Gold-catalyzed conversion of aryl- and alkyl-substituted 1-(o-aminophenyl)-2-propyn-1-ones to the corresponding 2-substituted 4-quinolones

Article abstract of DOI:10.1002/ejoc.201402224

Gold-catalyzed cyclization of alkyl- or aryl-substituted 1-(o-aminophenyl)-2-propyn-1-ones to the corresponding 2-substituted 4-quinolones was studied with various gold salts and complexes. Screening of the different catalysts showed highest performance w

Full text of DOI:10.1002/ejoc.201402224

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FULL PAPER
DOI: 10.1002/ejoc.201402224
Gold-Catalyzed Conversion of Aryl- and Alkyl-Substituted 1-(o-Aminophenyl)-
2-propyn-1-ones to the Corresponding 2-Substituted 4-Quinolones
Otto Seppänen,[a] Mikko Muuronen,[a] and Juho Helaja*[a]
Keywords: Synthetic methods / Homogeneous catalysis / Hydroamination / Gold / Density functional calculations
Gold-catalyzed cyclization of alkyl- or aryl-substituted 1-(o-
aminophenyl)-2-propyn-1-ones to the corresponding 2-sub-
tive to classic quinolone synthesis that requires harsh cy-
clocondensation conditions, the current method offers a mild
stituted 4-quinolones was studied with various gold salts and and atom-economic alternative. Mechanistically, DFT studies
complexes. Screening of the different catalysts showed high-
est performance with cationic AuI species. In particular
PPh3AuNTf2 complex was the most efficient catalyst. Rela-
at TPSS-D3/def2-TZVP level suggest that gold operates in
an alkynophilic manner rather than through conjugative
carbonyl activation.
the cycloisomerization of aminoalkynes to form tetra-
hydropyridines by NaAuCl4 catalysis.[17] Since then many
N-heterocycles with various ring sizes and degrees of satu-
ration have been prepared through intramolecular hydro-
amination upon development of new gold catalytic meth-
ods.[18]
Introduction
Nitrogen-containing heterocycles are recurrent structural
motifs in bioactive molecules.[1] Amongst the numerous
scaffolds, 4-quinolone is featured in many commonly used
antibiotics such as fluoroquinolones,[2] with proven effects
as antimalarial,[3] anticancer,[4,5] antiviral[6] and antidia-
betic[7] agents.
Various synthetic routes towards 4-quinolones have been
developed[8] and approaches based on cyclocondensation,
such as the Niementowski,[9] Conrad–Limpach[10] and
Camps cyclizations,[11] are widely employed. The major
shortcoming in these methods is the required harsh reaction
conditions, which rely on the use of high temperatures and/
or strong bases that dramatically limit the scope of these
reactions. Hence, new methodologies based on milder reac-
tion conditions are actively sought. Recent developments in
transition-metal catalysis have opened a few viable routes
mediated by Cu and Pd species.[11,12] The role of the transi-
tion metal is generally to activate an aryl–halide bond to
promote the coupling of the aryl carbon with either a carb-
onyl carbon or an amine.[13,14]
In connection with our previous reports on the cycliza-
tion reaction of 2-alkynylanilines to indoles by homogen-
eous cationic AuIII catalysis[19] and heterogeneous Au/C ca-
talysis,[20] we envisaged that a similar Au-catalyzed ap-
proach could be applied to the synthesis of 4-quinolones by
using 2-acetylic ketones of anilines as precursors
(Scheme 1). Further support to our hypothesis is provided
by some recent reports on hydroamination reactions cata-
lyzed by gold species. In particular, Gong at al. have devel-
oped a direct conversion of o-(2-propynyl)anilines into
tetrahydroquinolines catalyzed by both AuI and AuIII cata-
lysts,[21] whereas Gouault et al. recently used AuI salts in
the hydroamination step for the cyclization of asymmetric
N-tert-butoxycarbonyl (Boc) β-aminoynones into chiral N-
Boc-substituted pyridones.[22] Herein we report the catalytic
activity of several gold derivatives towards the synthesis of
2-substituted 4-quinolones (Scheme 1). Conditions, optimi-
zation and scope of the reaction are thoroughly explored,
together with computational evidence on the direct alkyne
activation by the gold species during the catalytic cycle.
During the last decade, gold catalysis has shown its su-
premacy in activations of unsaturated C–C bonds towards
various nucleophiles.[15] One valuable invention has been
the syntheses of nitrogen heterocycles through gold-cata-
lyzed hydroamination of internal alkynes, allenes and alk-
enes with primary and secondary amines as expedient nu-
cleophiles.[16] Pioneering work in this area was reported by
Utimoto and co-workers, who successfully accomplished
[a] Department of Chemistry, University of Helsinki,
A. I. Virtasen aukio 1, P. O. Box 55, 00014 University of
Helsinki, Finland
E-mail: juho.helaja@helsinki.fi
http://www.helsinki.fi/kemia/orgaaninen/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402224.
Scheme 1. Envisaged gold-catalyzed synthesis of 2-substituted 4-
quinolones.
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FULL PAPER
gave fair yields in CH2Cl2 and MeCN after 24 h at room
temp., whereas the reaction progressed to 40% conversion
within 5 h at room temp. (Table 1, Entries 13 and 14). A
increase in temperature to 60 °C increased the yield to 66%
in MeCN (Table 1, Entry 15). The corresponding phos-
phine complex, PPh3AuNTf2, was the best-performing cata-
lyst. However, its catalytic activity was poor in CH2Cl2
(Table 1, Entry 16). The change of solvent to MeCN dra-
matically improved the yield to 80% and 96%, after 8 and
24 h, respectively, when reactions were performed at room
temperature (Table 1, Entries 17 and 18).
The observed performance differences of the phosphine
and NHC carbene ligand in cationic AuI catalysts in
CH2Cl2 and MeCN can be rationalized in view of recent
work by Hammond, Xu and co-workers, that showed envi-
ronmental effects, such as solvent, critically affect AuI dis-
proportionation and consequently catalytic activity.[25] Al-
though catalyst stability is enhanced in the presence of σ-
donors, such as MeCN, catalytic activity diminishes. In our
systems this likely explains the slow but steady catalysis by
AuI with phosphine ligands in MeCN. In contrast, catalyst
decomposition becomes a limiting factor for experiments
performed in CH2Cl2.
Results and Discussion
Initial screening of the catalysts was carried out on
model phenyl-substituted 2-alkynylaniline 1a (Table 1).
Both the Au catalyst supported on carbon (see the Exp.
Sect.) and the homogeneous auric acid catalysis in ethanol
turned out to be inactive even at high temperatures
(Table 1, Entries 1, 2 and 3). A change of solvent to MeCN
gave slight conversion to product 2a at room temp. (Table 1,
Entry 4), but did not improve at elevated temperatures
(Table 1, Entry 5). By mimicking Arcadi indole synthesis
conditions,[23] (AuIII-catalyzed annulation of 2-alkynylanil-
ines) gave a better result with KAuCl4, which was inactive
in EtOH at room temp., but provided some conversion
when heated at 70 °C (Table 1, Entries 6 and 7), with iso-
lated yields reaching 61%. Correspondingly, no yield or
only poor outcomes were obtained when the reaction was
performed in MeCN at room temp. or 70 °C, respectively
(Table 1, Entries 8–9).
Table 1. Screening of catalyst and reaction conditions with precur-
sor 1a.[a]
With the optimized conditions in hand, we investigated
the scope of the reaction by varying the alkyne substituent.
Various substrates were prepared according to the synthetic
routes described in Scheme 2, and results for the 4-quino-
lone synthesis are presented in Table 2. 2-Aryl-4-quin-
olones including both electron-withdrawing and donating
substituents could be isolated with excellent yields (Table 2,
Entries 1–4). Similarly, straight chain alkyl substitution
gave high yields (Table 2, Entry 5). To our disappointment
cyclization did not take place at all with a simple TMS-
protected substrate (Table 2, Entry 6), whereas the unpro-
tected derivative underwent oligomerization to tar even in
the absence of catalyst.
