A convenient approach to an advanced intermediate toward the naturally occurring, bioactive 6-substituted 5-hydroxy-4-aryl-1H-quinolin-2-ones

Article abstract of DOI:10.1039/c5ob02680f

5-Hydroxy-4-aryl-3,4-dihydro-1H-quinolin-2-ones are a small family of natural products isolated from fungal strains of Penicillium and Aspergillus. Most of its members, which are insecticides and anthelmintics, carry an isoprenoid C-6 side chain. The synthesis of a 6-propenyl-substituted advanced intermediate for the total synthesis of these natural products is presented in this paper. This was achieved through the stereoselective construction of a β,β-diarylacrylate derivative from 6-nitrosalicylaldehyde, using a Wittig olefination and a Heck-Matsuda arylation, followed by a selective Fe⁰-mediated reductive cyclization. Installation of the 6-propenyl side chain was performed by 5-O-allylation of the heterocycle, followed by Claisen rearrangement and conjugative migration of the allyl double bond, as the key steps. The Grubbs II-catalyzed olefin cross metathesis of the 6-allyl moiety with 2-methylbut-2-ene to afford a precursor of peniprequinolone is also reported.

Full text of DOI:10.1039/c5ob02680f

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DOI: 10.1039/C5OB02680F
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PAPER
Convenient approach to an advanced intermediate toward the naturally
occurring, bioactive 6-substituted 5-hydroxy-4-aryl-1H-quinolin-2-ones
a
a
a
Sebastián O. Simonetti, Enrique L. Larghi* and Teodoro S. Kaufman*
Received (in XXX, XXX) Xth XXXXXXXXX 201X, Accepted Xth XXXXXXXXX 201X
5
DOI: 10.1039/b000000x
The 5-hydroxy-4-aryl-3,4-dihydro-1H-quinolin-2-ones are a small family of natural products, isolated
from fungal strains of Penicillium and Aspergillus. Most of its members, which are insecticides and
antihelmintics, carry an isoprenoid C-6 side chain. The synthesis of a 6-propenyl-substituted advanced
intermediate for the total synthesis of these natural products is disclosed. This was achieved through the
stereoselective construction of a b,b-diarylacrylate derivative from 6-nitro salicylaldehyde, using a Wittig
1
0
0
olefination and a Heck-Matsuda arylation, followed by a selective Fe -mediated reductive cyclization.
Installation of the 6-propenyl side chain was performed by 5-O-allylation of the heterocycle, followed by
Claisen rearrangement and conjugative migration of the allyl double bond, as key steps. The Grubbs II-
catalyzed olefin cross metathesis of the 6-allyl moiety with 2-methylbut-2-ene to afford a precursor of
peniprequinolone, is also reported.
1
5
Introduction
In addition, two strains of Aspergillus were the source of the
5
5
6
6
7
7
8
0
5
0
5
0
5
0
aflaquinolones A-D (4a-d) and the aflaquinolones E-G, which
The quinoline core is a privileged heterocyclic structure found in
many natural products and bioactive compounds. Interestingly,
filamentous fungi have been the source of relatively few
quinoline derivatives; however, certain strains of Penicillium and
5a
lack the 4’-OMe group. Some aflaquinolones have also been
1
obtained from the endophyte A. nidulans MA-143, together with
1
h and the aniduquinolones A-C. The latter, are analogous to
2
2
2
3
3
0
5
0
5
5b
yaequinolones C and F (1b and 1e), lacking the 4’-OMe group.
More recently, the unusual 22-O-(N-Methyl-L-valynyl) ester
of aflaquinolone B (4e) and its epimer 4f were isolated from the
mycelia of Aspergillus sp. XS-20090B15, together with the
Aspergillus produce 5-hydroxy-4-aryl-3,4-dihydro-1H-quinolin-
2
-ones, including those bearing a C-6 alkyl/alkenyl side chain,
which form a unique new family of natural products.
3
a
Thus, the yaequinolones B-F, J1 and J2 (1a-1g, Figure 1)
were isolated from Penicillium sp. FKI-2140, along with nine
related compounds, including peniprequinolone (1h) and the
5c
aflaquinolones A and D (or a diastereomer of it). Compound 4f
exhibited remarkable anti-Respiratory Syncytial Virus activity.
Genomic and biosynthetic studies suggested that this family
3
b-g
penigequinolones A and B (1i and 1j).
The cytotoxic and
may derive from anthranilic acid and phenylalanine or tyrosine,
3
c
antifungic 1h, previously reported from P. simplicissimum and
2a,3d
through the intermediacy of diketobenzodiazepines,
such as
3
f
P. namyslowskii, was also found to be a nematicidal antibiotic
against the root-lesion nematode Pratylenchus penetrans.
The diastereomeric 1i and 1j, pollen growth inhibitors and
nematicidal against Pratylenchus penetrans, were also isolated
from Penicillium sp. NO. 410 and P. scabrosum. On the other
hand, the related aspoquinolones A-D (1k-n) are cytotoxic and
4c
3
a,b, which have been isolated concomitantly. The latter
3
d
undergo ring opening and re-cyclization to afford the basic 3,4-
dihydro-1H-quinolin-2-one core, through the 4-phenylquinoline
3
d
5d-g
viridicatin as intermediate.
Next, O-methylation of the −OH
3
g
moieties, installation of the C-4 and C-5 −OH groups, attachment
the C-6 side chains and further functionalization, would explain
2
a
antiproliferative on some cancer cell lines.
This research also afforded the yaequinolones A1 and A2
5h
their diversity. The natural products are optically active,
3b,5a
displaying a 3S,4S configuration.
3
c,d, 4a
(2a,b) and the quinolinones A and B (2c,d).
Heterocycles 2a
Ectoparasiticidal and antiproliferative preparations containing
and 2b have been previously reported from a P. janczewskii strain
of marine origin,
6a-e
some of these heterocycles have been patented.
synthetic activity in this area has been very scarce.
However,
3
b,4b,c
whereas 2c and 2d were originally obtained
6f,g
4
0
from P. simplicissimum and found to behave as insecticidal
In pursuit of a common general synthetic approach toward the
members of this family of natural products, herein we report a
concise route to a potential common key intermediate for the 6-
3
c
3b
antibiotics, being toxic against various cancer cell lines.
_
_______________________________________________
Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad
de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de
Rosario, Suipacha 531, S2002LRK Rosario, Argentina. Tel/Fax: +54-
a
substituted
5-hydroxy-4-aryl-3,4-dihydro-1H-quinolin-2-ones,
4
5
bearing the fundamental structural motif 1. In addition, the
synthesis of a peniprequinolone (1h) derivative, lacking the 3,4-
glycol monomethyl ether feature, is disclosed.
3
41-4370477; E-mail: kaufman@iquir-conicet.gov.ar
†
Electronic Supplementary Information (ESI) available: selected spectra
of intermediates and final product. See DOI: 10.1039/b000000x/
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Page 2 of 11
HO
OH
OMe
OMe
4'
O
O
O
6'
a Yaequinolone B
d Yaequinolone E
Me
2'
HO
5
Me
OH
*
O
4
1
R
OMe
O
c Yaequinolone D
OH
Me
OMe
O
6
3
b Yaequinolone C
7
O
N
H
2
8
N
H
1
R1
Me
O
f Yaequinolone J1 (S)
g Yaequinolone J2 (R)
HO
e Yaequinolone F
O
O
R1 Me
O
Me
Me
Me
1
m R = a-H Aspoquinolone C
k,l Aspoquinolones A y B n R = b-H Aspoquinolone D h Peniprequinolone
1
i Penigequinolone A j Penigequinolone B
OMe
R
R1
R3
R4
OH
OH
OMe
OMe
O
R
R2
O
OH
R1
Me
N
H
N R
R2
N
H
O
R1
1
2
3
4
4a R= Me, R = H, R = b-Me, R ,R = O, Aflaquinolone A
N
1
4
2
3
O
4b R= Me, R = R = H, R = b-Me, R = OH, Aflaquinolone B
H
1
2
3
4
1
2
4c R= H, R = Me, R = a-Me, R ,R = O, Aflaquinolone C
2
2
2
2
a R= R = H, R = OH, ent-Yaequinolone A
1
1
2
3
4
2
1
1
4d R= Me, R = H, R = a-Me, R ,R = O, Aflaquinolone D
b R= R = H, R = OH, Yaequinolone A
c R= R = H, R = OMe, Quinolinone A
2
3a R=R = H, 4'-methoxycyclopeptin
1
4
2
3
2
1
1
4e R= Me, R =R = H, R = b-Me, R = N-methyl-L-Valinate
3b R,R = double bond, trans-dehydro-
4'-methoxycyclopeptin
4
1
2
3
1
2
4f R=R = H, R = Me, R = a-Me, R = N-methyl-L-Valinate
d R= OH, R = H, R = OMe, Quinolinone B
Figure 1. Chemical structures of representative naturally-occurring 6-substituted 5-hydroxy-4-aryl-1H-quinolin-2-ones and their congeners. Except for 2a
and 2d, it is assumed that the heterocycles bear a cis-3,4-dioxygenated pattern and exhibit the same 3S,4S configuration.
