4-Aryl-2-quinolones through a Pseudo-Domino Heck/Buchwald-Hartwig reaction in a molten tetrabutylammonium acetate/ tetrabutylammonium bromide mixture

Article abstract of DOI:10.1002/adsc.200600342

4-Aryl-2-quinolones can be prepared from readily available o-bromocinnamamide and aryl iodides using phosphine-free palladium(II) ace-tate as the precatalyst and a molten tetra(n-butyl)-ammonium acetate/tetra(n-butyl) ammonium bro-mide mixture as the reac

Full text of DOI:10.1002/adsc.200600342

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DOI: 10.1002/adsc.200600342
4-Aryl-2-quinolones through a Pseudo-Domino Heck/Buchwald–
Hartwig Reaction in a Molten Tetrabutylammonium Acetate/
Tetrabutylammonium Bromide Mixture
Gianfranco Battistuzzi,a Roberta Bernini,b Sandro Cacchi,a,* Ilse De Salve,b
and Giancarlo Fabrizia,b
a
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università degli Studi “La
Sapienza”, P. le A. Moro 5, 00185 Rome, Italy
Fax : (+39)-06-4991-2780; e-mail: sandro.cacchi@uniroma1.it
Dipartimento A.B.A.C., Università degli Studi della Tuscia, Via S. Camillo De Lellis, 01100 Viterbo, Italy
b
Received: July 11, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: 4-Aryl-2-quinolones can be prepared
from readily available o-bromocinnamamide and
aryl iodides using phosphine-free palladium(II) ace-
palladium-catalyzed C(aryl)-heteroatom bond forming
reaction in situ.
In particular, we decided to develop a new ap-
proach to the de novo 2-quinolone system construc-
tion using the readily available 3-(o-bromophenyl)-
acrylamide 1 as the building block according to the
domino process[10] outlined in Scheme 1. The initial
tate as the precatalyst and a molten tetra
A
ammonium acetate/tetra(n-butyl)ammonium bro-
AHCTREUNG
mide mixture as the reaction medium. The reaction
proceeds through a pseudo-domino process involv-
ing two mechanistically independent, sequential cat-
alytic cycles: a Heck reaction followed by an intra-
À
molecular Buchwald–Hartwig C N bond forming
reaction.
Keywords: aryl iodides; cyclization; domino reac-
tions; palladium
The construction of heterocyclic rings based upon the
concept of the domino Heck reaction/cyclization pro-
cess is a useful synthetic methodology.[1] We have de-
Scheme 1.
veloped this chemistry into new versatile and efficient Heck reaction should produce the vinylic substitution
procedures for the preparation of butyrolactones,[2] product 3 which, under the same conditions, should
cardenolides,[3] butenolides,[4] quinolines,[5] and cou- undergo an intramolecular palladium-catalyzed N-ar-
marins.[5,6] In all these processes, an a,b-unsaturated ylation to give the desired 2-quinolone product 4.
carbonyl compound bearing a nucleophile on the b
Although palladium catalysis proved to be a power-
substituent undergoes an initial palladium-catalyzed ful tool for the construction of heterocyclic rings,[11]
vinylic substitution followed, in some cases in situ, by very few examples of palladium-catalyzed synthesis of
an intramolecular nucleophilic attack of an oxygen or 2-quinolones have been reported. Internal alkynes
nitrogen nucleophile to the carbonyl group. Recent have been recently described by Larock et al.[12] to
developments in the palladium-catalyzed N- and O- give 2-quinolones via carbonylative annulation by N-
arylation process,[7] pioneered and extensively investi- substituted o-iodoanilines. Olefinic systems have also
gated by Buchwald[8] and Hartwig,[9] prompted us to been used as precursors. (Z)-2-Acetamido-a-bromo-
explore a different strategy, in which the Heck reac- styrene was converted into 2-quinolone via a carbony-
tion of an olefinic system, bearing an ortho C Br lation/cyclization process.[13] b-Substituted acrylic acid
À
bond on the b aryl substituent, could be followed by a derivatives and methyl acrylate were used to prepare
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Gianfranco Battistuzzi et al.
