Synthesis of 4-quinolones via a carbonylative sonogashira cross-coupling using molybdenum hexacarbonyl as a co source

Article abstract of DOI:10.1021/jo502400h

A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products

Full text of DOI:10.1021/jo502400h

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Article
Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-
Coupling Using Molybdenum Hexacarbonyl as a CO Source
Linda Åkerbladh, Patrik Nordeman, Matyas Wejdemar, Luke R. Odell, and Mats Larhed
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502400h • Publication Date (Web): 09 Jan 2015
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Synthesis of 4-Quinolones via a Carbonylative Sonogashira Cross-Coupling
Using Molybdenum Hexacarbonyl as a CO Source
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Linda Åkerbladh†, Patrik Nordeman†, Matyas Wejdemar†, Luke R. Odell†, Mats Larhed§,*
†Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry,
BMC, Uppsala University
§Department of Medicinal Chemistry, Science for Life Laboratory,
BMC, Uppsala University
Boxꢀ574, SEꢀ751 23 Uppsala, Sweden
Fax: (+46) 18 471 44 74
*Corresponding author: Eꢀmail: mats.larhed@orgfarm.uu.se
Keywords: palladium, catalysis, 4-quinolones, molybdenum hexacarbonyl, carbonylation,
microwave
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ABSTRACT
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A palladiumꢀcatalyzed CO gasꢀfree carbonylative Sonogashira/cyclization sequence for the
preparation of functionalized 4ꢀquinolones from 2ꢀiodoanilines and alkynes via two different
protocols is described. The first method (A) yields the cyclized products after only 20 minutes
of microwave (MW) heating at 120 °C. The second method (B) is a gasꢀfree oneꢀpot twoꢀstep
sequence which runs at room temperature allowing the use of sensitive substituents (e.g. nitro
and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid
source of CO.
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INTRODUCTION
4ꢀQuinolones are commonly used in the pharmaceutical chemistry as a versatile scaffold with
a wide range of biological activities e.g. antibacterial,1 antimalarial2 and anticancer.3 As a
result, the synthesis of 4ꢀquinolones has attracted considerable interest and there are several
synthetic procedures available in the literature.4 The most general method for the preparation
of 2ꢀsubstitutedꢀ4ꢀquinolones is the condensation of anilines with βꢀketo esters followed by
cyclization of the formed βꢀarylaminoacrylates. However, the reaction often performs poorly
when using electronꢀdeficient anilines.5,6 Further strategies include the heterocyclization of 2ꢀ
aminochalcone7 and the palladiumꢀcatalyzed carbonylation of Nꢀtosylꢀoꢀiodoanilines with
allenes.8
In addition, the palladium(0)ꢀcatalyzed multicomponent9 carbonylative coupling of terminal
acetylenes (1) with 2ꢀiodoanilines (2) under elevated pressures of carbon monoxide has
previously been described as a method to prepare functionalized 4ꢀquinolones (3)8,10,11
(Scheme 1, reaction aꢀb). This approach was first reported for aryl iodides, which were
carbonylatively coupled to terminal acetylenes using PdC12(PPh3)2 or Pd(dppf)Cl2 in neat
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diethylamine with in situ cyclization of the formed intermediate alkynone to generate 4ꢀ
quinolones (3).10–12 (Scheme 1, reaction a). The methodology was later adapted by Genelot
and coꢀworkers to enable the use of precatalyst, Pd(dppp)Cl2 under milder conditions using a
twoꢀstep procedure providing 3 from 4 after addition of Et2NH (Scheme 1, reaction b13). This
synthetic protocol was applied in the preparation of the key quinolone substructure of the
serine protease inhibitor BILN 2061.14 However, the published carbonylative reactions
require high pressures of CO gas, making them less attractive for labꢀscale medicinal
chemistry.
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Scheme 1. Palladium(0)ꢀcatalyzed carbonylative Sonogashira crossꢀcouplings, cyclizations,
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and the method developed herein.
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Palladium(0)ꢀcatalyzed carbonylation reactions, involving an aryl halide (or pseudohalide),
CO and a nucleophile, are commonly used for the synthesis of a multitude of arylcarbonyl
derivatives (e.g. amides, esters, acids, ketones etc).15–19 However, since many carbonylation
reactions are performed above atmospheric pressure, specialized equipment which can
withstand elevated pressures is often required to enable safe handling. In addition, CO is a
highly toxic and flammable gas, which is invisible, odorless, and tasteless. As a result, the
interest in solid reagents which release CO in a controlled manner has increased in the last
decades.19–31 Mo(CO)6 has been successfully used in several different carbonylative reactions,
e.g. aminocarbonylations,32–36 amidocarbonylations37 and carbonylative crossꢀcouplings.20,38,39
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In addition to this work, a nonꢀgaseous Sonogashira carbonylative coupling providing
alkynones using Mo(CO)6 has been described by Iizuka et al. (Scheme 1, reaction c).20
Nonetheless, one of the potential disadvantages of Mo(CO)6 is its ability to reduce nitro
containing aromatic substrates.40–42 In our group, we recently used a bridged twoꢀchamber
system,43 originally developed by Skrydstrup et al.,22–24 where CO is released from Mo(CO)6
in one of the two compartments. The solid COꢀsource is separated from the reaction mixture
and carbonylation occurs after free diffusion of the gas between the two chambers.43 Using
CO generated from COgen22,24 ex situ in a twoꢀchamber system, Neumann et al. recently
reported a carbonylative Sonogashira for the preparation of alkynones from aryl bromides
with excellent functional group tolerance (Scheme 1, reaction c).44 Despite the advantage with
the twoꢀchamber procedure it nevertheless demands specialized glassware and it is therefore
of practical value to develop carbonylative reactions which can be conducted in a standard
single vial system and tolerate sensitive functional groups.