Entry Catalyst
Catalyst Solvent
loading
[mol-%]
T
Isolated
yield
[%]
[°C]
1
2
3
4
5
6
Au/C
10
10
10
5
10
10
10
10
10
5
5
5
5
5
toluene
EtOH
EtOH
MeCN
MeCN
EtOH
90
r.t.
70
r.t.
70
r.t.
70
r.t.
70
r.t.
r.t.
90
r.t.
r.t.
60
r.t.
r.t.
r.t.
–
–
–
7
–
–
61
–
5
2
HAuCl4·3H2O
HAuCl4·3H2O
HAuCl4·3H2O
HAuCl4·3H2O
KAuCl4
7
8
KAuCl4
KAuCl4
EtOH
MeCN
MeCN
MeCN
CH2Cl2
toluene
CH2Cl2
MeCN
MeCN
CH2Cl2
MeCN
MeCN
9
KAuCl4
PtCl2
PtCl2
PtCl2
IMes-AuNTf2
IMes-AuNTf2
IMes-AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
10
11
12
13[b]
14
15
16
17[c]
18
3
17
40
51
66
20
80
96
[d]
8
5
5
5
[a] The concentration in reactions was 0.1 m and reaction time was
24 h. [b] Reaction time 5 h. [c] Reaction time 8 h. [d] IMes = 1,3-
bis(2,4,6-trimethylphenyl)imidazol-2-ylidene.
In the wake of the reported analogy to gold catalysts,
platinum-based π-acid catalysts have been applied in vari-
ous alkyne activations for nucleophiles.[24] We tested plati-
num(II) dichloride salt and although mildly active, yields
remained poor even after prolonged heating at 90 °C
(Table 1, Entries 10–12).
When cationic AuI complexes were employed, a signifi-
cant increase in overall performance was observed. The Au
N-heterocyclic carbene (NHC) complex, IMes-AuNTf2, Scheme 2. Synthetic pathways towards substrates 1a–1k and 3.
2
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Gold-Catalyzed Synthesis of 2-Substituted 4-Quinolones
Table 2. Gold-catalysed synthesis of 2-substituted 4-quinolones.[a]
[a] The concentration of reactions was 0.1 m.
Studies of various aliphatic branched-chain ethers re- at best with 15 mol-% auric acid loading in EtOH at 70 °C
vealed that oxygen and bulkiness in the vicinity of the alk- with 68% isolated yield. This is somewhat surprising given
yne result in lower yields (Table 2, Entries 7–11). Benzyl that direct use of Boc-free starting material under the same
ether at the α-position gives 33% isolated yield, whereas the reaction conditions did not lead to any conversion (Table 1,
yield is almost doubled (58%) for the corresponding ether Entry 3). We propose that the activity of auric acid origi-
at the β-position (Table 2, Entries 7 and 8). Branching at nates from the combination of two actions: it catalyzes Boc
the alkyne α-carbon leads to poor yields; for benzyl ether removal, and the Boc moiety chelates the ligand-free gold
combined with a butyl chain the yield is 42%, whereas it prior to its cleavage. These possibilities will be studied in
decreases to 26% for tert-butyl ether combined with methyl our future work.
substitution. A further decrease in yield (19%) is found
with a combination of dimethyl and benzyl ether substitu- mechanism, we performed DFT calculations at TPSS-D3/
tion (Table 2, Entry 11). def2-TZVP level with COSMO solvation model for aceto-
To provide some theoretical insights into the reaction
For analysis of N-Boc-protected aliphatic amines used by nitrile.[26] Important scalar relativistic effects for gold were
Gouault et al., we also decided to run catalytic tests with taken into account by using a small-core ECP from the
N-Boc-functionalized 3 as a substrate (see Supporting In- same basis set.[27,28] Structures related to either Au coordi-
formation, Table S1). The course of the reaction was quite nation or alkyne activation and leading to cyclization were
unexpected. The cationic catalysts showed no or poor ac- also taken into account. At first, we studied different coor-
tivity, whereas conversion to Boc-free product 2a took place dination modes between gold and the functional groups of
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substrate 1a, i.e. amine, carbonyl and alkyne (Figure 1). The conjugated addition reaction pathways, i.e. activation of the
respective computations were done for three different Au alkyne through carbonyl coordination (2-[Au]), was studied
species: AuCl3, dimethylimidazole-coordinated (NHC) and with PMe3-liganded Au complex and proved to be unlikely
PMe3-coordinated cationic AuI. Ground-state coordination because the activation energy barrier was remarkably high
energies were also calculated by using PPh3 as ligand. The (30.3 kcal/mol relative to 1-[Au]).
energy gap between amine- and alkyne-coordinated struc-
Close inspection of the transition-state structures in Fig-
tures (1-[Au] and 3-[Au]) justify the approximation of PMe3 ure 3 reveals that the bond forming C–N distance is dis-
as a model system.[29]
tinctly longer for the AuCl3 complex (2.77 Å) than that for
the cationic species (ca. 2.4 Å). One could expect that the
long bond-forming distance, together with a low-energy cy-
clization barrier after the alkyne coordination step would
Figure 1. Different coordination modes of gold catalyst to substrate
1a.
Figure 2 shows that cationic Au species have quite similar
energy profiles, i.e. NHC- and PMe3-coordinated gold com-
plexes, whereas AuCl3 displays some different features.
Overall, amine-gold coordination was found to be the pre-
ferred binding mode between the studied substrates and Au
species. Notably, binding between the amine and AuCl3 is
more exothermic relative to alkyne coordination. For the
cationic Au species, the coordination on the carbonyl is
slightly more endothermic, ca. 1 kcal/mol, whereas the Au–
alkyne bonding lies at 2.8 and 4.2 kcal/mol higher energy
level, respectively. For these species direct alkyne activation
for cyclization has similar energy barriers being ca. 13 kcal/
mol. In addition to the highly exothermic amine binding
of AuCl3 species its transition state for cyclization through
alkyne coordination is only 6.6 kcal/mol higher than the co-
ordination itself. Notably, the energy of related cyclized in-
Figure 3. TPSS-D3/def2-TZVP optimised transition states TS3–4-
termediate 4-[Au] is drops by –14.5 kcal/mol. Alternative [Au].
Figure 2. Reaction profile for the cyclisation reaction of 1a including different Au complexes according to TPSS-D3/def2-TZVP computa-
tions in MeCN.
4
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Gold-Catalyzed Synthesis of 2-Substituted 4-Quinolones
1.5 Hz, 1 H), 7.62–7.55 (m, 3 H), 7.38–7.30 (m, 1 H), 6.36 (s, 1
H) ppm. 13C NMR (75 MHz, DMSO): δ = 176.94, 150.10, 134.29,
131.76, 130.41, 128.98, 127.40, 124.80, 124.68, 123.28, 118.79,
107.27 ppm. HRMS (EI+): calcd. for [C15H11NO]+ m/z 221.0841;
found 221.0839.
result in facile reactivity for AuCl3 catalysis. Yet, experimen-
tally its performance was rather poor relative to cationic
AuI complexes. This cannot be fully explained by the
slightly higher global energy barrier of AuCl3, (ca. 2.0 kcal/
mol), than that of the cationic complexes. Single-point ener-
gies computed at PW6B95-D3/def2-TZVPP level on TPSS-
D3 geometries showed similar behavior (see Supporting In-
formation).[30] We presume that the reason behind the poor
experimental performance of AuIII lies in the catalyst de-
composition over the course of the reaction as suggested by
the observed gold mirrors in the catalytic experiments. The
tighter amine–AuCl3 coordination might lead to inhibition
and also some decomposition through a redox mechanism
of the gold catalyst.
2-(4-Methylphenyl)quinolin-4(1H)-one (2b): The general procedure
afforded 30.6 mg (96%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.64 (s, 1 H), 8.10 (dd, J = 8.1, 1.3 Hz,
1 H), 7.81–7.71 (m, 1 H), 7.66 (ddd, J = 8.4, 6.9, 1.5 Hz, 1 H), 7.39
(d, J = 7.9 Hz, 1 H), 7.33 (ddd, J = 8.0, 7.0, 1.1 Hz, 1 H), 6.32 (s,
1 H), 2.40 (s, 3 H) ppm. 13C NMR (75 MHz, DMSO): δ = 176.92,
149.90, 140.50, 140.33, 131.71, 131.27, 129.53, 127.21, 124.85,
124.69, 123.15, 118.66, 106.91, 20.88 ppm. HRMS (EI+): calcd. for
[C16H13NO]+ m/z 235.0997; found 235.0995.