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2-quinolones through a Heck reaction/cyclization pro- Heck reaction is a vital prerequisite for the success of
cess with, respectively, o-iodoanilines[1] and o-bromo- the cyclization step.[29]
nitrobenzenes.[14] The utility of the olefinic-based
methods, however, appears to be severely limited.
p-Iodoanisole and 1 were used as the model system
and the following reaction variables were examined:
On the other hand, the 2-quinolone motif is abun- the bases, the additives, the nature of phosphine li-
dant in many biologically active compounds and this gands, and the reaction temperature. Under a variety
appears to justify efforts to develop new and versatile of conditions typical for the Heck reaction, using 5
synthetic procedures. For example, 2-quinolone deriv- mol% of Pd(OAc)2 as the source of Pd(0), Et3N
N
atives have been evaluated as inhibitors of HIV-1 re- (3 equivs.) as the base, PPh3 (10 mol%) and DMF as
verse transcriptase,[15] gonadotropin-releasing hor- the solvent at 1008C the starting olefin was recovered
mone antagonists,[16] NMDAand AMPAantago-
in 80–90% yield. The use of the Herrmann catalyst[30]
nists,[17] anti-infectives,[18] antiviral and antihyperten- under the same conditions produced the vinylic sub-
sive agents.[19] The 4-aryl-2-quinolone derivative tipi- stitution product 3a in 58% yield along with minor
farnib exhibits anticancer activity.[20,21] 2-Quinolones amounts of 4a (18%). The starting material was re-
are also useful synthetic intermediates. For example, covered in 18%. Increasing temperature to 1208C
they can be readily converted into 2-chloroquinoline gave 3a in 38% yield and the starting olefin was re-
derivatives[22] and quinoline 2-triflates[23] and then into covered in 38% yield. Neither the vinylic substitution
2-aminoquinoline derivatives. 2-Chloroquinolines[24] derivative nor the quinolone product was formed at
and quinoline 2-triflates[25] can also be involved in pal- 100–1208C under the conditions developed by Buch-
ladium-catalyzed reactions to afford a wide range of wald et al. for the intramolecular aryl amidation[28g]
quinoline products.
(toluene, MOP[31] or Xantphos,[32] K2CO3). Attempts
to combine some typical elements of the intramolecu-
Herein, we report the results of this study.
Initial attempts focused on exploring the feasibility lar N-arylation of amides with those of the vinylic
of the domino process outlined in Scheme 1. Particu- substitution met with failure. For example, treatment
larly, we decided to develop reaction conditions in of 1 with 1.5 equivs. of p-iodoanisole, 2 equivs. of
which a single palladium-based catalytic system would Cs2CO3, 0.05 equivs. of Pd(OAc)2, 0.05 equivs. of
G
share two mechanistically unrelated sequential cata- Xantphos in DMF at 1008C for 48 h, led to the isola-
lytic cycles.[26,27] The successful execution of this type tion of 3a and 4a in 40 and 11% yields, respectively.
of domino processes – a palladium-catalyzed pseudo- Omitting phosphine ligands led again to the forma-
domino (Pd-PDOM) type I process according to the tion of 3a as the main reaction product under a varie-
definition given by Poli et al.[26f] – is not a trivial task. ty of reaction conditions (Table 1, entries 1–6).
Possible and often unpredictable incompatibilities
Noteworthy, although formation of E/Z mixtures
among the different catalytic cycles can in fact make has been reported in previous vinylic substitution re-
this synthetically useful chemistry not viable. In the actions of b-substituted acrylamides,[29] only the Heck
present case, it is also necessary to avoid the intermo- product containing the amide group on the same side
lecular N-arylation of the starting amide, a reaction of the carbon-carbon double bond as the preexisting
which might be expected to be competitive.[28a–e] Fur- b-substituent was formed, most probably as the result
thermore, the formation of the Z isomer 3 in the of a diastereoselective Heck reaction. The involve-
Table 1. Bases, additives and temperature in the palladium-catalyzed synthesis of 4a from 1 and p-iodoanisole.[a]
Entry
Reaction conditions
8C/h
Yield [%] of 3a[b]
Yield [%] of 4a[b]
1
2
3
4
5
6
7
8
DMF,[c] Et3N (3 equivs.)
100/48
100/48
100/48
100/48
100/48
100/12
120/48
120/48
120/48
120/48
120/48
56
46
40
40
53
87
12
50
35
23
-
-
-
-
-
22
-
33
25
35
52
73
DMF,[c] Et3N (3 equivs.), LiCl (5 equivs.)
DMF,[c] Cs2CO3 (2 equivs.), LiCl (5 equivs.)
DMF,[c] Na2CO3 (2 equivs.), LiCl (5 equivs.)
DMF,[c] n-Bu4NOAc (2 equivs.)
Et3N (5 equivs.)
DMF,[c] n-Bu4NOAc (2 equivs.)
n-Bu4NOAc (1 equiv), n-Bu4NBr (3 equivs.)
n-Bu4NOAc (2 equivs.), n-Bu4NBr (2 equivs.)
n-Bu4NOAc (2.5 equivs.), n-Bu4NBr (4 equivs.)
n-Bu4NOAc (3 equivs.), n-Bu4NBr (3 equivs.)
9
10
11
[a]
Reactions were carried out on a 0.5 mmol scale under argon using 1 equiv. of 1, 1.5 equivs. of p-iodoanisole, and 0.05
equivs. of Pd(OAc)2.
Yields are given for isolated products.
2 mL.