installed by olefin cross-metathesis of a 6-vinyl quinolin-2-one. It
2
5
was also inferred that the cis-3,4-diol monoether system could
5
Results and discussion
3
,4
10
result from dihydroxylation of a ∆ precursor, and selective
alkylation of the less hindered alcohol, uncovering 6 as the
suitable common advanced key intermediate sought.
There are five main synthetic approaches toward 4-alkyl/aryl-
substituted 1H-quinolin-2-ones (Figure 2), which relate to the
7
a
Generally, b-substituted styrenes are less costly and easier to
single bond involved in closing the heterocyclic ring. These
7
b-g
8a
8b
8c,d
8e,f
30 prepare than their styrene counterparts, also being more stable
comprise types (a),
strategies of types (b) and (c) are unsuitable for the synthesis of
-hydroxy/alkoxy substituted heterocycles, mainly due to their
(b), (c), (d),
and (e).
However,
and less prone to undergo homodimerization or spontaneous
1
0
1
1a-d
polymerization.
Therefore, it was considered installing a 6-
5
1
1e
propenyl side chain (6a), taking advantage of the 5-OH group.
narrow scope and difficult availability of the starting materials,
whereas type (a) demands starting from 1,2,4-substituted
Conjecturing that the heterocyclic ring could be accessed by
9
a-g
35 lactamization of a b,b-diarylacrylate with a suitably placed amine
benzenoids,
to block the preferred alternative cyclization
1
2a,b
9h,i
attached to the aromatic ring [type (d)],
or by N-arylation
unveiled 7 as a potential precursor of 6a (Route
a). In turn, it was conceived that b,b-diarylacrylate 7 could be
1
5
mode, en route to 7-hydroxy/alkoxy derivatives.
8
e,f,12c,d
[type (e)],
Type (a)
1
3a,b
obtained from a cinnamic acid derivative (8).
R'O
5
R
Type (b)
Type (c)
4
4
5
0
5
0
On the other side, it was supposed that compound 9, which
could also be made available from cinnamate 8, might also be
considered a suitable precursor of 6a (Route b); however,
previous findings on the reluctance of certain 1H-quinolin-2-ones
4
3
2
N
O
Type (d)
Type (e)
1
1
2c
H
to undergo the Heck reaction on C-4 discouraged exploration
of this alternate route as the first choice. Further disconnection of
Figure 2. Most relevant general strategies for the synthesis of 4-
substituted 1H-quinolin-2-ones.
1
4
8 uncovered a precursor aldehyde moiety and unveiled a
phenol, suggesting aldehydes 10, accessible from commercially
available phenols 11, as suitable starting materials.
2
0
Hence, our approach to the natural products (5, Scheme 1)
relied on a retrosynthetic analysis involving strategies of types (d)
and (e). The C-6 substituent of the target was disconnected at the
double bond level, considering that the side chains could be
The type (e) approach was explored first. Therefore,
salicylaldehyde (12) was submitted to a Williamson etherification
with benzyl chloride in absolute EtOH, employing K
2 3
CO as
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DOI: 10.1039/C5OB02680F
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Organic & Biomolecular Chemistry
base, which afforded 99% of benzyl ether 13 (Scheme 2). In turn,
the aldehyde 13 was exposed to a Hörner-Wadsworth-Emmons
HWE) reaction with (MeO) P(O)CH CO Me, furnishing 55% of
It seems likely that the lability of 18 toward the cyclization
conditions that would lead to 19a may be related to its structure,
because exposure of the b,b-diphenylacrylic acid tosylimide to
the same cyclization conditions afforded 70% of the expected 4-
(
2
2
2
cinnamate 14. However, better results were obtained when 13
5
was subjected to a Wittig olefination with carbethoxymethylene 35 phenyl-1H-quinolin-2-one, fully agreeing with the literature.
triphenyl phosphorane, which gave 88% of cinnamate 14a, as a
1
HO
BnCl, K CO ,
EtOH, 70ºC,
overnight
2
3
BnO
(MeO) P(O)CH CO Me,
2 2 2
4
:1 mixture of geometric (E:Z) isomers, according to the
H
K CO H O,
2 3, 2
NMR integration
CHO
CHO
reflux, 30 min (55%)
or PPh =CHCO Et,
(
99%)
3
2
MeO
MeO
CH Cl , rt, 5h (88%)
Claisen
rearrangement
Isomerization
2 2
Route b
Pd-assisted
C-C bond
formation
12
13
d 8.10
(d, J = 16.2 Hz)
R
Z
HO
OH
OMe
HO
5
4
BnO
H
Pd(OAc)2,
5, Et N,
MeO
I
1
6
3
3
CO R
2
A
B
N
H
1
00ºC, 17h
Dihydroxylation
Alkylation
15
E
Olefin
cross
O
N
O
(
60%)
H
Route a
Pg Route a
Lactamization
d 6.55
metathesis
N-arylation
(d, J = 16.2 Hz)
5
OMe
OMe
1
1
4 R= Me
4a R= Et
6
Z= H; 6a Z= Me
Pg= Ts, Boc
R= See Figure 1 (1a-g; 1i-n)
1
R = OMe, OEt, ArSO NH
R = Bn, PMB
TsNCO,
Et N, THF, BnO
rt, 24h
2
Route b
2
BnO
H
H
3
nOe
3
OR
2
R = Me, Et
X= H, Br, NH (NO )
(
95%)
2
2
H
Z
CO R
Route a
2
N
O
HO
N
H
O
Ts
KOH, EtOH-H O,
16 R= Et
17 R= H
2
Lactamization
18
18h, rt (90%)
9
PdCl , Cu(OAc) , O ,
DMSO, 120ºC, 16h
2
2
2
NH Cl/SiO , TsCl,
4 2
(
80%)
X
Et N, rt, 1 min
3
X
11
OMe
Pd-assisted
C-C bond
formation
OMe
OMe
4'
Wittig/HWE
Olefination
Etherification
5'
3'
R2
2
6'
2'
HO
O
R O
BnO
t
BnO
2
CuI, K BuO, PPh ,
1'
3
CHO
CO
2
R3
xylene, 100ºC, 14h
1
X
3
COR1
or CuI, Bipy, DMA,
1
40ºC, 12h
4
CONH2
X
X
X
6
N
R
O
5
10
8
7
1
0
1
1
9 R= H
9a R= Ts
20
Scheme 1. General retrosynthetic analysis of the natural products 5.
Target heterocycles 6 and 6a as advanced key intermediates.
Scheme 2. Attempted synthesis of intermediates 19 from salicylaldehyde
12).
