takes place, which converts the aza-
Baylis-Hillman adduct 3a to the N-tosyl amine 4a.[17]
Other reaction conditions previously employed in
the synthesis of 4-quinolone derivatives under Pd
catalysis were also tested. Therefore, next attempt
was performed with Pd2(dba)3 and racemic BINAP in
the presence of t-BuONa as a base.[18] Again under
these conditions, 4-quinolone 5a was isolated in poor
yield (Table 2, entry 3). Similarly, when Pd(OAc)2
was employed as the metal promoter and PPh3 as a
ligand, the desired compound 5a was obtained in only
27% yield (Table 2, entry 4).[19]
the solvent (Table 1, entry 2). However, changing the
solvent to diethyl ether led to the precipitation of the
aza-Baylis-Hillman adduct, which was isolated by
simple filtration in pure form and good yield (Table 1,
entry 3). These reaction conditions were tested on p-
methoxyphenyl imine 2b, which was not soluble in
diethyl ether and the reaction did not proceed (Table 1,
entry 4). Likewise the use of THF or more
nucleophilic phosphines such as PPh2Me and PPhMe2
was not effective and decomposition of the starting
imine 2b was detected after stirring the reaction
mixture for 24h (Table 1, entries 5-7). Best results
were obtained when P(PMP)3 was employed as a
Lewis base, either in THF or CH3CN. Under these
conditions the reaction proceeded in a small extent,
affording only 20% of the desired compound 3b
together with the decomposition product of imine 2b
(Table 1, entries 8, 9). From these results, it seems
that the aza-Baylis-Hillman reaction is reversible and,
only when the product precipitates in diethyl ether,
the equilibrium is shifted to the right and the Baylis-
Hillman adduct 3a can be isolated in reasonable
yield.[15]
Table 2. Optimization of the intramolecular Buchwald-Hartwig amination.a)
2
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
Entry
Base
Solvent
toluene
toluene
toluene
Dioxane
DMSO
DMF
Metal-(ligand)
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd2(dba)3-BINAPc)
Pd(OAc)2-PPh3
CuI
time [h] T [º C] Yield 5a [%]b)
1
2
t-BuOK
Cs2CO3
24
24
24
24
24
24
24
12
24
24
45
110
110
110
95
10
11
17
27
---
---
47
76
---
---
3
4
t-BuONa
K2CO3
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
5
6
CuI
95
7
CH3CN
CH3CN
CH3CN
CH3CN
CuI
82
8
CuI
82
9
CuOAc
CuI-Phend)
82
10
82
a) Reactions were carried out by mixing 3a (1 equiv), with the corresponding base (5 equiv) and
b)
metal-(ligand) (2 equiv) in the solvent indicated. Isolated yields of 5a after purification by
c)
d)
column chromatography. Racemic BINAP was used as ligand. Reaction performed with
1,10-phenanthroline as ligand.
reversibility of the reaction. This would entail a
It is known that copper salts (more economical than
palladium ones) catalyze this type of cross-coupling
reactions. The unique combination of copper iodide
and cesium acetate was found to mediate
intramolecular aminations under mild conditions.[20]
Therefore, we tested those conditions with our
substrate, although no identifiable product could be
detected either in DMSO and DMF as solvents (Table
2, entries 5, 6). When the reaction was carried out in
refluxing acetonitrile for 24h, quinolone 5a was
obtained in 47% yield through the domino process
1,3-rearrangement/ intramolecular amination (Table 2,
entry 7). We found that lowering the reaction time
was crucial in order to improve the chemical yield.
Thus, compound 5a was isolated in 76% yield when
the reaction was allowed to proceed for 12h (Table 2,
entry 8). The use of other copper salts or additional
ligands such as 1,10-phenanthroline resulted in the
complete suppression of the process (Table 2, entries
9, 10).
With these data in hand, the optimized conditions
to perform the domino 1,3-rearrangement/
intramolecular amination lay in heating the aza-
Baylis-Hillman adduct in acetonitrile for 12h in the
presence of CuI (2 equiv) and CsOAc (5 equiv) as a
base.