ACHTREUNG
[b]
[c]
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4-Aryl-2-quinolones through a Pseudo-Domino Heck/Buchwald–Hartwig Reaction
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ment of an E/Z equilibrium following the syn-b-elimi- n-Bu4NBr) which produced 4a in 73% yield (Table 1,
nation step was ruled out on the basis of the following entry 11).
experiment. Apure sample of 5 (the stereoisomer of
This result is particularly interesting because phos-
3a), prepared via the reaction of cinnamamide with o- phine ligands are known to play a pivotal role in
iodobromobenzene, was subjected to the best condi- Buchwald–Hartwig N-arylation of amides[28] and, to
tions producing vinylic substitution products (Table 1, the best of our knowledge, no examples of this type
entry 6) in the presence of 6 (the N,N-dimethyl deriv- of chemistry have been reported so far with phos-
ative was used to make separation of the reaction phine-free palladium catalysts. Most probably, under
mixture easier) and p-iodoanisole (Scheme 2). The our conditions the reaction involves tetraalkylammo-
nium-stabilized palladium nanoparticles[34] and this
may have an influence on the reaction outcome. The
À
intramolecular nature of the C N bond forming pro-
cess must also favor the reaction.
No evidence of the vinylic substitution intermediate
3a was attained by monitoring the reaction mixture
by TLC or HPLC. However, subjecting a pure sample
of 3a to the conditions shown in Table 1, entry 11 pro-
duced 4a in 80% yield (no starting material was de-
tected by HPLC when we monitored the reaction
mixture after 45 min). In addition, the reaction under
the same conditions of p-iodoanisole with the parent
quinolone 8 – which might form via an E/Z isomeriza-
tion of 1 followed by a cyclization step – did not
afford the quinolone derivative 4a[35] (Scheme 3).
Scheme 2.
3,3-diarylacrylamide 7, formed via the reaction of 6
with p-iodoanisole, was isolated in 92% yield. Com-
pound 5 was recovered in almost quantitative yield
and its stereochemistry was maintained, even on pro-
longing the reaction time to 24 h.
Scheme 3.
Only after switching to n-Bu4NOAc as the base in
DMF at 1208C did the mixture contain predominantly Compound 8 was recovered in almost quantitative
the desired 4a (Table 1, entry 7). Although the yield yield. Taken together, these results support the view
was unsatisfactory from a synthetic standpoint, the that 3a is the precursor of 4a and that a fast cycliza-
À
very high selectivity in favor of the intramolecular C
tion step follows the Heck reaction under these condi-
N bond forming reaction compared with the intermo- tions.
lecular reaction was rewarding. Indeed, formation of
We have also repeated the experiment described in
the N-arylation product generated via intermolecular Scheme 2 using the reaction conditions shown in
palladium-catalyzed reaction of the amide group of 1 Table 1 entry 11. The 3,3-diarylacrylamide 7 was iso-
with p-iodoanisole, expected as a possible side-reac- lated in 87% yield, compound 5 was recovered in
tion, was observed only in trace amounts.
70% yield and quinolone 4n was obtained in 15%
We next explored the use of a molten n-Bu4NOAc/ yield (no evidence of its stereoisomer 3a was ob-
n-Bu4NBr mixture as the reaction medium. This tained). This result suggests that under these condi-
molten salt mixture was recently shown by us to be tions an E/Z isomerization process might follow the
particularly suited for performing highly stereoselec- vinylic substitution step.
tive Heck reactions on cinnamate esters[33] and
The best conditions found with the model reaction
domino Heck reaction/cyclization processes producing [n-Bu4NOAc (3 equivs.), n-Bu4NBr (3 equivs.), Pd-
coumarins.[6] Initial attempts were discouraging since
(OAc)2 (0.05 equivs.), 1208C] were then used when
AHCTREUNG
3a was still the main reaction product (Table 1, the pseudo-domino reaction was extended to other
entry 8). However, the reaction outcome was found to aryl iodides in order to examine the scope and limita-
depend on the n-Bu4NOAc/n-Bu4NBr molar ratio tions of this process. The results are summarized in
and, after some experimentation (the results of a Table 2. 4-Aryl-2-quinolones were isolated in accepta-
couple of the runs we carried out are shown in ble to good yields in many cases with a variety of aryl
Table 1, entries 9 and 10), we arrived at the optimal iodides including those with ether, amide, and ester
combination (3 equivs. of n-Bu4NOAc and 3 equivs. of functionalities. Unfortunately, m-iodobenzaldehyde
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299

Gianfranco Battistuzzi et al.