Installation of the 4-methoxyphenyl moiety was accomplished
(
1
5
by means of a Heck reaction of 14a with 4-iodoanisole (15) in
refluxing Et N, under Pd(OAc) catalysis, which provided the
1
2
2
3
5
0
5
0
3
2
40
In view of this outcome, the copper-catalyzed cyclization of
amide 20 was explored as an alternative. Amidation of ester 16
1
b,b-diphenylacrylate 16 as a 86:14 ( H NMR integration) mixture
of geometric isomers, in combined 60% yield. The Z-
configuration of the main isomer of 16 was ascertained with the
aid of nOe experiments, which revealed mutual signal
1
7a
with ammonia met with failure;
amidated with NH Cl/TsCl supported on silica gel, under Et
promotion, affording 80% of 20. However, exposure of the
therefore, the acid 17 was
4
3
N
1
7b
8
f,18
enhancement between the vinylic proton next to the carboxylate 45 amide to various copper-mediated C-H activation protocols,
ester and the aromatic protons located meta to the 4’-methoxy
group (2’-H and 6’-H).
In order to insert the required nitrogen atom and properly
activate the b,b-diphenylethylene derivative toward cyclization,
the ester 16 was saponified (90%) and the resulting carboxylic
resulted in complete recovery of the starting amide 20.
Therefore, the attention changed to a type (d) strategy, which
involves forming the Ar-N bond prior to cyclization or entails
8
d,e
using starting materials which already contain the heteroatom.
50
3-Nitrophenol (21) was selected as the new starting material,
considering that the nitro moiety could mask the required amino
group during the initial stages, and that it could be engaged in a
acid 17 was reacted with tosyl isocyanate in the presence of Et
furnishing the tosylimide derivative 18 (95%).
3
N,
Unfortunately,
however, all attempts to cyclize 18 under Pd catalysis, with
8
e,16
1
9
one-pot reductive cyclization (7→6), under conditions that
could also result in the removal of the protecting benzyl ether.
With these ideas in mind, compound 21 was submitted to a
8
e
Cu(OAc)2 as co-catalyst and aerobic conditions, met with
failure, resulting in complete degradation of the tosylimide.
55
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Duff formylation with hexamethylenetetraamine (HMTA) in
F CCO H at 110 ºC during 12h, affording the expected aldehyde
concomitant reduction of the nitro moiety to the corresponding
amino-derivative 29 and further cyclization toward 27 was
attempted on 26. However, when the Pd-mediated catalytic
3
2
2
2 as an 85:15 mixture with its isomer 22a, in combined 54%
2
7
yield. Notably, previous syntheses of 22 took place with rather
hydrogenation was attempted under a variety of conditions, it
lower yields. In turn, phenol 22 was subjected to a Williamson 45 exhibited several unforeseen problems, which ranged from partial
2
0
5
etherification with BnCl in refluxing EtOH, employing K
base, to give 23 in almost quantitative yield (Scheme 3).
2
CO
3
as
reduction of the nitro group to concomitant hydrogenation of the
acrylate double bond, despite being sterically hindered.
Thus, the hydrogenation with 10% Pd/C in MeOH at room
temperature produced equal amounts of 19 and its debenzylated
50 analog 27 in combined 30% yield (Table 1, entry 1), whereas the
reaction proceeded more sluggishly in EtOH (entry 2).
HO
HO
BnCl, K
EtOH, 70ºC,
overnight
2
CO3,
BnO
2
HMTA, TFA,
R1
R
1
CHO
NO2
9
0ºC, 12h
3
4
(
46%)
(99%)
NO2
NO2
6
However, addition of Et N to the ethanolic medium provoked
3
5
1
the hydrogenation of the nitro moiety and the subsequent
cyclization, but also the debenzylation and hydrogenation of the
2
1
22 R= CHO, R = H
23
1
2
2a R= H, R = CHO
3
,4
5
5
∆
double bond, furnishing 61% of 28 (entry 3). On the other
MeO
N2+ F B-
side, when the reaction was run in refluxing toluene, a 30:70
mixture of cyclized (19) and debenzylated and uncyclized
products (29) were obtained in 25% combined yield (entry 4).
4
PPh =CHCO Et,
3
2
(
88%)
CH Cl , rt, 5h
2
5
2
2
OMe
d 7.73
d, J = 16.2 Hz)
4
'
(
6
0
Table 1. Optimization of the reductive cyclization of 26.
5
'
3'
2
'
OMe
OMe
OMe
6
'
4-MeO-C H -I,
6 4
Pd(OAc)2,
BnO
2
H
nOe
BnO
H
1
'
1
6
H
Et N, 100ºC
E
3
CO Et
2
3
4
(55%), or
Z
H
RO
HO
HO
CO Et
25, Pd(OAc)2,
MeOH, 70ºC,
2
NO2 d 6.58
(d, J = 16.2 Hz)
Conds.
NO2
5
+
+
26
6h (80%)
2
6
24
CO
NH2
Et
2
N
H
O
N
H
O
1
1
2
2
3
3
4
0
5
0
5
0
5
0
Scheme 3. Synthesis of the intermediate 26 from 3-nitrophenol (21).
1
2
9 R= Bn
7 R= H
28
29
Introduction of the two-carbon moiety required to build the
H-quinolin-2-one feature was performed by means of a Wittig
1
Entry
Reducing
system
, 10%Pd/C MeOH
Solvent Time Temp. Yield (%) 19/27/28/29
2
1
(h)
2
(ºC)
rt
reaction
with ethyl (triphenyl-λ5-phosphanylidene)-acetate,
2
2
1
2
3
4
5
6
7
H
H
H
H
2
2
2
2
30
15
61
25
40
35
50/50/0/0
-
affording 88% of cinnamate 24. The coupling constants of the
vinylic hydrogens (J = 16.2 Hz) unequivocally established the
stereochemistry of 24 as E.
, 10%Pd/C EtOH
3
3
rt
rt
a
, 10%Pd/C EtOH
0/0/100/0
30/0/0/70
37/0/0/63
0/0/0/100
-
When the Heck conditions leading to 16 were applied to 24,
the corresponding b,b-diarylacrylate was obtained in 55% yield,
confirming previous observations where the reaction was found
to loss efficiency when attempting to introduce electron-rich aryl
, 10%Pd/C PhMe
2
110
rt
SnCl
2
2
EtOH
EtOH
17
SnCl
0
17 reflux
2
3
Fe , CaCl
2
EtOH 0.5 reflux decomp.
110 74
groups. This suggested the need of an alternate strategy.
Despite alternative Heck protocols were available,
2
4a
0
the
8
Fe (8 equiv.) AcOH 14
100/0/0/0
Heck-Matsuda reaction seemed a suitable transformation to fulfil
our expectations, since it is apparently devoid of this
a
3
Et N was added.
2
4b-e
drawback.
Recent examples from the laboratory of Correia
Considering the above results, a stepwise strategy was
approached, prioritizing the sequential nitro group reduction-
cyclization toward 19. Unfortunately, SnCl
were encouraging; furthermore, the p-anisidine reagent required
to introduce the 4-methoxyphenyl moiety is readily available, and
is several times less expensive than p-iodoanisol.
6
7
7
5
0
5
28
2
in EtOH also gave
4
0% of a 37:63 mixture of 19 and 29, when the reaction was
performed at room temperature (entry 5) and only 29 was isolated
35%) when the transformation was carried out under reflux
(entry 6). The formation of 29 under these different conditions,
ruled out employing SnCl as the reducing agent for this step.
On the other hand, the use of the Fe/CaCl system in refluxing
unexpectedly furnished solely degradation products
entry 7). However, to our delight, exposure of 26 to elemental
Thus, exposure of a refluxing methanolic mixture of cinnamate
2
4 and the diazonium tetrafluoroborate 25, derived from p-
(
2
4d
anisidine
2
to Pd(OAc) catalysis, furnished 80% of the b,b-
diarylacrylate 26.
2
An nOe experiment, revealing mutual signal enhancement
between the vinylic proton of the acrylate motif (d 6.45, singlet),
and the neighbouring aromatic protons of the 4-methoxyaryl
moiety (d 7.33, d, J = 8.8 Hz), established the Z geometry of 26.
This outcome of the Heck-Matsuda reaction, analogous to that of
2
29a
EtOH
(
iron powder in glacial AcOH at 110 ºC resulted in the selective
reduction of the nitro moiety to 30 and subsequent lactamization,
cleanly affording 74% of 19, as the sole product (entry 8).