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In this study, we present two approaches for the preparation of 4ꢀquinolones (3) using nonꢀ
gaseous Mo(CO)6ꢀpromoted carbonylative methods. The first protocol provides the desired
compounds after only 20 minutes of microwave (MW) heating whereas the second procedure
is a oneꢀpot twoꢀstep approach which operates at ambient temperature and tolerates sensitive
functional groups, i.e. nitro groups and bromides. Both methods furnished a diverse set of 4ꢀ
quinolone products in moderate to good yields.
RESULTS AND DISCUSSION
Initially, the feasibility of the carbonylative reaction was evaluated using a model reaction and
microwave heating at 120 °C for 20 minutes in sealed vials. Phenylacetylene (1a, 2 equiv)
and 2ꢀiodoaniline (2a) were treated with various palladium catalysts (10 mol%) in the
presence of base (3 equiv), Mo(CO)6 (2 equiv) with diethylamine (1.5 mL) as the solvent. The
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results of the screening are presented in Table 1. When Pd(dppf)Cl2 was employed using
sodium acetate as the base, the product 3a was obtained in 76% isolated yield (entry 1).
Changing to a triphenylphosphine catalytic system (Pd(OAc)2 and PPh3) only furnished trace
amounts of the product (entry 2). When Pd[(tꢀBu)3P]2 or a phosphineꢀfree ligand system with
Pd2(dba)3 was used, moderate yields were obtained (entries 3ꢀ4, 52% and 41%, respectively).
Upon changing the base to Cs2CO3 with Pd(dppf)Cl2 as the catalytic species, 82% of 3a was
isolated after chromatography (entry 5). DBU was found to be deleterious for the reaction
(entry 6). Finally, when Pd2(dba)3 (5 mol%) was used with an excess (20 mol%) of dppf the
desired product was isolated in 85% yield (entry 7). Mo(CO)6 has been reported to have
catalytic activity in carbonylation reactions.45–47 Therefore, a control reaction without the
addition of a palladium catalyst was performed, but no conversion of aryl iodide was observed
(entry 8).
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Table 1.Optimization of the reaction conditions for the synthesis of 4ꢀquinolone 3a from 1a
and 2a using MW.
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Entry Pd/La
Base
Yield (%)b
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3
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5
6
7
8
Pd(dppf)Cl2
NaOAc 76
NaOAc Trace
NaOAc 52
NaOAc 41
Cs2CO3 82
c
Pd(OAc)2, PPh3
Pd[(tꢀBu)3P]2
Pd2(dba)3
Pd(dppf)Cl2
Pd(dppf)Cl2
DBU
ꢀ
Pd2(dba)3 , dppfc
d
Cs2CO3 85
Cs2CO3
ꢀ
ꢀ
Reaction conditions: 2ꢀIodoaniline 2a (0.5 mmol), phenylacetylene (1 mmol), base (1.5
mmol), Mo(CO)6 (1 mmol), Et2NH, 120 °C, 20 min. a10 mol% of palladium catalyst.
bIsolated yield. c20 mol%. d5 mol%.
Based on the reaction conditions developed, the scope of the microwave heated carbonylative
Method A was investigated next. When the aromatic 1ꢀethynylꢀ4ꢀfluorobenzene (1b) was
reacted with 2a, 4ꢀquinolone 3b was obtained in 70% yield. The chloroꢀsubstituted 2ꢀ
iodoanline (2b) gave products 3c-d in 64ꢀ76% yield. Methyl ester substituted 2ꢀiodoanilines
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(2c and 2d) furnished the 6ꢀ or 7ꢀsubstituted 4ꢀquinolones 3e-g and 3i in 59ꢀ72% yield. In
addition, the aliphatic alkynes, 1ꢀheptyne (1c) and cyclopentylacetylene (1d), performed well
in the reaction and furnished products 3h-j in 67ꢀ76% yield. Moreover, when 3ꢀ
ethynylthiophene (1e) was used 3k and 3l were obtained in 62% and 51% yield, respectively.
In contrast, 2ꢀiodoꢀ4ꢀnitroaniline (2e) gave product 3m in a low yield of 29%. The lower
isolated yield was probably due to the known thermally induced reduction of the nitro group
by Mo(CO)6.41,43
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Table 2. Scope of the Mo(CO)6ꢀmediated reaction of 2ꢀiodoanilines with acetylenes using
MW (Method A).a, b
Pd2(dba)3
dppf
Cs2CO3
O
I
Et2NH
R2
R2
R1
MW 120 °C
20 min
H2N
R1
N
H
1a-e
2a-e
3a-m
O
O
O
O
N
H
N
H
N
H
Cl
F
N
H
Cl
3a, 85%
3b, 70%
3c, 76%
3d, 64%
F
O
O
O
O
OMe
OMe
OMe
N
N
H
N
H
H
O
O
3e, 72%
3f, 59%
3g, 63%
F
F
O
O
O
O
O
OMe
Pent
N
H
Pent
N
H
N
H
N
H
S
3h, 76%
3i, 67%
3j, 74%
3k, 62%
O
O
NO2
N
H
Cl
F
N
H
S
3l, 51%
3m, 29%
aReaction conditions: 1 (1 mmol), 2 (0.5 mmol), 5 mol% Pd2(dba)2, 12 mol% dppf, Mo(CO)6
(1 mmol), Et2NH, 120 °C, 20 min. b Isolated yield.