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Table 2. Synthesis of 2-quinolones 4 through a domino Heck/Buchwald–Hartwig process.[a]
Entry
Aryl iodide 2
t [h]
Yield [%] of 4[b]
1
2
3
4
5
6
7
8
p-MeO-C6H4-I
p-Me-C6H4-I
m-MeO-C6H4-I
m-F-C6H4-I
m-CF3-C6H4-I
p-CO2Et-C6H4-I
o-F-C6H4-I
2a
2b
2c
2d
2e
2f
2g
2h
24
36
36
36
36
36
48
48
73
65
65
62
50
40
40
20[c]
4a
4b
4c
4d
4e
4f
4g
4h
m-HCO-C6H4-I
9
2i
24
60
4i
10
11
p-MeCO-C6H4-I
2j
48
24
-
4j
2k
80
4k
12
13
14
p-MeCON(Me)-C6H4-I
m-MeCON(Me)-C6H4-I
PhI
2l
2m
2n
48
48
24
65
54
75
4l
4m
4n
[a]
Unless otherwise stated, reactions were carried out on a 0.5 mmol scale at 1208C under argon using 1 equiv of 1, 1.5
equivs. of 2, 3 equivs. of n-Bu4NOAc, 3 equivs. of n-Bu4NBr and 0.05 equivs. of Pd
Yields are given for isolated products.
Calculated by NMR analysis.
A
[b]
[c]
gave the corresponding 2-quinolone product in low
yield (Table 2, entry 8) and when p-iodoacetophenone
was subjected to our standard conditions the corre-
sponding quinolone derivative was not obtained at all
(Table 2, entry 10). However, appropriately protected
aldehydic and ketonic aryl iodides afforded the de-
sired products in good to high yield. (Table 2, en-
tries 9 and 11).
Attempts to extend the reaction to aryl bromides
were also made. However, aryl bromides such as N,N-
dimethyl-p-bromoaniline, p-bromoanisole, o-fluoro-
bromobenzene, and p-bromobenzonitrile failed to
give quinolone products, generating instead complex
reaction mixtures that we have not further investigat-
ed. Very likely, oxidative addition of the aryl bromide
Scheme 4.
fragment of 1 to Pd(0) may be a significant competi- mechanistically independent, sequential catalytic
tive reaction in these cases. Nevertheless, m-trifluoro- cycles. On the whole, the present procedure may rep-
methylbromobenzene produced the corresponding 2- resent a convenient alternative to the known, olefinic-
quinolone derivative in satisfactory yield (Scheme 4), based[1,13,14] palladium-catalyzed syntheses of this class
comparable to that obtained with m-trifluoromethy- of compounds.
liodobenzene (Table 2, entry 5).
To conclude, we have developed a straightforward
new approach to 4-aryl-2-quinolones from readily
Experimental Section
available starting materials using Pd(OAc)2 as the
N
precatalyst and a molten n-Bu4NOAc/n-Bu4NBr mix-
ture as the reaction medium. The phosphine-free cat-
Melting points were determined with a Büchi B-545 appara-
tus and are uncorrected. The acetal 2i and the ketal 2k were
prepared according to standard methods from the corre-
sponding carbonyl derivative. Compounds 2l and 2m were
prepared via N-methylation of the corresponding acet-
À
alyst system works well even in the intramolecular C
N bond forming step. Although isolated yields are
moderate to good, they refer to a multistep palladi-
um-catalyzed pseudo-domino process involving two amides. All the other reagents, catalysts, and solvents are
300
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4-Aryl-2-quinolones through a Pseudo-Domino Heck/Buchwald–Hartwig Reaction
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commercially available and were used as purchased, without References
further purification. Reaction products were purified on ax-
ially compressed columns, packed with SiO2 25–40 mm (Ma-
cherey–Nagel), connected to a Jasco RI-031 Plus solvent de-
livery system and to a Jasco PU-2087 Plus refractive index
detector, and eluting with n-hexane/ethyl acetate mixtures.
1H NMR (400 MHz), 13C NMR (100.6 MHz) and 19F NMR
(376.5 MHz) spectra were recorded with a Bruker Avance
400 spectrometer. IR spectra were recorded with a Jasco
FT/IR-430 spectrometer. Mass spectra were recorded with a
Shimadzu GCMS-QP2010S.
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(0.78%), 224.90 (M+,
N
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(0.093 mL, 0.75 mmol), n-BuN4OAc (0.452 g, 1.5 mmol) and
n-BuN4Br
(0.483 g, 1.5 mmol),
Pd
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(0.006 g,
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115.8, 114.1, 55.2; MS: m/z (relative intensity)=251 (M+,
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Acknowledgements
Work carried out in the framework of the National Project
“Stereoselezione in Sintesi Organica. Metodologie ed Appli-
cazioni” supported by Ministero dell’Istruzione, dell’Universi-
tà e della Ricerca (MIUR). The authors are also greatly in-
debted to the University “La Sapienza” and FIRB 2003 for
financial support of this research.
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Gianfranco Battistuzzi et al.
COMMUNICATIONS
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302
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