2
5
26
the Heck arylation, has been explained mechanistically.
29b-d
Next, the one pot benzyl ether group hydrogenolysis with
With the core 1H-quinolin-2-one 19 in hands (Scheme 4), the
4
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Organic & Biomolecular Chemistry
3
2
next steps were devoted to the installation of the C-6 b-propenyl
side chain. Therefore, proper conditions were sought for the
selective debenzylation of 19 and O-allylation of 27.
and inhibiting enzymes as well as lipid peroxidation.
The acquisition of compound 32 enabled the proposed
35 synthesis of 33, a peniprequinolone (1h) analog, lacking its 3,4-
glycol monoether feature (Scheme 5). This target was
conveniently conquered in 77% yield by the olefin cross
metathesis of 32 with 2-methylbut-2-ene, under Grubbs II
3
0a
OMe
OMe
OMe
3
3
o
catalyst promotion in refluxing CH Cl .
2 2
Fe , AcOH,
BnO
110ºC, 18h BnO
BnO
4
0
However, the achievement of the second and main objective
resulted more difficult. Unexpectedly, the isomerization of the
terminal double bond of 32 toward 34, proved to be challenging
under a wide range of catalysts and conditions.
(74%)
O
CO Et
NO2
..
2
NH OEt
N
O
2
H
OMe
OMe
2
6
30
19
2
-Methylbut-2-ene,
OMe
Grubbs II (5 mol%)
CH Cl reflux, 2h
OH
2
2,
OH
(sealed tube)
(77%)
BrCH CH=CH ,
H2, Pd/C,
EtOAc-EtOH (1:1),
1 atm, rt, 4h,
2
2
OH
K CO , EtOH,
2
3
70ºC, overnight
N
R
O
Me
Me
N
H
O
(65%)
(89%)
3
2 R= H
Boc O, Et N, DMAP,
33
N
H
O
2
3
35 R= Boc
CH Cl , rt, 20h (63%)
2
2
OMe
OMe
2
7
Stressed Grubbs II,
MeOH, rt
RhCl .3H O,
EtOH, rt,
3
2
or RhCl .3H O,
OMe
OMe
3
2
31h (50%)
O
OH
EtOH, rt
or Pd(PPh
1
,2-Cl -C H ,
MW, 190ºC, 2h
3
)
2
Cl2,
2
6
4
CH
Cl2, reflux
2
(
65%)
OH
OH
N
H
O
N
H
O
Me
Me
X
31
32
5
N
H
O
N
O
Scheme 4. Construction of the 2-quinolonic ring and synthesis of 32.
Boc
34
36
4
5
The results of Table
1 seemed to confirm literature
observations, that characterized the selective debenzylation of
aryl benzyl ethers in the presence of C-C double bonds as
Scheme 5. Syntheses of the target compounds 33 and 36.
1
1
2
2
3
0
5
0
5
0
3
0b
The attempts employing stressed Grubbs-II catalyst (MeOH,
‘difficult’.
However, in the case of 19, after several trial and
6
4
0 ºC, 3 h), RhCl
0 ºC, 4 h) and [(C
3
.3H
2
O (EtOH, rt, 7 h), Pd(PPh
3 2 2 3
) Cl (CHCl ,
error attempts under different conditions, it was learned that 10%
Pd/C in a cold 1:1 (v/v) EtOH-EtOAc solvent mixture under an
atmospheric pressure of hydrogen, was an effective system for
6
H
5
)
3
3
P] Ru(CO)(Cl)H (PhMe, 90 ºC, 18 h)
5
5
6
6
0
5
0
5
met with failure, and the unexpected complete degradation of
the starting material with concomitant production of complex
mixtures of unidentifiable products, was invariably observed.
This was somehow reminiscent of the outcome of a similar
attempt at allyl group isomerization during the synthesis of an
3
,4
selectively cleaving the benzyl ether without affecting the ∆
3
0c
double bond. Under these conditions, 89% of 27 was reliably
obtained after 4 h.
Next, the selective O-allylation of the phenol moiety of 27 was
undertaken. Literature precedents suggested that the ambident
3
4
intermediate for fumimycin.
3
0a,31
We speculated that under the isomerization conditions, either
the free phenol or the amide of 34 (or even its less contributing
phenolic lactim moiety), could lead to structural destabilization of
the product, by acid-base or metal-promoted tautomerization to
quinone methides, which in turn could undergo degradation.
It has been proposed that quinone methides are formed as
intermediates during Pd-catalyzed reactions of 2-vinyl phenols
and other conditions involving easily protonable or otherwise
reactive benzylic positions and properly placed phenolic
anion at N-1–C-2 is a potentially competitive reaction site
and that, in principle the O-allylation should predominate.
3
0a
In fact, when compound 27 was subjected to a conventional
Williamson allylation, with K CO in EtOH at 60 ºC, 65% of the
2
3
expected O-allyl derivative 31 was obtained and, to our delight,
no other alkylation products were observed. Submission of ether
3
1 to the projected Claisen rearrangement took place under
microwaves irradiation in 1,2-dichlorobenzene, affording 75% of
the desired 6-allyl derivative 32.
Interestingly, the 6-allyl 1H-quinolin-2-ones have elicited
great synthetic and pharmaceutical interest, having also been used
as intermediates toward drugs for treating cardiac diseases,
protecting against the UV rays, scavenging active oxygen species,
3
5
groups. These are highly reactive species, capable to undergo
different reactions, among them polymerization. Further after
t
observing that 34 was fully recovered after exposure to K BuO in
THF for 12 h at room temperature, it was conceived that perhaps
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Page 6 of 11
the organometallic intermediates and not the isomerized product
The flash column chromatographies were run with Merck’s
silica gel 60 H, eluting with hexane/EtOAc mixtures, under
positive pressure and employing gradient of solvent polarity
techniques.
All new compounds gave single spots on TLC plates (silica gel
60 GF254) run in different hexane/EtOAc and EtOAc/EtOH
solvent systems. The chromatographic spots were detected by
exposure to 254 nm UV light, followed by spraying with
ethanolic p-anisaldehyde/sulfuric acid reagent, 1% methanolic
3
4 may be those that trigger the degradation of the heterocycle.
In light of this situation, it was decided to block the possible
involvement of the lactam moiety of 32 in the tautomerization
3
6
5
0
5
0
reaction, through its protection as the N-Boc derivative 35. This
was accomplished in 63% yield with Boc O and Et N in CH Cl
60
2
3
2
2
.
Surprisingly, however, the isomerization remained challenging,
as compound 35 was also reluctant to cleanly afford the
isomerized product. Its exposure to [(C H ) P] Ru(CO)(Cl)H in
6
5 3
3
1
1
2
toluene for 17 h at 70 ºC did not afford any isomerized product, 65 FeCl
3
,
ninhydrin or Dragendorff reagent (Munier and
3
7
whereas heating at 90 ºC for 24 h furnished the expected
Macheboeuf modification),
and final careful heating of the
heterocycle 36, albeit contaminated with PPh O, which turned
plates for improving selectivity.
3
hard to be removed chromatographically. On the other hand, the
use of Pd(PPh ) Cl (CHCl , rt, 3 h) gave a mixture of
Apparatus
3
2
2
3
unidentifiable products.
The melting points were measured on an Ernst Leitz Wetzlar
Finally, our expectations were met when exposure of 35 to 70 model 350 hot-stage microscope and are reported uncorrected.
RhCl .3H O in absolute EtOH resulted in the smooth
The IR spectra were recorded with a Shimadzu Prestige 21
3
2
isomerization of the allyl moiety, furnishing 50% of the sought
spectrophotometer, as thin films held between NaCl cells, as solid
product 36, when the reaction was left 31 h at room temperature.
Analysis of its H NMR spectrum, which exhibited signals at d
dispersions in KBr disks, or with a Pike ATR accessory.