2-(4-Methoxyphenyl)quinolin-4(1H)-one (2c): The general pro-
cedure afforded 31.6 mg (95%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.58 (s, 1 H), 8.09 (dd, J = 8.0, 1.0 Hz,
1 H), 7.86–7.73 (m, 3 H), 7.70–7.61 (m, 1 H), 7.32 (t, J = 7.1 Hz,
1 H), 7.13 (d, J = 8.8 Hz, 2 H), 6.30 (s, 1 H), 3.85 (s, 3 H) ppm.
13C NMR (75 MHz, DMSO): δ = 176.84, 161.03, 149.65, 140.48,
131.63, 128.82, 126.22, 124.78, 124.67, 123.07, 118.58, 114.38,
106.49, 55.43 ppm. HRMS (EI+): calcd. for [C16H13NO2]+ m/z
251.0946; found 251.0955.
Conclusions
We have developed a gold-catalyzed route to the synthe-
sis of 2-substituted 4-quinolones from aryl- and alkyl-sub-
stituted aniline-2-propynones. The reaction takes place with
a cationic AuI catalyst at ambient temperature and products
can be isolated with high yields. DFT analysis suggests that
the cyclization step in the reaction proceeds through direct
gold activation of the alkyne rather than through conjuga-
tion of the carbonyl group. Our experimental and computa-
tional results are in agreement on the major role of the de-
activation of the catalyst during the reaction, which ex-
plains the observed sluggish catalytic performance of
AuCl3.
2-(4-Fluorophenyl)quinolin-4(1H)-one (2d): The general procedure
afforded 24.8 mg (88%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.72 (s, 1 H), 8.10 (d, J = 8.0 Hz, 1 H),
7.91 (dd, J = 7.7, 5.9 Hz, 2 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.67 (t,
J = 7.6 Hz, 1 H), 7.42 (t, J = 8.7 Hz, 2 H), 7.34 (t, J = 7.4 Hz, 1
H), 6.35 (s, 1 H) ppm. 13C NMR (75 MHz, DMSO): δ = 164.99,
161.70, 149.11, 140.58, 131.75, 130.78, 129.89, 129.77, 128.64,
124.63, 123.29, 118.85, 116.07, 115.78, 107.24 ppm. HRMS (EI+):
calcd. for [C15H10FNO]+ m/z 239.0746; found 239.0737.
2-Propylquinolin-4(1H)-one (2e): The general procedure afforded
24.8 mg (89%) of the desired product. 1H NMR (300 MHz,
DMSO): δ = 11.49 (s, 1 H), 11.49 (s, 1 H), 8.05 (dd, J = 8.1, 1.3 Hz,
1 H), 8.05 (dd, J = 8.1, 1.3 Hz, 1 H), 7.60 (ddd, J = 8.2, 6.8, 1.4 Hz,
1 H), 7.60 (ddd, J = 8.2, 6.8, 1.4 Hz, 1 H), 7.53 (dd, J = 7.7, 0.5 Hz,
1 H), 7.53 (dd, J = 7.7, 0.5 Hz, 1 H), 7.30–7.23 (m, 1 H), 7.31–7.23
(m, 1 H), 5.93 (s, 1 H), 2.59–2.53 (m, 2 H), 1.84–1.55 (m, 2 H),
0.93 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, DMSO): δ =
176.80, 153.31, 140.15, 131.39, 124.73, 124.60, 122.68, 117.86,
107.67, 35.13, 21.65, 13.37 ppm. HRMS (EI+): calcd. for
[C12H13NO]+ m/z 187.0997; found 187.0999.
Experimental Section
General Remarks: Unless otherwise specified, all commercial mate-
rials were used as received without further purification. Dry tetra-
hydrofuran (THF) was taken directly from VAC Solvent Purifier.
Reactions that involved the use of air- and moisture-sensitive mate-
rials were carried out in an atmosphere of dry argon by using
Schlenk techniques. PPh3AuNTf2 was purchased from Sigma–Ald-
1
rich. H and 13C{1H} NMR spectra were recorded with a Varian
Mercury 300. 1H spectra were referenced to tetramethylsilane
(TMS, 0.0 ppm) or to dimethyl sulfoxide (DMSO; δ =2.50 ppm)
and are reported as follows: chemical shift, multiplicity (s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet). Chemical shifts
of the 13C{1H} NMR spectra were measured relative to CDCl3 (δ
= 77.16 ppm) or to DMSO (δ = 39.52 ppm). HRMS data was ac-
quired with a JEOL JMS-700 instrument in EI ionization mode.
Column chromatographic purifications were performed with
Merck Silica gel 60 (230–400 mesh). Thin layer chromatography
was performed with TLC Silica gel 60 F256 plates.
2-[(Benzyloxy)methyl]quinolin-4(1H)-one (2g): The general pro-
cedure afforded 11.2 mg (33%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.65 (s, 1 H), 8.07 (d, J = 8.1 Hz, 1 H),
7.63 (d, J = 3.6 Hz, 2 H), 7.34 (dd, J = 28.1, 8.7 Hz, 6 H), 6.10 (s,
1 H), 4.61 (s, 2 H), 4.54 (s, 2 H) ppm. 13C NMR (75 MHz, DMSO):
δ = 176.97, 149.13, 140.15, 137.64, 131.68, 128.31, 127.72, 125.01,
124.79, 122.95, 118.25, 107.14, 71.94, 68.32 ppm. HRMS (EI+):
calcd. for [C17H15NO2]+ m/z 265.1103; found 265.1113.
General Procedure for Gold-Catalyzed Cyclization Reactions Lead-
ing to 2a–2k: Compound 6 (0.06–0.13 mmol) was dissolved in
MeCN (c = 0.1 m). PPh3AuNTf2 (5 mol-%) was added and the mix-
ture was mixed at room temperature for 24 h. The solvent was
evaporated and the product was purified by flash chromatography
with CH2Cl2 and methanol (20:1) as eluent.
2-[(Benzyloxy)ethyl]quinolin-4(1H)-one (2h): The general procedure
afforded 11.7 mg (58%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 10.36 (s, 1 H), 7.59 (dd, J = 13.4, 10.3 Hz,
2 H), 7.41–7.22 (m, 9 H), 7.03 (t, J = 7.3 Hz, 2 H), 6.93 (d, J =
7.8 Hz, 1 H), 6.31 (s, 1 H), 4.50 (s, 3 H), 3.54 (t, J = 6.4 Hz, 3 H),
2.59 (td, J = 6.4, 1.9 Hz, 3 H) ppm. 13C NMR (75 MHz, DMSO):
δ = 150.62, 138.22, 135.68, 129.45, 128.21, 127.40, 124.57, 122.63,
119.52, 114.10, 87.12, 76.12, 71.69, 67.90, 67.37, 19.46 ppm.
HRMS (EI+): calcd. for [C18H17NO2]+ m/z 279.1259; found
279.1258.