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To further expand the preparative scope of the reaction, we sought to develop an alternative
method (Method B) that would tolerate the use of reductionꢀprone and other sensitive
moieties. Based on the work by Iizuka et al. (Scheme 1, c)20 we believed that 2ꢀiodoanilines
could also be used in a gasꢀfree Mo(CO)6ꢀmediated procedure at room temperature to yield
the arylalkynone intermediate (4) followed by subsequent cyclization induced by
diethylamine. With the aim to develop Method B to be carried out at room temperature, the
use of a catalyst with stabilizing bidentate dppf was not optimal. Gratifyingly, the desired
product 3m was obtained in 67% when 2e and 1b were stirred in acetonitrile with
triethylamine, Pd(OAc)2, [HP(tꢀBu)3]BF4 and Mo(CO)6 at room temperature for 16 h
followed by the addition of 3.5 equiv of diethylamine. Minor adjustments to the ligand
loading and the amount of diethylamine led to a reliable protocol, which furnished nitro group
containing 3m in 79% isolated yield (Table 3), a considerable increase in yield compared to
when the MWꢀheated protocol was used (29%, see Table 2).
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Table 3.Scope and limitations of the Mo(CO)6ꢀmediated carbonylative twoꢀstep protocol
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(Method B).a,b
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Pd(OAc)2
[HP(t-Bu)3]BF4
Mo(CO)6
Et3N
O
O
I
Et2NH
rt, 5 h
R2
R2
R2
R1
1a-n
R1
MeCN
rt, 16 h
H2N
H2N
R1
N
H
2a-b, 2d-f
4
3
O
O
O
O
N
H
N
H
N
H
Cl
Pent
N
H
F
3a, 84%
3b, 84%
3c, 72%
3h, 50%
O
O
O
O
NO2
NO2
N
H
N
H
N
H
N
H
S
F
3j, 71%
3k, 58%
3m, 79%
3n, 79%
O
O
O
O
O
Br
Me
OMe
N
H
N
H
N
H
N
H
MeO
3o, 68%
3p, 32%d
3q, 75%
3r, 63%
O
O
O
O
N
H
N
H
N
H
N
H
3t, 72%
3u, 38%c
3v, 32%d
Br
Br
N
3s, 82%
O
O
O
O
N
H
N
H
O
N
H
N
H
N
Boc
3w, 47%d
3x, 50%
3y, 80%
3z, 72%
H2N
Me
N
H
N
H
aReaction conditions: i) 1 (1 mmol), 2 (0.5 mmol), 3 mol% Pd(OAc)2, 6 mol% [HP(tꢀ
b
c
Bu)3]BF4, Mo(CO)6, Et3N, MeCN, rt, 16 h. ii) Et2NH, rt, 5 h. Isolated yield. Prepared from
d
trimethylsilyacetylene (1h). The reaction gave full conversion of the limiting reagent but a
problematic purification in combination with low solubility contributed to the low yield.
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Next, we wanted to investigate the scope and limitations of the reaction using various 2ꢀ
iodoanilines (Table 3). In general, the reaction was found to be insensitive towards changes in
the electronic properties of the aniline. The unsubstituted 2ꢀphenylꢀ4ꢀquinolone was obtained
in 84% (3a) which is comparable to the result obtained using method A (85%, see Table 2).
Anilines bearing electronꢀwithdrawing substituents afforded the desired product in 68ꢀ79%
yield (3c, 3m and 3n-o) with the exception of the methyl ester (3p) which was obtained in
32% isolated yield. When compound 3p was produced by Method B, unidentified byproducts
were formed, which were difficult to separate from the product. In addition, the compounds
were poorly soluble in most common organic solvents which gave broad bandwidth on the
silica column. These two factors contributed to the low yield. The electronꢀdonating methyl
substituted aniline also performed well and the product was isolated in 75% (3q). Due to the
mild reaction conditions nitro groups were well tolerated and no reduced byꢀproducts could be
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1
observed by LCꢀMS or HꢀNMR (3m-n; both obtained in 79%). Furthermore, 6ꢀbromoꢀ2ꢀ
phenylquinolinꢀ4(1H)ꢀone (3o) was prepared in 68% yield and no traces of dehalogenated or
other byꢀproducts resulting from palladiumꢀmediated activation of the ArꢀBr bond were
detected (LCꢀMS).
To further evaluate the scope of the reaction we investigated the performance of various
alkyne substrates in the reaction (Table 3). Aliphatic 1ꢀheptyne and cyclopentylacetylene
were transformed into the desired products in moderate to good yields (3h and 3j; 50% and
71% respectively). Electronꢀpoor arylacetylenes performed well in the reaction (3b, 3m, 3s,
3t; 72ꢀ84%) which may be related to the acidity of the acetylenic proton. In contrast, electronꢀ
rich arylacetylenes in general gave slightly lower yields (3r, 3xꢀy; 50ꢀ72%). Although the
yield of aniline 3x is probably related to the formation of unidentified byproducts or
coordination to the metalꢀcatalyst.