1
1
The H NMR spectra were acquired at 300.13 MHz in CDCl
3
,
6
.19 (dd, J = 6.3 and 15.7 Hz, CH
3
-CH=CH-Ar) and d 6.36 (d, J 75 except when noted otherwise, on a Bruker Avance spectrometer.
=
15.7 Hz, CH -CH=CH-Ar), unequivocally confirmed the E-
3
Chemical shifts are reported in parts per million on the δ scale
and J-values are given in Hertz. The peak of the residual
stereochemistry of the b-methylstyrene unit in 36.
3 3
protonated solvent (CHCl in CDCl , δ 7.26) was used as the
1
3
internal standard. The C NMR spectra were recorded at 75.48
MHz on a Bruker Avance spectrometer. The solvent peak
Conclusions
8
8
9
9
0
5
0
5
2
3
3
4
5
0
5
0
We have developed a convenient approach towards an advanced
common key intermediate for the synthesis of relevant members
of the 6-substituted 5-hydroxy-4-aryl-3,4-dihydro-1H-quinolin-2-
one family of natural products. The synthetic strategy entailed
building and cyclization of a substituted b,b-diarylacrylate
derivative to construct the heterocyclic core. The sequence was
completed by an optimized selective catalytic debenzylation and
installation of the anchoring b-propenyl moiety, by an O-
allylation, followed by Claisen rearrangement and conjugative
double bond migration of the resulting 6-allyl-1H-quinolin-2-one.
The synthesis took place in nine steps and proceeded in 6.1%
overall yield, from the known 2-hydroxy-6-nitrobenzaldehyde, in
turn available in one step from commercial 3-nitrophenol.
3
(CDCl , δ 77.0) was used as the internal standard. DEPT 135 and
DEPT 90 experiments aided the interpretation and assignment of
13
the fully decoupled C NMR spectra. In special cases, 2D-NMR
experiments (COSY, HMBC and HMQC) were also employed.
Pairs of signals marked with an asterisk (*) indicate that their
assignments may be exchanged.
The high resolution mass spectra were obtained with a Bruker
MicroTOF-Q II instrument (Bruker Daltonics, Billerica, MA).
Detection of the ions was performed in electrospray ionization,
positive ion mode. The GC-MS experiments were carried out
with a Shimadzu QP2010 plus instrument. The runs were
performed in split injection mode (ratio: 50), column SPB-1 (30
m × 0.25 mm × 0.25 µm); oven temperature program TInit.: 50 ºC
Further, an analog of peniprequinolone, lacking its 3,4-glycol
monomethyl ether feature, was also synthesized by means of a
Grubbs II-catalyzed cross metathesis of the 6-allyl-1H-quinolin-
(3 min.); TEnd: 300 ºC, at 25 ºC/min; He flow: 1.0 mL/min. Mass
spectra were obtained under the following conditions: TInterface
:
3
7
00 ºC; TIon source: 230 ºC; Solvent cut time: 3 min; Ionization =
0 eV; range: 60-600 Da. The microwave-assisted reactions were
2
-one intermediate with 2-methylbut-2-ene.
Studies are under way in order to establish conditions for the
performed in a CEM Discover microwave oven.
installation of the characteristic C-3–C-4 monoprotected cis-diol
feature. The results will be communicated in due time.
1
00 2-Hydroxy-6-nitrobenzaldehyde (22)
4
5
Experimental section
A solution of 3-nitrophenol (21, 1000 mg, 7.20 mmol) in
3 2
F CCO H (8 mL), was treated with HMTA (1200 mg, 8.59
General information
mmol) and the mixture was heated at 90 ºC for 12 h. The reaction
was poured over ice-water (25 mL), the resultant mixture was
05 stirred for 15 min and then extracted with EtOAc (3 × 40 mL).
The organic layers were washed with brine (20 mL), dried under
All the reactions were carried out under dry Nitrogen or Argon
atmospheres, employing oven-dried glassware. Anhydrous THF
1
and anhydrous CH
purification and dispenser system. Absolute MeOH and EtOH
were accessed by refluxing the solvents over clean Mg/I and
2 2
Cl were obtained from an M. Braun solvent
5
0
Na
2 4
SO and concentrated in vacuo. Chromatography of the oily
2
residue afforded 22 (560 mg, 46%), as a yellow solid, m.p.: 52-54
2
0a
distilling from the resulting magnesium alkoxides; anhydrous 1,2-
dichlorobenzene was prepared by a 4 h reflux of the solvent over
ºC (Lit.: 53-54 ºC). IR (KBr, ν): 3300, 2955, 2922, 2851, 1693,
-1
1
1
10 1645, 1531, 1454, 1352 and 1284 cm . H NMR (d): 7.30 (d, 1H,
J = 8.0, H-3), 7.56 (d, 1H, J = 8.0, H-5), 7.63 (t, 1H, J = 8.0, H-
P2O followed by atmospheric pressure distillation. All other
5
1
3
5
5
reagents were used as received.
4
), 10.33 (s, 1H, CHO) and 12.11 (s, 1H, OH). C NMR (d):
6
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Organic & Biomolecular Chemistry
1
1
7
12.4 (C-1), 116.1 (C-5), 124.2 (C-3), 135.9 (C-4), 151.2 (C-6),
63.3 (C-2) and 193.9 (CHO). EI-MS (m/z, rel. int., %): 167 (M ,
), 149 (39), 137 (61), 120 (25), 119 (25), 109 (19), 107 (13), 92
of the starting material was confirmed by TLC analysis. Then, the
reaction mixture was concentrated under reduced pressure and the
residue was chromatographed to afford the β,β-diphenylacrylate
60 26 (194 mg, 60%), as a yellow solid, m.p.: 102-104 ºC. IR (KBr,
ν): 2934, 1717, 1603, 1526, 1508, 1448, 1362, 1269, 1163 and
+
(59), 91 (32), 93 (11), 81 (100) and 63 (85).
5
–
1 1
7
41 cm . H NMR (d): 1.08 (t, 3H, J = 7.1, OCH CH ), 3.82 (s,
2 3
2
-Benzyloxy-6-nitrobenzaldehyde (23)
3
3 2 3
H, ArOCH ), 3.98 (q, 2H, J = 7.1, OCH CH ), 5.02 (q, 2H, J =
K CO (560 mg, 4.00 mmol) was added to a solution of nitro-
12.3, OCH Ar), 6.45 (s, 1H, H-3), 6.85 (d, 2H, J = 8.8, H-11 and
2
3
2
salicylaldehyde 22 (223 mg, 1.334 mmol) in EtOH (3 mL). The 65 H-13), 7.04 (dd, 2H, J = 2.8 and 6.3, ArH of Benzyl), 7.21 (d,
mixture was stirred for 10 minutes at room temperature, when
benzyl chloride (338 mg, 2.67 mmol) was added dropwise and
the mixture was stirred overnight at 70 °C. After confirming the
complete consumption of the starting material, the solvent was
evaporated under reduced pressure and the residue was diluted 70 (C-3), 116.4 (C-6),* 117.0 (C-8),* 124.9 (C-1), 126.9 (2C,
with brine (10 mL) and 1M NaOH (10 mL). The product was
1H, J = 8.3, H-8), 7.23-7.26 (m, 3H, ArH of Benzyl), 7.33 (d, 2H,
J = 8.8, H-10 and H-14), 7.45 (t, 1H, J = 8.3, H-7) and 7.72 (d,
1
1
2
2
0
5
0
5
1
3
1H, J = 8.3, H-6). C NMR (d): 14.0 (OCH CH ), 55.3 (OCH ),
2
3
3
60.0 (OCH CH ), 70.8 (OCH Ar), 113.9 (C-11 and C-13), 116.0
2
3
2
Benzyl), 127.9 (C-4’), 128.4 (2C, Benzyl), 128.7 (C-10 and C-
14), 129.1 (C-7), 130.6 (C-9), 136.0 (Benzyl), 149.0 (C-7), 149.2
extracted with EtOAc (3 × 20 mL); the combined organic extracts
were washed with water (10 mL), dried over Na
2
SO
4
,
(C-6), 155.9 (C-2), 160.8 (C-4’) and 165.6 (CO Et). EI-MS (m/z,
2
+
concentrated and filtered through a short path of silica gel to yield
rel. int., %): 433 (M , 1), 416 (10), 151 (58), 150 (100), 133 (20),
the benzyl ether derivative 23 (342 mg, 99%), as a yellowish 75 122 (47), 121 (21), 115 (29), 107 (22), 106 (30), 105 (31), 104
3
8
oil. IR (film, ν): 3734, 3250, 1646, 1626, 1578, 1368, 1340,
(20), 103 (59), 94 (36), 93 (28), 91 (56) and 77 (92). HRMS m/z
–
1
1
+
1283, 1153, 1081, 1010, 842 and 669 cm . H NMR (d): 5.22 (s,
H, OCH Ar), 7.29 (d, 1H, J = 8.1, H-3), 7.36-7.41 (m, 5H, ArH
of Benzyl), 7.45 (d, 1H, J = 8.1, H-5), 7.56 (t, 1H, J = 8.1, H-4)
calcd. for C H NO 434.1604 [M + H] ; found: 434.1598.