2-Phenyl-quinolin-4(1H)-one (2a): The general procedure afforded
26.1 mg (96%) of the desired product. 1H NMR (300 MHz,
DMSO): δ = 11.73 (s, 1 H), 8.12 (dd, J = 8.1, 1.3 Hz, 1 H), 7.88–
7.81 (m, 2 H), 7.78 (d, J = 8.2 Hz, 1 H), 7.67 (ddd, J = 8.4, 7.0,
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2-[1-(Benzyloxy)pentyl]quinolin-4(1H)-one (2i): The general pro-
cedure afforded 8.1 mg (42%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.54 (s, 1 H), 8.06 (d, J = 7.3 Hz, 1 H),
7.70 (d, J = 8.2 Hz, 1 H), 7.66–7.59 (m, 1 H), 7.59–7.47 (m, 2 H),
1.13 mL, 1.13 mmol) was added dropwise to the solution. The mix-
ture was mixed at room temperature for 30 min. Compound 5
(100.0 mg, 0.45 mmol) was dissolved in dry THF (4 mL) and added
dropwise to the flask. The mixture was mixed at room temperature
7.38–7.26 (m, 7 H), 6.08 (s, 1 H), 4.52 (d, J = 11.9 Hz, 1 H), 4.39 for 24 h. NH4Cl (aq, 5 mL) was added to the mixture and the crude
(d, J = 11.9 Hz, 1 H), 4.33 (dd, J = 7.8, 5.6 Hz, 1 H), 1.97–1.67
(m, 2 H), 1.30 (m, 4 H), 0.84 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(75 MHz, DMSO): δ = 176.92, 152.70, 140.27, 137.81, 131.59,
128.24, 127.75, 127.62, 125.16, 124.73, 122.97, 118.46, 106.79,
78.48, 70.59, 34.82, 27.20, 21.82, 13.83 ppm. HRMS (EI+): calcd.
for [C21H23NO2]+ m/z 321.1729; found 321.1738.
product was extracted with ethyl acetate. The product was purified
by flash chromatography with n-hexane and ethyl acetate (3:1) as
eluent.
General Procedure for Attaching Alkylacetylenes (Procedure B):
Acetylene (1.13 mmol) was dissolved in dry THF (5 mL) under ar-
gon in a flame-dried Schlenk flask. nBuLi (2.5 m in hexanes,
0.45 mL, 1.13 mmol) was added dropwise to the solution. The mix-
ture was mixed at room temperature for 30 min. Compound 3
(100.0 mg, 0.45 mmol) was dissolved in dry THF (4 mL) and added
dropwise to the flask. The mixture was mixed at room temperature
for 24 h. NH4Cl (aq, 5 mL) was added to the mixture and the crude
product was extracted with ethyl acetate. The product was purified
by flash chromatography with n-hexane and ethyl acetate (3:1) as
eluent.
2-[1-(tert-Butoxy)ethyl]quinolin-4(1H)-one (2j): The general pro-
cedure afforded 6.2 mg (19%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.18 (s, 1 H), 8.04 (d, J = 7.7 Hz, 1 H),
7.83 (d, J = 8.0 Hz, 1 H), 7.74–7.52 (m, 2 H), 7.44–7.22 (m, 5 H),
6.12 (s, 1 H), 4.30 (s, 2 H), 1.62 (s, 6 H) ppm. 13C NMR (75 MHz,
DMSO): δ = 177.20, 155.17, 140.38, 138.47, 131.69, 128.79, 128.14,
127.71, 127.33, 124.55, 122.89, 118.69, 106.33, 75.97, 65.23,
25.93 ppm. HRMS (EI+): calcd. for [C19H19NO2]+ m/z 293.1416;
found 293.1420.
tert-Butyl [2-(1-Hydroxy-3-phenylprop-2-yn-1-yl)phenyl]carbamate
(6a): Following general procedure A afforded 126.3 mg (92%) of
the desired product. 1H NMR (300 MHz, CDCl3): δ = 7.86 (d, J
= 8.1 Hz, 1 H), 7.68 (s, 1 H), 7.56 (dd, J = 7.7, 1.6 Hz, 1 H), 7.50–
7.44 (m, 2 H), 7.37–7.27 (m, 3 H), 7.07 (td, J = 7.5, 1.2 Hz, 1 H),
5.71 (s, 1 H), 3.15 (s, 1 H), 1.50 (s, 9 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 180.58, 153.01, 142.86, 135.88, 134.61, 133.06, 130.97,
128.79, 121.78, 121.20, 120.06, 118.82, 94.21, 87.17, 80.86,
28.37 ppm. HRMS (EI+): calcd. for [C20H21NO3]+ m/z 323.1521;
found 323.1532.
2-[2-(Benzyloxy)propan-2-yl]quinolin-4(1H)-one (2k): The general
procedure afforded 14.0 mg (26%) of the desired product. 1H NMR
(300 MHz, DMSO): δ = 11.36 (s, 1 H), 8.04 (d, J = 8.1 Hz, 1 H),
7.73 (d, J = 8.3 Hz, 1 H), 7.61 (ddd, J = 8.4, 1.4, 0.7 Hz, 1 H), 7.28
(t, J = 7.5 Hz, 1 H), 6.10 (s, 1 H), 4.68 (q, J = 6.5 Hz, 1 H), 1.38 (d,
J = 6.5 Hz, 3 H), 1.16 (s, 9 H) ppm. 13C NMR (75 MHz, DMSO): δ
= 176.95, 157.00, 140.05, 131.38, 125.02, 124.65, 122.83, 118.48,
105.01, 74.77, 67.12, 27.79, 24.04 ppm. HRMS (EI+): calcd. for
[C15H19NO2]+ m/z 245.1416; found 245.1409.
tert-Butyl [2-(3-Phenylpropioloyl)phenyl]carbamate (3): Compound
6a (26.0 mg, 0.08 mmol) was dissolved in CH2Cl2 (5 mL). MnO2
(85%, 35.0 mg, 0.4 mmol) was added and the mixture was mixed
for 5 h at room temperature. The mixture was filtered through silica
and the solvents evaporated to afford 25.9 mg (99%) of the desired
tert-Butyl
{2-[1-Hydroxy-3-(p-tolyl)prop-2-yn-1-yl]phenyl}carb-
amate (6b): Following general procedure A afforded 122.7 mg
(91%) of the desired product. 1H NMR (300 MHz, CDCl3): δ =
7.85 (d, J = 8.0 Hz, 1 H), 7.75 (s, 1 H), 7.51 (dd, J = 7.6, 1.3 Hz,
1 H), 7.34 (d, J = 8.1 Hz, 2 H), 7.32–7.25 (m, 1 H), 7.08 (d, J =
7.9 Hz, 2 H), 7.03 (td, J = 7.6, 1.1 Hz, 1 H), 5.65 (s, 1 H), 3.52 (s,
1
product. H NMR (500 MHz, CDCl3): δ = 10.78 (s, 1 H), 8.50 (d,
J = 8.6 Hz, 1 H), 8.36 (d, J = 7.9 Hz, 1 H), 7.68 (d, J = 7.9 Hz, 1 1 H), 2.32 (s, 3 H), 1.48 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
H), 7.57 (t, J = 7.9 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.43 (t, J
= 7.7 Hz, 1 H), 7.10 (t, J = 7.6 Hz, 1 H), 1.55 (d, J = 8.0 Hz, 1
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 180.70, 153.12, 142.95,
135.96, 134.69, 133.14, 131.03, 128.86, 121.88, 121.26, 120.18,
118.91, 94.27, 87.24, 80.97, 28.45 ppm. HRMS (EI+): calcd. for
[C20H19NO3]+ m/z 321.1365; found 321.1377.
δ = 153.56, 138.87, 137.00, 131.72, 129.36, 129.06, 127.98, 123.43,
122.12, 119.23, 87.91, 86.45, 80.58, 63.75, 28.37, 21.50 ppm.
HRMS (EI+): calcd. for [C21H23NO3]+ m/z 337.1678; found
337.1689.
tert-Butyl {2-[1-Hydroxy-3-(4-methoxyphenyl)prop-2-yn-1-yl]phen-
yl}carbamate (6c): Following general procedure
A afforded
tert-Butyl (2-Formylphenyl)carbamate (5): 2-Aminobenzylic alcohol
(4, 330.0 mg, 2.7 mmol) was dissolved in THF (20 mL). Boc anhy-
dride (830.0 mg, 3.80 mmol) and NaHCO3 (500.0 mg, 5.95 mmol)
was added to the solution. After mixing the solution at room tem-
perature for 42 h the solvent was evaporated. The obtained oil was
dissolved in CH2Cl2 (40 mL). MnO2 (activated 85%, 1.39 g,
13.5 mmol) was added to the solution. The mixture was mixed at
room temperature for 24 h. MnO2 was filtered and the solvent
evaporated. Purification of the crude mixture by column
chromatography with n-hexane and ethyl acetate (5:1) as eluent af-
forded 551.4 mg (93%) of the desired product. Spectral data was
found to match literature values. 1H NMR (300 MHz, CDCl3): δ
= 10.39 (s, 1 H), 9.90 (s, 1 H), 8.46 (d, J = 8.5 Hz, 1 H), 7.62 (dd,
J = 7.7, 1.6 Hz, 1 H), 7.60–7.53 (m, 1 H), 7.13 (td, J = 7.5, 1.0 Hz,
1 H), 1.54 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 195.12,
153.01, 141.94, 136.19, 136.06, 121.61, 121.36, 118.38, 81.07,
28.42 ppm.