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Demonstrating the mild conditions, 1ꢀbromo 4ꢀethynylbenzene (1f) and 1ꢀbromoꢀ2ꢀ
ethynylbenzene (1g) were used to prepare aryl bromide products 3s and 3t in high yields
(82% and 72% respectively). Moreover, the Bocꢀprotected aniline were well tolerated in the
reaction (3z; 72%). The parent compound quinolinꢀ4(1H)ꢀone (3u) could be prepared from
trimethylsilylacetylene (TMSꢀacetylene) (1h) and was isolated after spontaneous deprotection
of the TMS group under the basic reaction conditions in 38% yield. In conjuction, when
TBDMSꢀprotected and free propargyl alcohol were tested as substrates in Method B only
traces of the alkynone intermediate were observed after the initial carbonylative Sonogashira
crossꢀsoupling.Various heterocycles could, however, also be incorporated albeit in low to
moderate yields (3k and 3v-w; 32ꢀ58%).
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These results compare favorably to the pressurized COꢀgas carbonylations in the literature in
which 5 examples of 3 were obtained in yields of 26ꢀ75% (1 example was obtained in 98%
when isolated as a hydrochloride salt).13 Notably, 2ꢀphenylꢀquinolinꢀ4ꢀone (3a) has
previously been obtained in 62% yield,13 however, using our nonꢀgaseous carbonylation
Method B we were able to isolate the same compound in an improved yield of 84% (Table 3).
Several attempts were made to adapt the developed protocol to 2ꢀbromoanilines. However, no
conversion of starting material was observed and the desired product could not be detected
even at elevated temperatures.
Scheme 2. Comparison of the synthesis of 2ꢀquinolones (5) and 4ꢀquinolones (3) from 1 and
2.
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Interestingly, Chen et al. have reported a Mo(CO)6ꢀmediated protocol for the synthesis of 2ꢀ
quinolones (5) from 1 and 2 using similar reaction conditions as in Method A but using a
tertiary amine base (Scheme 2).48 Under those conditions, a mixture of 3ꢀ and 4ꢀsubstituted 2ꢀ
quinolones (5) were obtained following a nonꢀcarbonylative Sonogashira crossꢀcoupling and a
carbonylative cyclization. In contrast, the formation of 2ꢀquinolones was never detected
(confirmed by NMR) using the protocol described herein, not even when Et3N was used in
place of Et2NH. Under our conditions (A and B) we firmly believe that a carbonylative
Sonogashira reaction yields the alkynone (4) which is subsequently cyclized by addition of
diethylamine. This is in accordance with previous studies showing that arylalkynones with
orthoꢀamine or hydroxyl substituents can be cyclized in a 6ꢀendoꢀtrig mode to yield 4ꢀ
quinolones and flavones, respectively, by the addition of secondary amines such as
diethylamine.11,13,49 To confirm that the reaction follows the proposed mechanism, alkynone
4a was also prepared using our Method B in 72% yield, and subsequently cyclized to 3a in
82% isolated yield.
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CONCLUSION
In conclusion, we report two new methods for the CO gasꢀfree carbonylative heteroannulation
using Mo(CO)6 as a convenient solid source of CO. Method A rapidly produces products in
the absence of sensitive functional groups and as a complement, Method B tolerates nitro and
bromide substituents. The developed protocols have a broad scope and quinolones can be
obtained in moderate to good yields from a wide variety of 2ꢀiodoanilines and alkynes,
including electronꢀrich and electronꢀpoor anilines, arylacetylenes, aliphatic alkynes and
heterocyclic alkynes. Despite the use of a oneꢀpot system, we could prepare nitro substituted
quinolones in good yields using Method B. The problem with Mo(CO)6ꢀmediated nitro
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reduction has previously been solved by separating Mo(CO)6 from the reaction mixture in a
twoꢀchamber system.43 However, due to the mild reaction conditions employed in Method B,
nitro substituted quinolones were obtained and no reduced byꢀproducts could be detected.
Finally, several bromo substituted quinolones, suitable for subsequent functionalization, were
prepared in good yields.
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EXPERIMENTAL SECTION
General Information. Analytical thinꢀlayer chromatography (TLC) was performed on silica
gel 60 Fꢀ254 plates and visualized with UV light. Flash column chromatography was
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performed on silica gel 60 (40ꢀ63 µm). H and 13CꢀNMR spectra were recorded at 400 and
101 MHz, respectively. The chemical shifts for 1H NMR and 13C NMR are referenced to TMS
via residual solvent signals (1H, MeOD at 3.31 ppm, CDCl3 at 7.26 ppm and DMSOꢀd6 at
2.50 ppm; 13C, MeOD at 49.0 ppm, CDCl3 at 77.0 ppm and DMSOꢀd6 at 39.5 ppm).