2
5
24
6
2
2
5
-Benzyloxy-4-(4’-methoxyphenyl)-1H-quinolin-2-one (19)
1
3
2
and 10.40 (s, 1H, CHO). C NMR (d): 71.6 (OCH Ar), 115.9 (C-
5
), 117.6 (C-3), 121.2 (C-1), 127.2 (C-1’ and C-6’), 128.6 (C-4’), 80 Clean iron turnings (206 mg, 3.69 mmol) were added to a stirred
128.9 (C-3’ and C-5’), 133.4 (C-4), 135.0 (C-1’), 148.7 (C-3),
58.8 (C-2) and 187.6 (CHO).
solution of b,b-diphenylacrylate 26 (200 mg, 0.461 mmol) in
glacial AcOH (2 mL) pre-heated at 110 °C. Stirring was
continued during 18 h, when the solution was brought to room
temperature, and the precipitate was filtered off and washed with
EtOAc (10 mL). The combined organic solutions were
evaporated under reduced pressure and the residue was
chromatographed to furnish 19 (120 mg, 74%), as a brown solid,
m.p.: 207-209 ºC. IR (KBr, ν): 3734, 3250, 1646, 1626, 1578,
1
Ethyl E-3-(2’-benzyloxy-6’-nitrophenyl)acrylate (E-24)
8
5
A mixture of aldehyde 23 (265 mg, 1.03 mmol) and ethyl
(triphenyl-λ5-phosphanylidene)-acetate (1180 mg, 2.06 mmol) in
dichloromethane (3 mL) was stirred at room temperature for 5 h.
Once demonstrated the complete consumption of the starting
material by TLC, the solvent was removed under reduced 90 (d): 3.62 (s, 3H, OCH ), 4.69 (s, 2H, OCH Ar), 6.28 (s, 1H, H-3),
pressure and the residue was chromatographed, affording E-24
3
3
4
4
0
5
0
5
–
1 1
1368, 1340, 1283, 1153, 1081, 1010, 842 and 669 cm . H NMR
3
2
6.57 (d, 2H, J = 8.5, H-3’ and H-5’), 6.57 (d, J = 8.3, 1H, H-6),
6.74 (d, 2H, J = 8.5, H-2’ and H-6’), 6.98 (d, 1H, J = 8.3, H-8),
7.03-7.14 (m, 5H, ArH of Benzyl), 7.30 (t, 1H, J = 8.3, H-7) and
(297 mg, 88%), as a yellow solid, m.p.: 80-82 ºC. IR (KBr, ν):
–
1 1
1
705, 1521, 1350, 1288, 1273, 1193, 1041, 840 and 746 cm . H
NMR (d): 1.32 (t, 3H, J = 7.1, OCH CH ), 4.25 (q, 2H, J = 7.1,
OCH CH ), 5.22 (s, 2H, OCH Ar), 6.58 (d, 1H, J = 16.2, 95 105.1 (C-6), 109.5 (C-8), 110.2 (C-4a), 112.5 (C-3’ and C-5’),
1
3
2
3
11.71 (s, 1H, N-H). C NMR (d): 54.9 (OCH ), 70.5 (OCH Ar),
3 2
2
3
2
CH=CHCO Et), 7.16 (dd, 1H, J = 2.0 and 8.0, H-3), 7.35 (dt, 1H,
122.4 (C-3), 127.2 (C-2’ and C-6’), 127.5 (Benzyl), 127.9
(Benzyl), 128.6 (Benzyl), 131.1 (C-7), 134.0 (C-1’), 135.7
(Benzyl), 140.8 (C-8a), 152.3 (C-4), 156.4 (C-5), 158.8 (C-4’)
and 162.9 (C-2). HRMS m/z calcd. for C H NNaO : 380.1257
2
J = 2.0 and 8.0, H-5), 7.36 (d, J = 8.0, 1H, H-4), 7.38-7.41 (m,
5
H, ArH of Benzyl) and 7.73 (d, 1H, J = 16.2, CH=CHCO
2
Et).
1
3
C
NMR (d): 14.3 (OCH
OCH
CH=CHCO
CH ), 60.7 (OCH CH ), 71.4
2 3 2 3
2
3
19
3
+
(
(
2
Ar), 116.3 (C-3), 116.5 (C-5), 118.7 (C-1), 125.9 100 [M + Na] ; found: 380.1245.
Et), 127.0 (Benzyl), 128.4 (C-4), 128.6 (Benzyl),
2
128.8 (Benzyl), 134.3 (CH=CHCO Et), 135.5 (Benzyl), 150.9 (C-
2
5
-Hydroxy-4-(4’-methoxyphenyl)-1H-quinolin-2-one (27)
6
C
), 157.5 (C-2) and 166.4 (CH=CHCO
2
Et). HRMS m/z calcd. for
+
18
H
18NO
5
: 328.1185 [M + H] ; found: 328.1179.
Method A: The benzyloxy derivative 19 (62 mg, 0.174 mmol)
was added to a stirred suspension of 10% Pd/C (3 mg) in a 1:1
05 mixture of EtOH:EtOAc (2 mL), cooled to 0 °C in an ice bath.
The system was placed under a hydrogen atmosphere (1 atm.)
and stirred during 4 h. Then, the reaction was diluted with EtOAc
1
Ethyl Z-3-(2-benzyloxy-6-nitrophenyl)-3-(4’-methoxyphenyl)
acrylate (26)
5
0
A mixture of cinnamate ester 24 (245 mg, 0.749 mmol) and
Pd(OAc) (17 mg, 0.0749 mmol) in MeOH (3 mL) was
2
vigorously stirred at 80°C for 30 s, when the p-anisidine
(10 mL) and filtered through Celite. The filtrate was dried over
Na SO , concentrated in vacuo and chromatographed, affording
2
4
1
10 the 5-hydroxy-1H-quinolin-2-one 27 (41 mg, 89%), as a tan
diazonium tetrafluoroborate salt (333 mg, 1.50 mmol) prepared
crystalline solid, m.p.: 260-262 ºC (Hexanes-EtOAc). IR (KBr,
2
4a
5
5
under literature conditions,
was added in one portion. The
–
ν): 2928, 2369, 1630, 1607, 1508, 1356, 1281, 1244 and 833 cm
1
1
reaction was further stirred at 80 ºC until complete consumption
.