105.7 mg (88%) of the desired product. 1H NMR (300 MHz,
CDCl3): δ = 7.87 (d, J = 8.1 Hz, 1 H), 7.72 (s, 1 H), 7.54 (dd, J =
7.7, 1.4 Hz, 1 H), 7.45–7.35 (m, 1 H), 7.31 (td, J = 8.1, 1.5 Hz, 1
H), 7.05 (td, J = 7.5, 1.2 Hz, 1 H), 6.82 (d, J = 8.9 Hz, 1 H), 5.68
(s, 1 H), 3.78 (s, 1 H), 1.50 (s, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.98, 153.56, 137.09, 133.36, 129.45, 128.02, 123.47,
122.16, 114.39, 114.02, 87.92, 85.74, 80.62, 63.89, 55.37, 28.44 ppm.
HRMS (EI+): calcd. for [C21H23NO4]+ m/z 353.1627; found
353.1642.
tert-Butyl {2-[3-(4-Fluorophenyl)-1-hydroxyprop-2-yn-1-yl]phenyl}-
carbamate (6d): Following general procedure A afforded 77.3 mg
(62%) of the desired product. 1H NMR (300 MHz, CDCl3): δ =
7.85 (d, J = 8.0 Hz, 1 H), 7.64 (s, 1 H), 7.53 (dd, J = 7.7, 1.3 Hz,
1 H), 7.49–7.39 (m, 3 H), 7.33 (td, J = 8.0, 1.5 Hz, 1 H), 7.17–6.89
(m, 3 H), 5.69 (d, J = 4.9 Hz, 1 H), 3.15 (d, J = 5.3 Hz, 1 H), 1.49
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.46, 161.14,
153.65, 136.98, 133.86, 133.75, 129.54, 129.42, 128.01, 123.64,
122.42, 118.44, 115.82, 115.53, 86.92, 86.66, 80.74, 63.77,
28.41 ppm. HRMS (EI+): calcd. for [C20H20FNO3]+ m/z 341.1427;
found 341.1420.
General Procedure for Attaching Aromatic Acetylenes (Procedure
A): Acetylene (1.13 mmol) was dissolved in dry THF (5 mL) under
argon in a flame-dried Schlenk flask. ZnEt2 (1.0 m in hexanes,
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42224
/KAP1
Date: 26-05-14 11:22:48
Pages: 10
Gold-Catalyzed Synthesis of 2-Substituted 4-Quinolones
tert-Butyl [2-(1-Hydroxyhex-2-yn-1-yl)phenyl]carbamate (6e): Fol-
HRMS (EI+): calcd. for [C24H29NO4]+ m/z 395.2097; found
lowing general procedure B afforded 75.1 mg (62%) of the desired
product. H NMR (300 MHz, CDCl3): δ = 7.86 (d, J = 8.1 Hz, 1
395.2108.
1
tert-Butyl
{2-[4-(Benzyloxy)-1-hydroxy-4-methylpent-2-yn-1-yl]-
H), 7.69 (s, 1 H), 7.47 (dd, J = 7.7, 1.4 Hz, 1 H), 7.33–7.25 (m, 1
H), 7.03 (td, J = 7.5, 1.2 Hz, 1 H), 5.46 (s, 1 H), 2.99 (s, 1 H), 2.25
(td, J = 7.1, 2.0 Hz, 2 H), 1.57 (dd, J = 14.5, 7.3 Hz, 2 H), 1.51 (s,
9 H), 1.00 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 153.45, 137.03, 129.48, 129.26, 127.79, 123.22, 121.81, 88.91,
80.47, 78.41, 63.52, 28.42, 22.03, 20.88, 13.61 ppm. HRMS (EI+):
calcd. for [C17H23NO3]+ m/z 289.1678; found 289.1680.
phenyl}carbamate (6k): Compound 4k reacted according to general
procedure B afforded 121.5 mg (76%) of the desired product. 1H
NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 8.1 Hz, 1 H), 7.72 (s, 1
H), 7.44 (t, J = 6.2 Hz, 1 H), 7.33–7.25 (m, 1 H), 7.02 (t, J =
7.5 Hz, 1 H), 5.50 (s, 1 H), 4.36 (q, J = 6.6 Hz, 1 H), 3.33 (s, 1 H),
1.50 (s, 9 H), 1.41 (dd, J = 6.6, 3.9 Hz, 3 H), 1.24 (d, J = 5.9 Hz,
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.35, 137.10, 129.29,
128.87, 127.81, 123.13, 121.66, 90.98, 81.31, 81.27, 80.44, 75.07,
63.30, 57.85, 28.44, 28.21, 24.29 ppm. HRMS (EI+): calcd. for
[C20H29NO4]+ m/z 347.2097; found 347.2103.
tert-Butyl {2-[1-Hydroxy-3-(trimethylsilyl)prop-2-yn-1-yl]phenyl}-
carbamate (6f): Following general procedure B afforded 58.0 mg
(54%) of the desired product. 1H NMR (300 MHz, CDCl3): δ =
7.86 (d, J = 8.2 Hz, 1 H), 7.60 (s, 1 H), 7.47 (dd, J = 7.6, 1.4 Hz,
1 H), 7.38–7.26 (m, 1 H), 7.05 (td, J = 7.6, 1.1 Hz, 1 H), 5.46 (s, 1
H), 3.03 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.47,
137.03, 129.51, 128.89, 128.01, 123.45, 122.02, 103.26, 93.12, 80.61,
63.66, 28.47, –0.11 ppm. HRMS (EI+): calcd. for [C17H25NO3Si]+
m/z 319.1604; found 319.1611.
General Procedure for the Boc-Deprotection Reaction Leading to
7a–7k: Compound 6 was dissolved in CH2Cl2 (10 mL). Trifluoro-
acetic acid (0.4 mL) was added dropwise to the solution. The solu-
tion was mixed at room temperature for 15 min. Water (15 mL) was
added and mixture was extracted with CH2Cl2. The product was
purified by flash chromatography with n-hexane and ethyl acetate
(3:1) as eluent.
tert-Butyl
{2-[4-(Benzyloxy)-1-hydroxybut-2-yn-1-yl]phenyl}carb-
amate (6g): Following general procedure B afforded 130.7 mg
(78%) of the desired product. 1H NMR (300 MHz, CDCl3): δ =
7.84 (d, J = 8.1 Hz, 1 H), 7.63 (s, 1 H), 7.48 (dd, J = 7.6, 1.5 Hz,
1 H), 7.40–7.18 (m, 6 H), 7.04 (td, J = 7.5, 1.2 Hz, 1 H), 5.52 (s, 1
H), 4.58 (s, 2 H), 4.23 (d, J = 1.8 Hz, 2 H), 3.37 (s, 1 H), 1.49 (s,
9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.54, 136.98, 129.49,
129.05, 128.52, 128.21, 128.02, 127.84, 126.66, 123.50, 122.19,
84.75, 83.80, 80.66, 71.80, 63.20, 57.40, 28.41 ppm. HRMS (EI+):
calcd. for [C22H25NO4]+ m/z 367.1784; found 367.1782.
1-(2-Aminophenyl)-3-phenylprop-2-yn-1-ol (7a): Following the gene-
ral procedure afforded 79.4 mg (91%) of the desired product. 1H
NMR (300 MHz, CDCl3): δ = 9.45 (s, 2 H), 7.52–7.45 (m, 2 H),
7.42–7.27 (m, 5 H), 7.11 (td, J = 7.6, 1.0 Hz, 1 H), 6.97 (d, J =
7.9 Hz, 1 H), 6.31 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
153.01, 135.09, 132.13, 130.07, 129.35, 128.47, 124.97, 123.82,
121.55, 119.00, 114.90, 89.27, 82.93, 69.91 ppm. HRMS (EI+):
calcd. for [C15H13NO]+ m/z 223.0997; found 223.0995.