Analytical HPLC/ESIꢀMS was performed using electrospray ionization (ESI) and a C18
column (50x3.0 mm, 2.6 µm particle size, 100 Å pore size) with CH3CN/H2O in 0.05%
aqueous HCOOH as mobile phase at a flow rate of 1.5 ml/min. High resolution molecular
masses (HRMS) were determined on a mass spectrometer equipped with an ESI source and 7ꢀ
T hybrid linear ion trap (LTQ). Compounds 1m50, 1n51, 2g52, 3a53, 3b54, 3c55, 3h56, 3k57, 3n13,
3o6, 3q55, 3r55, 3s54, 3u53, 3v57, 3w57 and 4a13 are known and spectral data were in agreement
with the proposed structures and matched those reported in the literature.
Caution! The closed-vessel carbonylation reactions described in this paper should not be
repeated on a larger scale or at higher temperatures than reported as this could result in an
explosion unless an appropriate pressure relief device is used.
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N-(4-ethynylphenyl)acetamide (1m): The title compound was obtained as a white solid (720
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mg, 90%) according to the literature.50
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tert-Butyl(4-ethynylphenyl)carbamate (1n): The title compound was obtained as a white
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solid (620 mg, 57%) according to the literature.51
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2-Iodo-4-methylaniline (2g): Was prepared according to a published procedure.58 Beige solid
(759 mg, 64%).52
General procedure for the preparation of 4-quinolones using method A. To a 0.5ꢀ2 mL
Smith® microwave vial was added corresponding 2ꢀiodoaniline (0.5 mmol), corresponding
ethylene (1.0 mmol, 2 equiv), tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol),
1,1′ꢀbis(diphenylphosphino)ferrocene (11.2 mg, 0.02 mmol), Mo(CO)6 (132 mg, 0.5 mmol, 1
equiv), cesium carbonate (490 mg, 1.5 mmol, 3 equiv) and 1.5 mL diethylamine. The vial was
purged with nitrogen, capped and irradiated in a Smith Initiator® at 120 ˚C for 20 minutes.
The reaction mixture was poured over water and extracted with chloroform (3 x 15 mL). The
combined organic phases were dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography eluting with CHCl3/MeOH
(100:1ꢀ20:1) to yield the desired products.
General procedure for the preparation of 4-quinolones using method B
A mixture of 2ꢀiodoaniline (0.5 mmol), Pd(OAc)2 (3 mg, 0.01 mmol), triꢀtertꢀ
butylphosphonium tetrafluoroborate (9 mg, 0,03 mmol) and Mo(CO)6 (198 mg, 0.75 mmol) in
a sealed vial was evacuated and backfilled with nitrogen three times. Acetonitrile (2 mL), the
alkyne (1 mmol) and triethylamine (0.14 mL, 1 mmol) were added through the septa by a
syringe. The reaction mixture was stirred at ambient temperature for 16 hours where after all
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starting material had been consumed (LCꢀMS). Diethylamine (0.26 mL, 2.5 mmol) was added
to the reaction mixture and stirring was maintained at rt for 5 h. The reaction mixture was
poured over water and extracted with chloroform (3 x 15 mL). The combined organic phases
were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was
purified by column chromatography eluting with CHCl3/MeOH (100:1ꢀ20:1) to yield the
desired products.
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2-Phenylquinolin-4(1H)-one (3a):53 Prepared from 1a and 2a using Method A or B yielding
3a as a tan powder. Method A (94 mg, 85%); 5 mmol of 2a (957 mg, 87%); Method B: 1
mmol of 2a (185 mg, 84%); IR (MeOH/CHCl3) cmꢀ1 1633.
2-(4-Fluorophenyl)quinolin-4(1H)-one (3b):54 Prepared from 1b and 2a using Method A or
B yielding 3b as a tan powder. Method A (84 mg, 70%) and Method B (106 mg, 84%); 13C
NMR (DMSOꢀd6) δ 176.9, 163.4 (d, J = 248.2 Hz), 149.0, 140.5, 131.9, 130.7 (d, J = 3.1 Hz),
129.9 (d, J = 8.8 Hz), 124.8, 124.7, 123.3, 118.7, 116.0 (d, J = 21.8 Hz), 107.4.
7-Chloro-2-phenylquinolin-4(1H)-one (3c):55 Prepared from 1a and 2b using Method A or
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B yielding 3c as a tan powder. Method A (97 mg, 76%) and Method B (95 mg, 72%); H
NMR (CDCl3/Methanolꢀd4 + 1 drop of conc HCl) δ 8.26ꢀ8.23 (m, 1H), 8.14 (d, J = 8.9 Hz,
1H), 7.81ꢀ7.74 (m, 2H), 7.50ꢀ7.38 (m, 4H), 7.27 (s, 1H); 13C NMR (CDCl3/Methanolꢀd4 + 1
drop of conc HCl) δ 169.8, 156.7, 141.3, 140.5, 132.7, 130.8, 129.4, 128.6, 128.3, 125.3,
119.2, 118.0, 104.2; HRMS (ESI) calcd for C15H11ClNO [M + H]+ m/z 256.0529, found m/z
256.0535; LC purity (254 nm) >99%.