H NMR (d): 3.89 (s, 3H, OCH
3
), 5.59 (s, 1H, N-H), 6.41 (s,
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1
0
1
H, H-3), 6.64 (dd, 1H, J = 0.7 and 8.3, H-6), 6.98 (dd, 1H, J =
.7 and 8.3, H-8), 7.06 (d, 2H, J = 8.7, H-3’ and H-5’), 7.39 (t,
H, J = 8.3, H-7), 7.41 (d, 2H, J = 8.7, H-2’ and H-6’) and 8.53 60 Ar), 5.93 (ddd, 1H, J = 6.5, 15.7 and 17.8, CH =CH-CH -Ar),
3.33 (d, 2H, J = 6.5, H-1’), 3.89 (s, 3H, OCH
3
), 4.99 (d, J = 15.7,
1H, CH =CH-CH -Ar), 5.04 (d, J = 17.8, 1H, CHtrans=CH-CH2-
cis
2
2
2
1
3
(s, 1H, OH). C NMR (d): 55.5 (OCH ), 108.3 (C-4a), 108.7 (C-
6.41 (s, 1H, H-3), 6.99 (d, 1H, J = 8.3, H-8), 7.06 (d, 2H, J = 8.7,
H-3’ and H-5’), 7.30 (d, 1H, J = 8.3, H-7) and 7.40 (d, 2H, J =
3
5
0
5
0
6), 110.4 (C-8), 115.0 (C-3’ and C-5’), 121.8 (C-3), 129.4 (C-2’
and C-6’), 129.6 (C-1’), 132.1 (C-7), 139.9 (C-8a), 150.2 (C-4),
1
%
1
3
8.7, H-2’ and H-6’). C NMR (d): 34.0 (CH
(OCH ), 108.2 (C-4a), 108.4 (C-8), 115.0 (C-3’ and C-5’), 115.6
): 357 (M , 6), 91 (100), 73 (14) and 71 (18). HRMS m/z calcd. 65 (CH =CH-CH -Ar), 120,6 (C-8a), 121.9 (C-3), 129.5 (C-2’ and
2
=CH-CH -Ar), 55.4
2
54.3 (C-5), 160.7 (C-12), and 163.0 (C-2). EI-MS (m/z, rel. int.,
3
+
2
2
+
for C H NO : 268.0974 [M + H] ; found: 268.0968.
2 2
C-6’), 129,7 (C-1’), 133.3 (C-7), 136.5 (CH =CH-CH -Ar), 138.6
1
6
14
3
1
1
2
Method B: A magnetically stirred mixture of compound 26 (24
mg, 0.055 mmol) and 10% Pd/C (1 mg) in anhydrous MeOH (2
mL) was exposed to a hydrogen atmosphere (1 atm.) during 2 h at
room temperature. Then, the suspension was filtered through a
short pad of Celite and the filtrate was concentrated under
reduced pressure. The ensuing light yellow solid was subjected to
flash chromatography affording compound 27 (4 mg, 30%) as a
brownish crystalline solid. The spectral data of this product were
in full agreement with those recorded for the product obtained
through Method A.
(C-6), 150.2 (C-4), 151.3 (C-5), 160.7 (C-4’) and 163.1 (C-2).
HRMS m/z calcd. for C19H18NO 308.1287 [M + H] ; found:
3
308.1281.
+
70
5
-Hydroxy-4-(4’-methoxyphenyl)-6-(3-methyl-but-2-enyl)-1H-
quinolin-2-one (33)
To a stirred solution of the allyl derivative 32 (12 mg, 0.039
mmol) in anhydrous CH Cl (0.5 mL) was added the Grubbs II
2
2
7
5
catalyst (1.6 mg, 5 mol%). Then, 2-methyl-but-2-ene (27.4 mg,
.391 mmol) was dripped in, the system was sealed and the
0
mixture was heated to reflux. After stirring for 2 h, the reaction
was cooled to rt and filtered through a silica plug, washing with
EtOAc (20 mL). The filtrate was concentrated under reduced
pressure to afford 33 (10 mg, 77%) as a brownish solid, m.p.:
222-224 ºC (EtOAc). IR (KBr, ν): 3480, 2926, 2359, 1645, 1634,
5
-Allyloxy-4-(4’-methoxyphenyl)-1H-quinolin-2-one (31)
A solution of 27 (316 mg, 1.183 mmol) in absolute EtOH (4 mL),
was treated with K CO (199 mg, 1.420 mmol). The resulting
suspension was stirred at room temperature during 10 min., when
allyl bromide (171 mg, 1.420 mmol) was added in one portion
and the reaction was heated under reflux during 4 h. After
confirming the complete consumption of the starting material by
80
2
3
–
1
1
2
3
3
4
4
5
0
5
0
5
1607, 1512, 1454, 1373, 1248, 1178, 1032 and 833 cm . H
NMR (d): 1.67 (s, 3H, C-CH ), 1.71 (s, 3H, C-CH ), 3.25 [d, 1H,
J = 6.7, CH -CH=C(CH ], 3.89 (s, 3H, OCH ), 5.24 [bs, 1H,
-CH=C(CH ], 5.67 (bs, 1H, -NH), 6.39 (s, 1H, H-3), 6.94
(d, 1H, J = 8.2, H-8), 7.07 (d, 2H, J = 8.3, H-3’ and H-5’), 7.29
3
3
2
3
)
2
3
TLC, the reaction mixture was treated with a 1M solution of HCl 85 CH
10 mL) and the products were extracted with EtOAc (3 × 15
mL). The combined extracts were dried with Na SO and
2
3 2
)
(
(
d, 1H, J = 8.2, H-7), 7.40 (d, 2H, J = 8.3, H-2’ and H-6’) and
2
4
1
3
1
1.91 (s, 1H, OH). C NMR (d): 17.8 (C-CH ), 25.7 (C-CH ),
concentrated under reduced pressure. The residue was submitted
3 3
to flash chromatography, affording compound 31 (235 mg, 65%),
28.2 [CH
2
-CH=C(CH
3
)
2
], 55.4 (OCH
-CH=C(CH
128.7 (C-4), 129.5 (C-2’ and C-6’), 129.9 (C-9), 132.9 (C-7),
133.2 [CH -CH=C(CH ], 138.2 (C-8a), 150.2 (C-6), 151.3 (C-
), 160.6 (C-4’) and 163.0 (C-2). HRMS m/z calcd. for
3
), 108.2 (C-8), 115.0 (C-3’
as a colorless solid, m.p.: 210-212 ºC (CH Cl ). IR (ATR, ν): 90 and C-5’), 122.1 (C-3), 122.2 [CH
3 2
)
], 127.3 (C-4a),
2
2
2
3
734, 3250, 1646, 1626, 1578, 1368, 1340, 1283, 1153, 1081,
–
1 1
1010, 842 and 669 cm . H NMR (DMSO-d
OCH ), 4.25 (d, J = 5.2, 2H, CH =CH-CH -Ar), 4.79 (d, J = 18.7,
H, CHtrans=CH-CH-Ar), 4.90 (d, J = 10.7, 1H, CHcis=CH-CH
Ar), 5.36 (ddd, J = 5.2, 10.7 and 18.7, 1H, CH =CH-CH -Ar)
.59 (s, 1H, NH), 6.41 (s, 1H, H-3), 6.66 (d, 1H, J = 8.2, H-6),
6.89 (d, 2H, J = 8.5, H-3’ and H-5’), 6.97 (d, 1H, J = 8.2, H-8),
6
, d): 3.77 (s, 3H,
2
3 2
)
5
3
2
2
+
C H NO : 336.1577 [M + H] ; found: 336.1594.
21 22
1
2
-
3
95
2
2
5
tert-Butyl 6-allyl-5-hydroxy-4-(4’-methoxyphenyl)-2-oxo-2H-
quinoline-1-carboxylate (35)
7
7
.17 (d, 2H, J = 8.5, H-2’ and H-6’), and 7.41 (t, 1H, J = 8.2, H-
1
3
To a solution of 32 (146 mg, 0.475 mmol), in anhydrous CH Cl
2
2
). C NMR (DMSO-d , d): 55.5 (OCH ), 69.2 (CH =CH-CH -
6
3
2
2
(2 mL) was added anhydrous Et N (144 mg, 1.425 mmol) and
3
Ar), 108.3 (C-4a), 108.7 (C-6), 110.4 (C-8), 115.0 (C-3’ and C-
’), 117.1 (CH =CH-CH-Ar), 121.8 (C-3), 129.4 (C-2’ and C-6’),
129.6 (C-9), 132.1 (C-7), 132.8 (CH =CH-CH-Ar), 139.9 (C-8a),
1
1
1
2
00 DMAP (17.3 mg, 0.142 mmol). Then, Boc O (310 mg, 1.425
5
2
mmol) was added in one portion and the resulting mixture was
stirred at room temperature for 20 h. After confirming the
complete consumption of the starting material by TLC, the
reaction was poured on H O (10 mL), and the product was
05 extracted with Et O (3 × 10 mL). The organic phase was washed
with NaHCO
combined organic layers were dried (Na
under reduced pressure. Chromatography of the residue afforded
the compound 35 (120 mg, 0.299 mmol) as a pale yellow solid,
2
1
50.2 (C-4), 154.3 (C-5), 160.7 (C-12) and 163.0 (C-2). HRMS
+
3
m/z for C19H18NO : 308.1287 [M + H] ; found: 308.1281.