As we mentioned in the discussion of Table 1, the
participation of tosyl imines different than 2a, derived
from benzaldehyde, in the PPh3 catalyzed aza-Baylis-
Hillman reaction is troublesome, probably due to the
poor solubility of those imines in diethyl ether and the
significant limitation in our synthetic strategy as we
would not access compounds different than 3a in
order to extend the scope of our domino 1,3-
rearrangement/ intramolecular amination leading to 4-
quinolones 5. On the other hand, from results showed
in Table 2, it becomes apparent that CsOAc is
responsible for the 1,3-rearrangement. Consequently,
we envisioned that the combination of both bases,
PPh3 and CsOAc, would trigger both processes, the
reversible aza-Baylis-Hillman and the 1,3-
rearrangement in a single step. In this manner, if the
rearrangement is an irreversible process, it would
push the aza-Baylis-Hillman equilibrium to the right,
hence allowing us to synthesize rearranged products 4
in a domino fashion. To test our hypothesis, we
treated ketone 1a and imine 2a with PPh3 and CsOAc
simultaneously in THF and, after 12h at room
temperature, the clean formation of the rearranged
product 4a was observed in 60% isolated yield. This
product was then treated with CuI in refluxing
acetonitrile, rendering the desired 4-quinolone 5a in
good yield (Scheme 2).
With the aim of improving our three-step synthesis
of quinolones, we intended to perform the complete
sequence in a one pot manner. To achieve that goal,
we conducted the domino 1,3-rearrangement/
intramolecular amination in CH3CN and, once TLC
revealed the total consumption of the starting
materials, CuI was added to the reaction mixture and
it was heated at reflux for 12h. In this manner, final
3
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
quinolone 5a was obtained in 40% overall yield,
which means that each individual reaction took place
in 75% average yield (Scheme 2).
Finally, the whole protocol developed for the
synthesis of alkyliden-quinolone 5a was tested in a
domino manner. To this end, PPh3, CsOAc and CuI
were added to a solution of ketone 1a and tosyl imine
2a in acetonitrile. The reaction mixture was stirred at
reflux for 12h and, after chromatographic purification,
final product 5a was obtained in 37% yield, which is
comparable to that of the one pot procedure (Scheme
2).
a)
Reactions were carried out with ketones 1 (1 equiv) and
imines 2 (1 equiv) in the presence of PPh3 (10 mol%),
CsOAc (5 equiv) and CuI (2 equiv) in CH3CN (0.1M) at
b)
reflux for 12h. Yields of quinolones 5 after purification
by flash column chromatography.
Scheme 2. Domino protocol to access quinolone 5a.
Having found suitable conditions to synthesize
quinolone 5a employing the three-step sequence in a
domino manner, the scope of the process was
evaluated next. Table 3 summarizes the results
obtained in the extension of our strategy to different
aryl vinyl ketones 1 and tosyl imines 2. Good overall
yields were achieved starting from aryl ketones 1
In order to examine the efficiency of the process, a
gram-scale reaction was performed. Thus, starting
from 2.16 g of ketone 1a and 1.73 g of imine 2c, 1.06
g of quinolone 5c were obtained (42% yield),
showing the feasibility of the process for scaling-up.
Finally, the deprotection of the sulfonamide moiety
bearing electron donating or electron withdrawing was attempted. Very recently, it was described that
substituents and either aromatic or heteroaromatic chemoselective acidic hydrolysis of sulfonamides can
tosyl imines 2.[21]
be effected with trifluoromethanesulfonic acid (triflic
acid) in a wide variety of examples of practical
importance.[22] Those conditions, that involve the
treatment of the sulfonamide with 2 equiv of triflic
acid in dichloroethane at room temperature for 12 h,
were applied to substrate 5c, affording the deprotected
quinolone 6 in 71% yield (Scheme 3).
Table 3. Scope of the domino protocol for the synthesis of
4-quinolones 5. a), b)
Scheme 3. Deprotection of quinolone 5c.
4
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
1
Conclusion
solid. Mp= 121-123 °C. H NMR (300 MHz, CDCl3) δ
7.98 (dd, J = 8.0, 1.6 Hz, 1H), 7.80 (t, J = 2.3 Hz, 1H), 7.33
– 7.27 (m, 1H), 7.23 (brs, 4H), 6.81 – 6.73 (m, 1H), 6.62 (d,
J = 8.2 Hz, 1H), 4.61 (brs, 2H), 4.35 (brs, 1H), 2.39 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 183.8, 151.2, 139.3, 135.9,
135.4, 132.5, 131.2, 130.1, 129.4, 128.7, 119.3, 118.4,
115.6, 44.8, 21.6. HRMS (ESI/Q-TOF): m/z [M + H]+
calcd for C17H15NO 250.1232 ; found 250.1238.
