Synthesis of 4-quinolones via cyclocondensation of substituted ortho-amidoacetophenones: A refit to the camps cyclization by applying trimethylsilyl trifluoromethanesulfonate/triethylamine

Article abstract of DOI:10.1055/s-0030-1260198

A modification of the classical Camps cyclization is described. A series of substituted 4-quinolone derivatives is prepared via trimethylsilyl trifluoromethanesulfonate/triethylamine induced cyclocondensation of substituted ortho-amidoacetophenones. The process shows a broad substrate scope and allows selective preparation of 2-aryl- and 2-alkyl-substituted 4-quino-lones. Enantiopure starting materials react without loss of optical purity using the modified conditions. Subsequent transformations of the products involving preparation of a 4-quinolyl nonaflate and O-selective methylation are also described. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260198

PAPER
3261
Synthesis of 4-Quinolones via Cyclocondensation of Substituted
ortho-Amidoacetophenones: A Refit to the Camps Cyclization by Applying
Trimethylsilyl Trifluoromethanesulfonate/Triethylamine
4
-Quinolones via
h
Cycloconde
r
nsation
of
ortho
s
-Amidoa
c
t
etophe
i
nones an Eidamshaus, Therese Triemer, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83855367; E-mail: hans.reissig@chemie.fu-berlin.de
Received 2 July 2011; revised 19 July 2011
tion of mixtures of regioisomeric 2- and 4-quino-
Abstract: A modification of the classical Camps cyclization is de-
scribed. A series of substituted 4-quinolone derivatives is prepared
via trimethylsilyl trifluoromethanesulfonate/triethylamine in-
duced cyclocondensation of substituted ortho-amidoacetophe-
lones.11a,12c Herein we describe a modification of the
classical Camps cyclization conditions, which features
milder reaction conditions and does not require the use of
nones. The process shows a broad substrate scope and allows a strong base.
selective preparation of 2-aryl- and 2-alkyl-substituted 4-quino-
Our group has previously developed a new approach to
lones. Enantiopure starting materials react without loss of optical
purity using the modified conditions. Subsequent transformations
of the products involving preparation of a 4-quinolyl nonaflate and
O-selective methylation are also described.
highly functionalized 4-pyridinone/4-hydroxypyridine
derivatives 2 based on a trimethylsilyl trifluoromethane-
sulfonate (TMSOTf) promoted cyclocondensation reac-
tion of b-ketoenamides 1 (Scheme 1).13 We demonstrated
that this process tolerated many functional groups and that
enantiopure starting materials reacted without loss of
enantiopurity.14 In the present work, we have shown that
this concept was also applicable to the cyclization of
structurally related ortho-amidoacetophenones 3, leading
to 4-quinolones 4 which are benzannulated analogues of
pyridinones 2.
Key words: Camps cyclization, 4-quinolones, cyclocondensation,
ortho-amidoacetophenones, nonaflates
Substituted 4-quinolone derivatives represent an impor-
tant class of nitrogen-containing heterocycles as they of-
ten exhibit specific biological activities.1 For instance,
many broad-spectrum antibiotics such as the fluoroquino-
lones feature a 4-quinolone core.2 In addition to their anti-
bacterial properties, quinolone derivatives have been
identified as anti-malarial,3 anti-cancer,4 anti-viral5 and
anti-diabetic agents,6 thus new methods for construction
of the quinolone core are highly desirable. Despite recent
approaches involving transition metal catalyzed bond-
forming processes,7 and other strategies,8 classical syn-
thetic methods such as the Conrad–Limpach,9 the Gould–
Jacobs10 and the Camps cyclization11 are still widely em-
ployed for the construction of substituted 4-quinolones.
However, all these methods feature thermal cycloconden-
sation reactions, typically requiring harsh conditions em-
ploying high temperatures (>200 °C) and/or strong bases.
This limits the scope of these methods and often results in
a tedious purification. Since the required starting materi-
als are easily available these methods are still of synthetic
relevance. The Camps cyclization, which proceeds via
base-induced cyclocondensation of ortho-amidoaceto-
phenones, still attracts significant attention and some
modified versions have been reported.12 However, all the
protocols developed so far require strong bases such as so-
dium hydroxide or metal alkoxides, which leads to a rath-
er limited substrate scope. In addition, base-sensitive
2-alkyl-4-quinolones cannot be accessed selectively using
these methods since the reaction conditions lead to forma-
R2
O
R3
O
R2
NH
O
HN
R1
refs. 13 and 14
R3
R1
R4
R4
2
1
R2
O
R3
O
Et3N, TMSOTf
CH2Cl2, Δ
R2
R1
NH
O
HN
R3
this
study
R1
4
3
Scheme 1 TMSOTf/Et3N-promoted cyclocondensations of precur-
sors 1 and 3 leading to 4-pyridinones 2 and 4-quinolones 4
In a preliminary experiment we found that the reaction
conditions employed for the cyclocondensation of b-ke-
toenamides could be transferred to the cyclization of
known ortho-amidoacetophenone 3a to afford the expect-
ed product, 2-phenylquinolin-4-one (4a) in moderate
yield. To test the generality of this cyclocondensation re-
action a series of substituted ortho-amidoacetophenones
3a–l was prepared (Table 1). The required starting mate-
rials were synthesized following established procedures
by either condensation of substituted ortho-aminoace-
tophenones with acyl chlorides (method A) or directly
with carboxylic acids using bromotripyrrolidin-1-ylphos-
SYNTHESIS 2011, No. 20, pp 3261–3266
x
x.
x
x
.
2
0
1
1
Advanced online publication: 01.09.2011
DOI: 10.1055/s-0030-1260198; Art ID: T66411SS
© Georg Thieme Verlag Stuttgart · New York