2
2
6
-Allyl-5-hydroxy-4-(4’-methoxyphenyl)-1H-quinolin-2-one
3
(10 mL), brine (10 mL), and H
2
O (10 mL). The
5
0
(32)
2
SO ) and concentrated
4
The O-allyl derivative (31) (200 mg, 0.651s mmol) was dissolved
in 1,2-dichlorobenzene (4 mL) and the solution was placed in a
sealed tube. The mixture was heated in a microwave reactor (300
W) at 190 °C for 120 min. The crude product was purified by
flash chromatography on silica gel, to give 32 (0.150 g, 75%) as a
colorless oil, m.p.: > 300 ºC (EtOAc). IR (KBr, ν): 2928, 2369,
10 m.p.: 172-174 ºC (CH Cl ). IR (KBr, ν): 2930, 1666, 1661, 1514,
2
2
–
1
1
1371, 1101, 876 and 833 cm . H NMR (d): 1.26 (s, 9H, C-
(CH ), 3.28 (d, 2H, J = 6.5, CH -CH=CH ), 3.88 (s, 3H, OCH ),
5.03 (m, 1H, CHcis=CH-CH -Ar), 5.08 (m, 1H, CHtrans=CH-CH
Ar), 5.85 (ddd, 1H, J = 6.5, 9.4 and 16.2, CH =CH-CH -Ar), 6.54
5
5
3
)
3
2
2
3
2
2
-
–
1 1
1
630, 1607, 1508, 1356, 1281, 1244 and 833 cm . H NMR (d):
2
2
8
|
Org. Biomol. Chem., 2016, vol, 00–00
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DOI: 10.1039/C5OB02680F
Page 9 of 11
Organic & Biomolecular Chemistry
(
=
s, 1H, H-3), 6,97 (d, 2H, J = 8.6, H-3’ and H-5’), 7.32 (d, 2H, J
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O. Larsen, J. Smedsgaard, J. C. Frisvad, U. Anthoni and C.
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C.-Y. An, X.-M. Li, H. Luo, C.-S. Li, M.-H. Wang, G.-M. Xu and
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Kempter, U. Roos, S. Schorderet Weber, Y. Ebinger and S. Glaser,
Patent WO 060015, 2009; (c) C. Kempter, U. Roos, D. Blaser and C.
Epe, Patent WO 128095, 2010; (d) H. Tomoda, R. Masuma, S.
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Scherlach, H.-M. Dahse and C. Hertweck, Patent DE 102006006893,
8.6, H-2’ and H-6’), 7.36 (d, 1H, J = 8.6, H-8) and 7.42 (d, 1H,
13
J = 8.6, H-7). C NMR (d): 27.3 [C-(CH ) ], 33.7 (CH =CH-
CH
9), 113.6 (C-3’ and C-5’), 115.0 (C-8), 116.8 (CH =CH-CH -Ar),
1
1
3
3
2
2 3 3 3
-Ar), 55.3 (OCH ), 83.3 [C-(CH ) ], 104.3 (C-6), 113.4 (C-
5
2
2
24.0 (C-3), 127.5 (C-3), 131.8 (C-4a), 132.5 (C-2’ and C-6’),
35.4 (CH =CH-CH -Ar), 138.8 (C-8a), 143.2 (C-5), 150.4 [N-
2
2
4
5
(
C=O)-O], 151.0 (C-4), 159.4 (C-4’) and 163.2 (C-2). HRMS m/z
+
calcd. for C H NNaO : 430.1625 [M + Na] ; found: 430.1610.
2
4
25
5
1
0
tert-Butyl 5-hydroxy-4-(4’-methoxyphenyl)-2-oxo-6-propenyl-
H-quinoline-1-carboxylate (36)
1
To a solution of allyl derivative 35 (10 mg, 0.024 mmol) in EtOH
1 mL) was added RhCl .3H O (2.13 mg, 0.0082 mmol). The
(
3
2
1
2
2
3
5
0
5
0
resulting mixture was stirred during 31 h to room temperature.
Then, the reaction was filtered through silica-pad with EtOAc as
eluent. The filtrate was concentrated under reduced pressure to
afford compound 36 (5 mg, 50%) as a white solid, m.p.: 139-140
ºC (CH Cl ). IR (KBr, ν): 3690, 2928, 2853, 2370, 1751, 1663,
2
2
–
1 1
1549, 1508, 1458, 1248, 1151 and 833 cm . H NMR (d): 1.18
s, 9H, C-(CH ], 1.78 (d, 3H, J = 6.3, CH -CH=CH-Ar), 3.80 (s,
), 6.19 (dd, J = 6.3 and 15.7, 1H, CH -CH=CH-Ar),
.36 (d, J = 15.7, 1H, CH -CH=CH-Ar), 6.53 (s, 1H, H-3), 6,95
[
3
6
3
)
3
3
6
H, OCH
3
3
3
(
d, 2H, J = 8.6, H-3’ and H-5’), 7.19 (d, 2H, J = 8.6, H-2’ and H-
1
3
6’), 7.28 (d, 1H, J = 8.8, H-7) and 8.73 (d, 1H, J = 8.8, H-8).
NMR (DMSO-d
5
5
4
C
6
3 3 3
, d): 18.6 (CH -CH=CH-Ar), 26.8 [C-(CH ) ],
2
2
007; (f) X. Li, X. Huo, j. Li, X. She and X. Pan, Chin. J. Chem.,
009, 27, 1379–1381; (g) H. Ueki, T. K. Ellis, M. A. Khan and V. A.
5.1 (OCH ), 82.5 [C-(CH ) ], 112.3 (C-6), 113.2 (C-3’ and C-
3
3 3
3
’), 114.2 (C-7), 123.2 (CH -CH=CH-Ar), 124.3 (C-3), 124.5 (C-
Soloshonok, Tetrahedron, 2003, 59, 7301–7306.
a), 127.9 (CH -CH=CH-Ar), 128.5 (C-8), 129.1 (C-2’ and C-6’),
3
7
(a) E. V. Babaev, Chem. Heterocyclic Comp., 1993, 9, 801-822; (b)
D. S. Choi, J. H. Kim, J. Y. Lee, U. S. Shin, C. E. Song and M. Y.
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131.4 (C-9), 139.5 (C-8a), 143.2 (N(C=O)-O), 149.3 (C-4), 149.8
C-5), 158.8 (C-4’) and 160.4 (C-2). HRMS m/z calcd. for
(
+
24 5
C H25NNaO : 430.1625 [M + H] ; found: 430.1609.
8
505; (d) K. Nakamura, T. Shibuya and K. Tanaka, Beilstein J. Org.
Chem., 2011, 7, 944–950; (e) L.-P. Guan, F.-N. Li, Z.-S. Quan, L.-P.
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Acknowledgements
The authors are thankful to Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET) and Agencia Nacional de
Promoción Científica y Tecnológica (ANPCyT) for financial
support (PIP Nº 2012-0471 and PICTs Nº 2011-0399 and 2014-
3
5
8
(a) A. Doléans-Jordheim, J.-B. Veron, O. Fendrich, E. Bergeron, A.
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0
445). S.O.S. also acknowledges CONICET for his fellowship.
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This journal is © The Royal Society of Chemistry 2016
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Organic & Biomolecular Chemistry
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1
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