1-(2-Aminophenyl)-3-(p-tolyl)prop-2-yn-1-ol (7b): Following the ge-
neral procedure afforded 68.2 mg (81%) of the desired product. 1H
NMR (300 MHz, DMSO): δ = 10.46 (s, 2 H), 7.45–7.29 (m, 4 H),
7.20 (d, J = 7.9 Hz, 2 H), 7.10 (t, J = 7.5 Hz, 1 H), 6.97 (d, J =
7.9 Hz, 1 H), 6.59 (s, 1 H), 2.31 (s, 3 H), 1.91 (s, 1 H) ppm. 13C
NMR (75 MHz, DMSO): δ = 150.57, 139.44, 135.77, 131.60,
129.67, 129.41, 124.69, 122.88, 119.14, 117.71, 114.31, 87.76, 83.77,
68.14, 21.03 ppm. HRMS (EI+): calcd. for [C16H15NO]+ m/z
237.1154; found 237.1147.
tert-Butyl {2-[5-(Benzyloxy)-1-hydroxypent-2-yn-1-yl]phenyl}carb-
amate (6h): Following general procedure B afforded 62.4 mg (38%)
1
of the desired product. H NMR (300 MHz, CDCl3): δ = 7.85 (d,
J = 8.1 Hz, 1 H), 7.65 (s, 1 H), 7.54–7.45 (m, 1 H), 7.39–7.20 (m,
1 H), 7.01 (td, J = 7.5, 1.1 Hz, 1 H), 5.43 (d, J = 15.1 Hz, 1 H),
4.52 (s, 1 H), 3.67–3.53 (m, 1 H), 3.11 (s, 1 H), 2.57 (ddd, J = 11.6,
6.8, 1.6 Hz, 1 H), 1.50 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 153.49, 137.96, 137.07, 129.34, 128.53, 128.28, 127.80, 126.72,
123.36, 122.04, 85.61, 80.50, 79.49, 73.06, 68.26, 64.74, 63.34,
28.47, 20.36 ppm. HRMS (EI+): calcd. for [C23H27NO4]+ m/z
381.1940; found 381.1959.
1-(2-Aminophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-ol (7c): Follow-
ing the general procedure afforded 66.6 mg (88%) of the desired
product. 1H NMR (300 MHz, DMSO): δ = 10.44 (s, 2 H), 7.47–
7.37 (m, 3 H), 7.33 (td, J = 7.7, 1.3 Hz, 1 H), 7.09 (td, J = 7.5,
1.0 Hz, 1 H), 7.02–6.89 (m, 3 H), 6.57 (s, 1 H), 3.77 (s, 3 H) ppm.
13C NMR (75 MHz, DMSO): δ = 160.06, 150.62, 135.76, 133.37,
129.62, 124.69, 122.85, 119.25, 114.42, 114.28, 112.58, 87.78, 83.00,
68.23, 55.29 ppm. HRMS (EI+): calcd. for [C16H15NO2]+ m/z
253.1103; found 253.1108.
tert-Butyl
{2-[4-(Benzyloxy)-1-hydroxyoct-2-yn-1-yl]phenyl}carb-
amate (6i): Following general procedure B afforded 68.2 mg (36%)
1
of the desired product. H NMR (300 MHz, CDCl3): δ = 7.87 (d,
J = 8.0 Hz, 1 H), 7.64 (d, J = 3.2 Hz, 1 H), 7.58–7.44 (m, 1 H),
7.42–7.19 (m, 6 H), 7.04 (td, J = 7.5, 1.2 Hz, 1 H), 5.54 (s, 1 H),
4.77 (dd, J = 11.8, 3.3 Hz, 1 H), 4.50 (dd, J = 11.8, 2.4 Hz, 1 H),
4.22–4.12 (m, 1 H), 3.14 (s, 1 H), 1.89–1.69 (m, 2 H), 1.49 (s, 9 H),
1.47–1.19 (m, 4 H), 0.89 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 153.46, 137.93, 137.07, 129.50, 129.09,
128.66, 128.44, 128.08, 127.79, 126.71, 123.40, 122.00, 87.31, 83.92,
80.64, 70.79, 68.89, 63.23, 35.47, 28.43, 27.56, 22.44, 14.06 ppm.
HRMS (EI+): calcd. for [C26H33NO4]+ m/z 423.2410; found
423.2413.
1-(2-Aminophenyl)-3-(4-fluorophenyl)prop-2-yn-1-ol (7d): Following
the general procedure afforded 47.4 mg (87%) of the desired prod-
1
uct. H NMR (300 MHz, DMSO): δ = 10.47 (s, 1 H), 7.56 (dd, J
= 8.2, 5.6 Hz, 2 H), 7.41 (d, J = 7.5 Hz, 1 H), 7.34 (t, J = 7.7 Hz,
1 H), 7.24 (t, J = 8.6 Hz, 2 H), 7.10 (t, J = 7.5 Hz, 1 H), 6.97 (d,
J = 7.9 Hz, 1 H), 6.61 (s, 1 H) ppm. 13C NMR (75 MHz, DMSO):
δ = 164.09, 160.79, 150.49, 135.76, 134.22, 134.11, 129.71, 124.71,
122.89, 118.95, 117.19, 116.23, 115.93, 114.31, 86.54, 84.16,
68.04 ppm. HRMS (EI+): calcd. for [C15H12FNO]+ m/z 241.0903;
found 241.0897.
tert-Butyl {2-[4-(tert-Butoxy)-1-hydroxypent-2-yn-1-yl]phenyl}carb-
amate (6j): Following general procedure B afforded 94.6 mg (57%)
1
of the desired product. H NMR (300 MHz, CDCl3): δ = 7.88 (d,
J = 8.1 Hz, 1 H), 7.60 (s, 1 H), 7.44 (dd, J = 7.7, 1.4 Hz, 1 H),
7.36–7.17 (m, 6 H), 7.02 (td, J = 7.5, 1.1 Hz, 1 H), 5.49 (s, 1 H), 1-(2-Aminophenyl)hex-2-yn-1-ol (7e): Following the general pro-
4.62 (s, 2 H), 2.92 (s, 1 H), 1.57 (d, J = 1.8 Hz, 6 H), 1.49 (s, 9
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.40, 138.95, 137.07,
129.56, 129.00, 128.41, 127.87, 127.78, 127.51, 123.41, 121.97,
90.34, 82.48, 80.66, 70.85, 66.80, 63.30, 29.01, 28.94, 28.46 ppm.
cedure afforded 41.3 mg (84%) of the desired product. 1H NMR
(300 MHz, CDCl3): δ = 9.52 (s, 1 H), 7.36–7.24 (m, 2 H), 7.08 (t,
J = 7.5 Hz, 1 H), 6.93 (d, J = 7.7 Hz, 1 H), 6.06 (s, 1 H), 2.26 (td,
J = 7.0, 2.1 Hz, 2 H), 1.64–1.50 (m, 2 H), 0.99 (t, J = 7.4 Hz, 3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42224
/KAP1
Date: 26-05-14 11:22:48
Pages: 10
O. Seppänen, M. Muuronen, J. Helaja
FULL PAPER
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.34, 135.05, 129.78,
1-(2-Aminophenyl)-3-phenylprop-2-yn-1-one (8a): Following the ge-
124.80, 123.59, 119.60, 114.75, 90.77, 74.53, 69.80, 21.77, 20.84, neral procedure afforded 69.1 mg (90%) of the desired product. 1H
13.51 ppm. HRMS (EI+): calcd. for [C12H15NO]+ m/z 189.1154; NMR (300 MHz, CDCl3): δ = 8.17 (dd, J = 8.1, 1.2 Hz, 1 H), 7.68–
found 189.1160.
7.61 (m, 2 H), 7.48–7.35 (m, 3 H), 7.29 (ddd, J = 8.5, 7.0, 1.6 Hz,
1 H), 6.71 (ddd, J = 8.1, 7.0, 1.1 Hz, 1 H), 6.66 (d, J = 8.4 Hz, 1
H), 6.40 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 179.52,
151.20, 135.38, 134.50, 132.84, 130.44, 128.66, 120.61, 118.92,
116.87, 116.16, 92.36, 87.22 ppm. HRMS (EI+): calcd. for
[C15H11NO]+ m/z 221.0841; found 221.0842.