7-Chloro-2-(4-fluorophenyl)quinolin-4(1H)-one (3d): Prepared from 1b and 2b using
Method A yielding 3d as a yellow powder (88 mg, 64%); 1H NMR (DMSOꢀd6) δ 11.70 (br s,
1H), 8.09 (d, J = 8.6 Hz, 1H), 7.96ꢀ7.87 (m, 2H), 7.78 (s, 1H), 7.44 (t, J = 8.8 Hz, 2H), 7.36
(dd, J = 8.6, 1.7 Hz, 1H), 6.37 (s, 1H); Due to low solubility in common organic solvents a
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13CꢀNMR spectrum could not be obtained for 3d. This problem is known in the literature for
quinolones55; HRMS calcd C15H10ClFNO [M + H]+ 274.0435, found 274.0437; LC purity
(254 nm) = 98%.
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Methyl 4-oxo-2-phenyl-1,4-dihydroquinoline-7-carboxylate (3e): Prepared from 1a and 2c
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using Method A yielding 3e as a yellow powder (101 mg, 72%); H NMR (DMSOꢀd6) δ
11.98 (br s, 1H), 8.72 (d, J = 1.8 Hz, 1H), 8.18 (dd, J = 8.7, 2.1 Hz, 1H), 7.85 (d, J = 8.7 Hz,
3H), 7.70ꢀ7.50 (m, 3H), 6.42 (s, 1H), 3.90 (s, 3H); 13C NMR (DMSOꢀd6) δ 176.8, 165.8,
150.8, 143.4, 133.8, 131.6, 130.7, 129.0, 127.5, 127.2, 124.2, 124.1, 119.4, 108.4, 52.2;
HRMS calcd C17H14NO3 [M + H]+ 280.0974, found 280.0971; LC purity (254 nm) = 99%.
Methyl 2-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-6-carboxylate (3f): Prepared from
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1b and 2d using Method A yielding 3f as a yellow powder (87 mg, 59%); H NMR (DMSOꢀ
d6) δ 11.99 (br s, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.17 (dd, J = 8.7, 2.1 Hz, 1H), 7.93 (dd, J =
8.7, 5.4 Hz, 2H), 7.83 (d, J = 8.7 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 6.43 (s, 1H), 3.90 (s, 3H);
Due to low solubility in common organic solvents a 13CꢀNMR spectrum could not be obtained
for 3f. This problem is known in the literature for quinolones55; HRMS calcd C17H13FNO3 [M
+ H]+ 298.0879, found 298.0883; LC purity (254 nm) = 97%.
Methyl 2-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-7-carboxylate (3g): Prepared from
1b and 2c using Method A yielding 3g as a tan powder (93 mg, 63%); 1H NMR (DMSOꢀd6) δ
12.00 (br s, 1H), 8.71 (s, 1H), 8.17 (d, J = 10.8 Hz, 1H), 7.97ꢀ7.88 (m, 2H), 7.83 (d, J = 8.7
Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 6.43 (s, 1H), 3.90 (s, 3H); Due to low solubility in common
organic solvents a 13CꢀNMR spectrum could not be obtained for 3g. This problem is known in
the literature for quinolones55; HRMS calcd C17H13FNO3 [M + H]+ 298.0879, found
298.0883; LC purity (254 nm) = 96%.
2-Pentylquinolin-4(1H)-one (3h):56 Prepared from 1c and 2a using Method A or B yielding
3h as a tan powder. Method A (82 mg, 76%) and Method B (54 mg, 50%).
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Methyl 4-oxo-2-pentyl-1,4-dihydroquinoline-6-carboxylate (3i): Prepared from 1c and 2d
using Method A yielding 3i as a grey powder (92 mg, 67%);1H NMR (DMSOꢀd6) δ 11.74 (br
s, 1H), 8.66 (s, 1H), 8.11 (d, J = 10.7 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 6.00 (s, 1H), 3.88 (s,
3H), 2.65 – 2.53 (m, 2H), 1.74 – 1.61 (m, 2H), 1.37 – 1.28 (m, 4H), 0.88 (t, J = 6.7 Hz, 3H);
13C NMR (DMSOꢀd6) δ 176.7, 165.8, 154.5, 143.1, 131.3, 127.3, 123.9, 123.6, 118.5, 108.7,
52.2, 33.2, 30.7, 27.9, 21.8, 13.9; HRMS calcd C16H20NO3 [M + H]+ 274.1443, found
274.1440; LC purity (254 nm) = 95%.
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2-Cyclopentylquinolin-4(1H)-one (3j): Prepared from 1d and 2a using Method A or
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yielding 3j as a white powder. Method A (79 mg, 74%) and Method B (82 mg, 71%); H
NMR (DMSOꢀd6) δ 11.37 (br s, 1H), 8.08ꢀ8.02 (m, 1H), 7.67ꢀ7.57 (m, 2H), 7.28 (ddd, J =
8.1, 6.2, 1.9 Hz, 1H), 5.98 (d, J = 1.7 Hz, 1H), 3.07ꢀ2.92 (m, 1H), 2.16ꢀ1.97 (m, 2H), 1.90ꢀ
1.60 (m, 6H); 13C NMR (DMSOꢀd6) δ 177.0, 156.7, 140.2, 131.4, 124.69, 124.66, 122.7,
117.9, 105.4, 43.4, 32.0, 24.9; HRMS (ESI) calcd for C14H16NO [M + H]+ m/z 214.1232,
found m/z 214.1229; LC purity (254 nm) >99%.
2-(Thiophen-3-yl)quinolin-4(1H)-one (3k):57 Prepared from 1e and 2a using Method A or B
yielding 3k as an offꢀwhite powder. Method A (70 mg, 62%) and Method B (67 mg, 58%).