In conclusion, we have developed a domino protocol
for the synthesis of 3-alkyliden-2,3-dihydro-4-
quinolones 5. Starting from readily available aryl
vinyl ketones 1 and tosyl imines 2, the sequence aza-
Baylis Hillman/ 1,3-rearrangement/ intramolecular
amination was performed in the presence of PPh3,
CsOAc, and CuI, giving rise to final products 5 in
good overall yields in a domino fashion. The key for
the success of this three-step synthesis is the
simultaneous addition of PPh3 and CsOAc, which
allows to perform the aza-Baylis-Hillman and the
subsequent 1,3-rearrangement in a domino fashion,
avoiding the low extension in which the first step
takes place as an individual reaction.
Acknowledgements
We gratefully thank the Spanish Ministerio de Economía y
Competitividad (CTQ-2017-85026-R to C. P.) M. E. and F. R.-A.
thank the Spanish Ministerio de Educación, Cultura y Deporte
for a predoctoral fellowship (FPU16/04533 and FPU14/03520
respectively). J. T. thanks Generalitat Valeniana for a predoctoral
fellowship (ACIF/2018/078).
Experimental Section
References
General procedure for the domino synthesis of
quinolones 5. To a solution of ketone 1 (1 equiv) and
imine 2 (1 equiv) in acetonitrile (0.1 M), PPh3 (10 % mol),
CsOAc (5 equiv) and CuI (2 equiv) were added. The
reaction mixture was stirred at reflux for 12 hours under N2
atmosphere (monitored by TLC). Then, it was cooled to
room temperature and filtered through a short pad of
Celite®, washing with small portions of EtOAc. The
filtrate was concentrated under reduced pressure and the
crude mixture was purified by flash chromatography to
afford quinolones 5.
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(E)-3-(4-Methylbenzylidene)-1-tosyl-2,3-
dihydroquinolin-4(1H)-one (5c). By means of the general
procedure described above, quinolone 5c (31 mg, 40%
yield) was obtained as a yellow solid starting from 40 mg
(0.189 mmol) of ketone 1a and 52 mg (0.189 mmol) of
imine 2c after flash chromatography with 6:1 n-hexanes:
ethyl acetate. Mp= 140-145 °C.1H NMR (300 MHz,
CDCl3) δ (ppm): 7.95 (d, J = 9.3 Hz, 1H), 7.82 (d, J = 8.1
Hz, 1H), 7.66 – 7.60 (m, 1H), 7.44 – 7.28 (m, 4H), 7.22 (d,
J = 8.0 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.2
Hz, 2H), 5.06 (d, J = 1.5 Hz, 2H), 2.45 (s, 3H), 2.34 (s,
3H). 13C NMR (75 MHz, CDCl3) δ (ppm): 182.6 (s), 144.2
(s), 141.3 (s), 140.4 (s), 138.6 (s), 134.5 (s), 134.1 (s),
133.1 (s), 133.0 (s), 131.4 (s), 130.2 (s), 129.7 (s), 129.5 (s),
129.0 (s), 128.8 (s), 128.2 (s), 127.4 (s), 127.4 (s), 48.0 (s),
21.6 (s). HRMS (ESI/Q-TOF): m/z [M + H]+ calcd for
C24H21NO3S 404.1320; found 404.1327.
[3] a) For a review, see: a) M. Daneshtalab, M.; A. J.
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General procedure for the deprotection of quinolone 5c.
To a solution of quinolone 5c (140 mg, 0.35 mmol) in
dichloroethane (3.5 mL, 0.1M), TfOH (62µL, 0.7 mmol, 2
equiv) was added. The reaction mixture was stirred at room
temperature for 12 hours under nitrogen atmosphere. Then,
saturated aqueous NaHCO3 solution was added and the
mixture was extracted with dicloromethane three times.
The combined organic layers were dried over anhydrous
Na2SO4, filtered and evaporated. Finally, solvents were
removed and the crude mixture was purified by flash
chromatography with 5:1 n-hexane: ethyl acetate as eluent
to afford quinolone 6 (61 mg, 71 % yield) as an orange
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5
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
Gopalakrishnan, G. Venkatraman, Bioorg. Med. Chem. [16] Those conditions were recently described in an
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6
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10.1002/adsc.201801490
Advanced Synthesis & Catalysis
FULL PAPER
Domino Synthesis of 3-Alkyliden-2,3-Dihydro-4-
Quinolones
Adv. Synth. Catal. Year, Volume, Page – Page
Esther Raga,a Marcos Escolano,a Javier Torres,a
Fernando Rabasa-Alcañiz,a María Sánchez-
Rosellóa and Carlos del Pozoa,*
7
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