1-(2-Aminophenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (7f): Following
the general procedure afforded 30.9 mg (75%) of the desired prod-
1
uct. H NMR (300 MHz, CDCl3): δ = 9.17 (s, 1 H), 7.40–7.25 (m,
1 H), 7.11 (td, J = 7.6, 1.0 Hz, 1 H), 6.91 (d, J = 7.9 Hz, 1 H), 6.08
(s, 1 H), 0.21 (s, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
152.85, 135.10, 130.04, 125.06, 123.81, 118.77, 114.72, 98.27, 95.40,
69.74, –0.25 ppm. HRMS (EI+): calcd. for [C12H15NOSi]+ m/z
217.0923; found 219.1073.
1-(2-Aminophenyl)-3-(p-tolyl)prop-2-yn-1-one (8b): Following the
general procedure afforded 58.2 mg (90%) of the desired product.
1H NMR (300 MHz, CDCl3): δ = 8.18 (dd, J = 8.1, 1.3 Hz, 1 H),
7.59–7.51 (m, 2 H), 7.31 (ddd, J = 8.5, 7.1, 1.6 Hz, 1 H), 7.21 (dd,
J = 8.5, 0.6 Hz, 2 H), 6.72 (ddd, J = 8.1, 7.1, 1.1 Hz, 1 H), 6.66
(dd, J = 8.3, 0.6 Hz, 1 H), 6.35 (s, 2 H), 2.40 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 179.61, 151.15, 141.06, 135.24,
134.48, 132.84, 129.44, 118.95, 117.46, 116.84, 116.09, 92.95, 87.02,
21.76 ppm. HRMS (EI+): calcd. for [C16H13NO]+ m/z 235.0997;
found 235.1001.
1-(2-Aminophenyl)-4-(benzyloxy)but-2-yn-1-ol (7g): Following the
general procedure afforded 76.4 mg (90%) of the desired product.
1H NMR (300 MHz, CDCl3): δ = 9.46 (s, 1 H), 7.42–7.17 (m, 7
H), 7.08 (t, J = 7.5 Hz, 1 H), 6.93 (d, J = 7.9 Hz, 1 H), 6.11 (s, 1
H), 4.57 (d, J = 1.2 Hz, 2 H), 4.25 (s, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 137.09, 134.86, 130.08, 128.55, 128.22,
128.06, 124.78, 123.81, 118.61, 114.92, 85.70, 80.71, 71.89, 69.31,
57.25 ppm. HRMS (EI+): calcd. for [C17H17NO2]+ m/z 267.1259;
found 267.1254.
1-(2-Aminophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-one (8c): Fol-
lowing the general procedure afforded 44.8 mg (80%) of the desired
product. 1H NMR (300 MHz, CDCl3): δ = 8.17 (dd, J = 8.1,
1.5 Hz, 1 H), 7.69–7.53 (m, 2 H), 7.30 (ddd, J = 8.4, 7.1, 1.6 Hz, 1
H), 6.98–6.83 (m, 2 H), 6.71 (ddd, J = 8.1, 7.1, 1.0 Hz, 1 H), 6.65
(dd, J = 8.3, 0.5 Hz, 1 H), 6.37 (s, 2 H), 3.83 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 179.74, 161.48, 151.10, 135.19,
134.85, 134.50, 119.07, 116.87, 116.15, 114.43, 112.47, 93.38, 87.02,
55.50 ppm. HRMS (EI+): calcd. for [C16H13NO2]+ m/z 251.0946;
found 251.0949.
1-(2-Aminophenyl)-5-(benzyloxy)pent-2-yn-1-ol (7h): The Boc pro-
tection was cleaved by using the general procedure. The product
was not purified at this stage. After checking the H NMR spectra
the crude product was dissolved in CH2Cl2 and oxidized according
to the general procedure.
1
1-(2-Aminophenyl)-4-(benzyloxy)oct-2-yn-1-ol (7i): Following the
general procedure afforded 21.4 mg (62%) of the desired product.
1H NMR (300 MHz, CDCl3): δ = 9.25 (s, 1 H), 7.42–7.23 (m, 7
H), 7.19–7.02 (m, 1 H), 6.93 (d, J = 7.8 Hz, 1 H), 6.14 (s, 1 H),
4.76 (dd, J = 11.7, 8.3 Hz, 1 H), 4.48 (dd, J = 11.7, 5.5 Hz, 1 H),
4.18 (td, J = 6.6, 1.2 Hz, 1 H), 1.77 (dq, J = 13.5, 6.8 Hz, 2 H),
1.55–1.19 (m, 6 H), 0.88 (td, J = 7.2, 3.0 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 152.90, 137.80, 135.06, 130.10, 128.51,
128.13, 127.87, 124.89, 123.84, 119.01, 114.80, 89.17, 79.88, 70.91,
69.46, 68.77, 35.26, 27.51, 22.45, 14.06 ppm. HRMS (EI+): calcd.
for [C21H25NO2]+ m/z 323.1885; found 323.1877.
1-(2-Aminophenyl)-3-(4-fluorophenyl)prop-2-yn-1-one (8d): Follow-
ing the general procedure afforded 40.3 mg (86%) of the desired
product. 1H NMR (300 MHz, CDCl3): δ = 8.14 (dd, J = 8.1,
1.6 Hz, 1 H), 7.71–7.59 (m, 2 H), 7.31 (ddd, J = 8.5, 7.0, 1.6 Hz, 1
H), 7.16–7.04 (m, 2 H), 6.79–6.62 (m, 2 H), 6.38 (s, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 179.43, 165.56, 162.21, 151.23,
135.47, 135.18, 135.06, 134.47, 118.90, 116.92, 116.37, 116.24,
116.07, 91.30, 87.12 ppm. HRMS (EI+): calcd. for [C15H10FNO]+
m/z 239.0746; found 239.0737.
1-(2-Aminophenyl)-4-(tert-butoxy)pent-2-yn-1-ol (7j): Following the
general procedure afforded 41.3 mg (77%) of the desired product.
1H NMR (300 MHz, CDCl3): δ = 9.52 (s, 1 H), 7.29 (t, J = 7.7 Hz,
2 H), 7.08 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 6.09 (s,
1 H), 4.37 (q, J = 6.4 Hz, 1 H), 1.41 (d, J = 6.7 Hz, 3 H), 1.23 (d,
J = 7.5 Hz, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 153.13,
135.00, 129.87, 124.78, 123.62, 118.96, 114.73, 92.95, 75.09, 69.47,
57.69, 28.15, 24.01 ppm. HRMS (EI+): calcd. for [C15H21NO2]+
m/z 247.1572; found 247.1581.
1-(2-Aminophenyl)hex-2-yn-1-one (8e): Following the general pro-
cedure afforded 30.9 mg (76%) of the desired product. 1H NMR
(300 MHz, CDCl3): δ = 8.08 (dd, J = 8.1, 1.5 Hz, 1 H), 7.27 (ddd,
J = 8.5, 7.1, 1.6 Hz, 1 H), 6.67 (ddd, J = 8.1, 7.1, 1.1 Hz, 1 H),
6.62 (dd, J = 8.5, 0.8 Hz, 1 H), 6.31 (s, 2 H), 2.46 (t, J = 7.0 Hz, 2
H), 1.76–1.62 (m, 2 H), 1.07 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 180.02, 151.06, 135.11, 134.72, 118.97,
116.77, 116.06, 95.70, 80.10, 21.56, 21.26, 13.73 ppm. HRMS (EI+):
calcd. for [C12H13NO]+ m/z 187.0997; found 187.0999.