7-Chloro-2-(thiophen-3-yl)quinolin-4(1H)-one (3l): Prepared from 1e and 2b using Method
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A yielding 3l as a brown powder (67 mg, 51%); H NMR (DMSOꢀd6) δ 11.55 (br s, 1H),
8.41ꢀ8.27 (m, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 4.3 Hz, 2H), 7.70 (d, J = 5.1 Hz, 1H),
7.34 (dd, J = 8.6, 1.8 Hz, 1H), 6.51 (s, 1H); 13C NMR (DMSOꢀd6) δ 176.5, 173.6, 145.1,
141.1, 136.3, 135.0, 128.2, 127.0, 126.6, 126.3, 123.5, 117.7, 107.0; HRMS calcd
C13H9ClNOS [M + H]+ 262.0093, found 262.0096; LC purity (254 nm) = 99%.
2-(4-Fluorophenyl)-6-nitroquinolin-4(1H)-one (3m): Prepared from 1b and 2e using
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Method B. Yellow powder (519 mg, 79%); H NMR (DMSOꢀd6) δ 8.49 (d, J = 2.7 Hz, 1H),
7.96 (dd, J = 9.2, 2.7 Hz, 1H), 7.69 (s, 1H), 7.35ꢀ7.15 (m, 4H), 6.71 (d, J = 9.2 Hz, 1H), 5.81
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(s, 1H); 13C NMR (DMSOꢀd6) δ 187.4, 161.9 (d, J = 244.4 Hz), 161.8, 155.3, 134.6, 133.1 (d,
J = 3.5 Hz), 130.1 (d, J = 8.3 Hz), 126.9, 126.7, 120.0, 115.9, 115.1 (d, J = 21.6 Hz), 93.8;
HRMS (ESI) calcd for C15H10FN2O3 [M + H]+ m/z 285.0675, found m/z 285.0670; LC purity
(254 nm) = 96%.
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6-Nitro-2-phenylquinolin-4(1H)-one (3n):13 Prepared from 1a and 2e using Method B.
Yellow powder (208 mg, 79%); IR (MeOH/CHCl3) cmꢀ1 3019, 1616, 1512, 1319.
6-Bromo-2-phenylquinolin-4(1H)-one (3o):6 Prepared from 1a and 2f using Method B.
Yellow powder (100 mg, 68%); 13C NMR (CDCl3/Methanolꢀd4 + 1 drop of conc HCl) δ
168.8, 156.2, 138.7, 137.9, 132.7, 130.8, 129.5, 128.4, 126.0, 121.8, 121.6, 120.8, 104.6.
Methyl 4-oxo-2-phenyl-1,4-dihydroquinoline-6-carboxylate (3p): Prepared from 1a and 2d
using Method B. Offꢀwhite powder (46 mg, 32%); 1H NMR (DMSOꢀd6) δ 8.76 (d, J = 2.0 Hz,
1H), 8.19 (dd, J = 8.7, 2.1 Hz, 1H), 7.91ꢀ7.81 (m, 3H), 7.65ꢀ7.56 (m, 3H), 6.44 (s, 1H), 3.94
(s, 3H); Due to low solubility in common organic solvents a 13CꢀNMR spectrum could not be
obtained for 3p. This problem is known in the literature for quinolones55; HRMS (ESI) calcd
for C17H14NO3 [M + H]+ m/z 280.0974, found m/z 280.0968; LC Purity (254 nm) >95%.
6-Methyl-2-phenylquinolin-4(1H)-one (3q):55 Prepared from 1a and 2g using Method B.
Offꢀwhite solid (91 mg, 75%).
2-(4-Methoxyphenyl)quinolin-4(1H)-one (3r):55 Prepared from 1i and 2a using Method B.
Beige solid (83 mg, 63%).
2-(4-Bromophenyl)quinolin-4(1H)-one (3s):54 Prepared from 1f and 2a using Method B.
Tan powder (124 mg, 82%); 13C NMR (DMSOꢀd6) δ 176.9, 148.8, 140.5, 133.3, 131.92,
131.90, 129.5, 124.9, 124.7, 124.0, 123.3, 118.7, 107.4.
2-(2-Bromophenyl)quinolin-4(1H)-one (3t): Prepared from 1g and 2a using Method B.
Dark red solid (111 mg, 72%);1H NMR (DMSOꢀd6) δ 7.70ꢀ7.61 (m, 2H), 7.41 (td, J = 7.5, 1.2
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Hz, 1H), 7.31 (ddd, J = 8.0, 7.4, 1.8 Hz, 1H), 7.23 (dd, J = 7.5, 1.7 Hz, 1H), 7.08 (ddd, J =
8.4, 7.1, 1.5 Hz, 1H), 6.61 (dd, J = 8.3, 1.2 Hz, 1H), 6.51 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 6.42
(br s, 1H), 5.87 (s, 1H); 13C NMR (DMSOꢀd6) δ 188.4, 158.4, 149.8, 138.3, 132.0, 131.3,
129.7, 129.44, 129.38, 127.4, 121.9, 121.7, 116.3, 114.4, 93.2; HRMS (ESI) calcd for
C15H11BrNO [M + H]+ 300.0024 m/z, found 300.0027 m/z; LC purity (254 nm) >99%.