1-(2-Aminophenyl)-4-(benzyloxy)-4-methylpent-2-yn-1-ol (7k): Fol-
lowing the general procedure afforded 33.3 mg (52%) of the desired
product. 1H NMR (300 MHz, CDCl3): δ = 9.26 (s, 1 H), 7.41–7.17
(m, 7 H), 7.08 (td, J = 7.6, 0.9 Hz, 1 H), 6.91 (dd, J = 8.2, 0.8 Hz,
1 H), 6.12 (s, 1 H), 4.60 (s, 2 H), 2.16 (s, 1 H), 1.58 (s, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 152.90, 138.73, 135.04, 130.06,
128.41, 127.82, 127.54, 124.82, 123.81, 118.96, 114.77, 92.11, 78.37,
70.80, 69.42, 66.90, 28.77 ppm. HRMS (EI+): calcd. for
[C24H29NO4]+ m/z 295.1572; found 295.1571.
1-(2-Aminophenyl)-3-(trimethylsilyl)prop-2-yn-1-one (8f): Following
the general procedure afforded 26.4 mg (89%) of the desired prod-
1
uct. H NMR (300 MHz, CDCl3): δ = 8.08 (dd, J = 8.1, 1.6 Hz, 1
H), 7.35–7.23 (m, 1 H), 6.69 (ddd, J = 8.1, 7.1, 1.1 Hz, 1 H), 6.63
(dd, J = 8.4, 0.8 Hz, 1 H), 6.32 (s, 2 H), 0.30 (s, 9 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 179.21, 151.26, 135.47, 134.77,
118.68, 116.79, 116.23, 101.33, 99.40, –0.46 ppm. HRMS (EI+):
calcd. for [C12H15NOSi]+ m/z 217.0923; found 217.0912.
General Procedure for the Oxidation of the Alcohols 8a–8k: Com-
pound 7 was dissolved in CH2Cl2 (10 mL). MnO2 (5 equiv.) was
added to the solution. The mixture was mixed for 5 h. The oxidant
was filtered and the solvent evaporated. The product was purified
by flash chromatography with n-hexane and ethyl acetate (5:1) as
eluent.
1-(2-Aminophenyl)-4-(benzyloxy)but-2-yn-1-one (8g): Following the
general procedure afforded 41.5 mg (63%) of the desired product.
1H NMR (300 MHz, CDCl3): δ = 8.04 (dd, J = 8.1, 1.6 Hz, 1 H),
7.44–7.20 (m, 6 H), 6.75–6.58 (m, 2 H), 6.34 (s, 2 H), 4.68 (s, 2 H),
4.43 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 178.87, 151.24,
136.99, 135.55, 134.59, 128.64, 128.26, 128.20, 118.46, 116.82,
8
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Pages: 10
Gold-Catalyzed Synthesis of 2-Substituted 4-Quinolones
116.23, 89.27, 84.56, 72.23, 57.35 ppm. HRMS (EI+): calcd. for
[4]
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[C17H15NO2]+ m/z 265.1103; found 265.1092.
1-(2-Aminophenyl)-5-(benzyloxy)pent-2-yn-1-one (8h): Following
the general procedure afforded 20.3 mg (44%) of the desired prod-
uct, yield was calculated from the amount of 6h. 1H NMR
(300 MHz, CDCl3): δ = 8.08 (dd, J = 8.3, 1.1 Hz, 1 H), 7.41–7.19
(m, 3 H), 6.62 (t, J = 7.8 Hz, 1 H), 6.29 (s, 1 H), 4.59 (s, 1 H), 3.72
(t, J = 6.7 Hz, 1 H), 2.78 (t, J = 6.7 Hz, 1 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 179.71, 151.07, 137.96, 135.25, 134.87,
128.60, 127.91, 127.83, 118.90, 116.74, 116.16, 92.22, 80.57, 73.27,
67.58, 20.86 ppm. HRMS (EI+): calcd. for [C18H17NO2]+ m/z
279.1259; found 279.1261.
[6]
[7]
[8]
[9]
[10]
[11]
1-(2-Aminophenyl)-4-(benzyloxy)oct-2-yn-1-one (8i): Following the
general procedure afforded 21.4 mg (83%) of the desired product.
1H NMR (300 MHz, CDCl3): δ = 8.05 (d, J = 6.6 Hz, 1 H), 7.46–
7.20 (m, 7 H), 6.75–6.58 (m, 2 H), 6.33 (s, 2 H), 4.87 (d, J =
11.7 Hz, 1 H), 4.58 (d, J = 11.7 Hz, 1 H), 4.35 (t, J = 6.6 Hz, 1 H),
1.97–1.82 (m, 2 H), 1.62–1.44 (m, 2 H), 1.35 (dd, J = 14.9, 7.2 Hz,
2 H), 0.92 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 179.18, 151.23, 137.66, 135.50, 134.60, 128.59, 128.16, 128.00,
118.73, 116.86, 116.26, 92.63, 83.97, 71.33, 68.94, 35.11, 27.57,
22.49, 14.06 ppm. HRMS (EI+): calcd. for [C21H23NO2]+ m/z
321.1729; found 321.1743.
[12]
[13]
[14]
[15]
[16]
[17]
1-(2-Aminophenyl)-4-(tert-butoxy)pent-2-yn-1-one (8j): Following
a) Y. Fukuda, K. Utimoto, H. Nozaki, Heterocycles 1987, 25,
297; b) Y. Fukuda, K. Utimoto, Synthesis 1991, 975.
the general procedure afforded 36.2 mg (91%) of the desired prod-
1
uct. H NMR (300 MHz, CDCl3): δ = 8.05 (dd, J = 8.1, 0.7 Hz, 1
[18] M. Rudolph, A. S. K. Hashmi, Chem. Commun. 2011, 47,
H), 7.28 (ddd, J = 8.5, 7.1, 1.6 Hz, 1 H), 6.73–6.59 (m, 2 H), 6.35
(s, 2 H), 4.52 (q, J = 6.7 Hz, 1 H), 1.50 (d, J = 6.7 Hz, 3 H), 1.30
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 179.43, 151.13,
135.27, 134.60, 118.70, 116.75, 116.04, 96.35, 81.65, 75.26, 57.81,
28.17, 23.64 ppm. HRMS (EI+): calcd. for [C15H19NO2]+ m/z
245.1416; found 245.1422.
6536–6544.
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MOLE, v. 6.4, 2012, a development of the University of
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www.turbomole.com.
1-(2-Aminophenyl)-4-(benzyloxy)-4-methylpent-2-yn-1-one (8k): Fol-
lowing the general procedure afforded 24.9 mg (80%) of the desired
product. 1H NMR (300 MHz, CDCl3): δ = 8.00 (dd, J = 8.3,
1.5 Hz, 1 H), 7.45–7.19 (m, 6 H), 6.70–6.54 (m, 2 H), 6.33 (s, 2 H),
4.72 (s, 2 H), 1.68 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
179.24, 151.22, 138.56, 135.47, 134.49, 128.52, 127.83, 127.69,
118.70, 116.87, 116.22, 95.21, 82.55, 71.03, 67.29, 28.54 ppm.
HRMS (EI+): calcd. for [C19H19NO2]+ m/z 293.1416; found
293.1420.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra, catalysis of N-Boc-protected sub-
strate, computational details including XYZ parameters of com-
puted structures.
Acknowledgments
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Theor. Chim. Acta 1990, 77, 123.
This work was supported by the Academy of Finland (grant to
J. H., grant number 258348). Dr Michele Melchionna is acknowl-
edged for scientific language editing.
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Received: March 7, 2014
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O42224
/KAP1
Date: 26-05-14 11:22:48
Pages: 10
O. Seppänen, M. Muuronen, J. Helaja
FULL PAPER
Gold Catalysis
O. Seppänen, M. Muuronen,
J. Helaja* ....................................... 1–10
Gold-Catalyzed Conversion of Aryl- and
Alkyl-Substituted
1-(o-Aminophenyl)-2-
propyn-1-ones to the Corresponding 2-
Substituted 4-Quinolones
A mild and atom-economic gold-catalyzed
route from aryl- and alkyl-substituted 1-(o-
aminophenyl)-2-propyn-1-ones to form 2-
substituted 4-quinolones has been devel-
oped. Cationic gold(I) catalysts were found
to be most efficient in direct alkyne acti-
vation for hydroamination reactions.
Keywords: Synthetic methods
geneous catalysis Hydroamination
Gold / Density functional calculations
/ Homo-
/
/
10
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