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Quinolin-4(1H)-one (3u):53 Prepared from 1h and 2a using Method B. Yellow powder (28
mg, 38%).
2-(Pyridin-3-yl)quinolin-4(1H)-one (3v):57 Prepared from 1j and 2a using Method B. Tan
powder (33 mg, 32%).
2-(Pyridin-2-yl)quinolin-4(1H)-one (3w):57 Prepared from 1k and 2a using Method B. Tan
powder (51 mg, 47%).
2-(4-Aminophenyl)quinoline-4(1H)-one (3x): Prepared from 1l and 2a using Method B. The
reaction mixture was poured into saturated NaHCO3 and extracted with 3 x 25 mL EtOAc.
The combined organic phases were extracted with 3 x 25 mL 1 M HCl (aq). The combined
aqueous phases were made basic with 6 M NaOH (aq). After cooling the formed precipitate
was collected by filtration and washed with MeCN. The precipitate was dissolved in
chloroform and methanol and heated with activated charcoal to remove any residual
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molybdenum residues yielding 3x as a yellow solid (61 mg, 50%); H NMR (DMSOꢀd6) δ
11.43 (br s, 1H), 8.08 (dd, J = 8.1, 1.5 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.69ꢀ7.56 (m, 3H),
7.31 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 6.76ꢀ 6.69 (m, 2H), 6.29 (s, 1H); 13C NMR (DMSOꢀd6) δ
176.4, 151.3, 150.6, 140.5, 131.4, 128.3, 124.5 (two overlapping signals found by HMBC),
122.9, 120.1, 118.5, 113.6, 104.8; IR (DMSO) cm−1 3428 (broad signal), 1629; HRMS (ESI)
calcd for C15H13N2O [M + H]+ 237.1028 m/z, found 237.1038 m/z; LC purity (254 nm) >99%.
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N-(4-(4-oxo-1,4-dihydroquinolin-2-yl)phenyl)acetamide (3y): Prepared from 1m and 2a
using Method B yielding 3y as a beige solid (107 mg, 80%); 1H NMR (DMSOꢀd6) δ 11.61 (br
s, 1H), 10.24 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 15.9 Hz, 5H), 7.68 (ddd, J = 8.4,
6.9, 1.6 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 6.34 (d, J = 1.8 Hz, 1H), 2.12 (s, 3H); 13C NMR
(DMSOꢀd6) δ 176.9, 168.7, 149.5, 141.3, 140.5, 131.7, 128.3, 127.9, 124.8, 124.7, 123.1,
118.9, 118.6, 106.6, 24.1; HRMS (ESI) calcd for C17H15N2O2 [M + H]+ 279.1134 m/z, found
279.1143 m/z; LC purity (254 nm) >99%.
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tert-Butyl (4-(4-oxo-1,4-dihydroquinolin-2-yl)phenyl)carbamate (3z): Prepared from 1n
1
and 2a using Method B yielding 3z as a white solid (120 mg, 72%); H NMR (DMSOꢀd6) δ
11.57 (br s, 1H), 9.70 (s, 1H), 8.10 (dd, J = 8.1, 1.5 Hz, 1H), 7.82ꢀ7.75 (m, 3H), 7.71ꢀ7.64 (m,
3H), 7.33 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 6.33 (d, J = 1.8 Hz, 1H), 1.52 (s, 9H); 13C NMR
(DMSOꢀd6) δ 176.8, 152.6, 149.6, 141.7, 140.5, 131.6, 127.9, 127.3, 124.8, 124.7, 123.1,
118.6, 117.9, 106.5, 79.5, 28.1; IR (MeOH/CHCl3) cmꢀ1 3268, 3019, 2943, 1720, 1633, 1216,
1158; HRMS (ESI) calcd for C20H21N2O3 [M + H]+ 337.1552 m/z, found 337.1566 m/z; LC
purity (254 nm) >99%.
1-(2-Aminophenyl)-3-phenylprop-2-yn-1-one (4a):13 A mixture of 2a (110 mg, 0.50 mmol),
Pd(OAc)2 (4.2 mg, 0.02 mmol), triꢀtertꢀbutylphosphonium tetrafluoroborate (9.6 mg, 0.03
mmol) and Mo(CO)6 (204 mg, 0.77 mmol) in a sealed vial was evacuated and backfilled with
nitrogen three times. Acetonitrile (2 mL), 1a (0.11 mL, 1.0 mmol) and triethylamine (0.14
mL, 1.0 mmol) were added through the septa by a syringe. The reaction mixture was stirred at
ambient temperature for 20 hours where after all starting material had been consumed (TLC).
The reaction mixture was poured over water and extracted with chloroform (3 x 15 mL). The
combined organic phases were dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by column chromatography eluting with CH2Cl2 to yield
4a as an orange solid (80 mg, 72%).
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Cyclization of 4a: Diethylamine (80 µL, 0.77 mmol) was added to a solution of 4a (34 mg,
0.15 mmol) in acetonitrile (2 mL) and stirred at rt for 22 h. The reaction mixture was filtered
over activated charcoal and concentrated under reduced pressure to yield 3a (28 mg, 82%).
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ASSOCIATED CONTENT
Supporting Information
1H and 13C NMR spectra and chromatograms of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: mats.larhed@orgfarm.uu.se
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The research was supported by Uppsala University. We wish to thank Mounir Andaloussi for
valuable discussions.
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