3262
C. Eidamshaus et al.
PAPER
phonium hexafluorophosphate (PyBroP)15 as the coupling ification of the work-up procedure, which involved a basic
reagent (method B). Alternatively, precursors 3 could be wash of the organic layer with sodium hydroxide solution
prepared by copper-catalyzed amidation of 2¢-bromo-sub- (2 M), the undesired salt by-product could be removed
stituted acetophenone derivatives following a procedure completely resulting in a simplified purification and a sig-
developed by Buchwald and co-workers (method C).12c It nificantly improved yield of 4-quinolone 4a (83%).
should be mentioned that no attempts were made to opti-
The results shown in Table 2 revealed that the scope of the
mize the syntheses of the starting materials; in some cases
cyclization was very broad. Aromatic and heteroaromatic
the yields could certainly be improved.
substituents such as phenyl and pyridyl were tolerated
leading to the 2-aryl- and 2-heteroaryl-substituted 4-qui-
nolone derivatives 4a and 4b in good yields (Table 2, en-
tries 1 and 2). In contrast, the 2-thienyl-substituted 4-
quinolone 4c was obtained in a moderate 39% yield
Table 1 Preparation of the Precursor ortho-Amidoacetophenones
3a–l
O
X
O
R2COY
method A, B or C
R2
R1
NH
O
(Table 2, entry 3). It can be speculated that this significant
drop in efficiency might be attributed to the electron-do-
nating properties of the thienyl group which decreases the
electrophilicity of the amide group. When alkyl ortho-
amidoacetophenone 3d was subjected to the cyclization
conditions the corresponding 2-alkyl-substituted 4-qui-
nolone 4d was obtained in excellent yield (Table 2, entry
4). In contrast to the classic conditions, where a 1:2 mix-
ture of 2- and 4-quinolones was formed in a total yield of
72%,12c the regioisomeric 2-quinolone arising from
deprotonation at the amide a-carbon atom was not detect-
ed by 1H NMR analysis of the crude product. Encouraged
by this finding we decided to further investigate the scope
of the cyclization reaction with respect to 2-alkyl-substi-
tuted 4-quinolones, which were not accessible selectively
via the classical Camps cyclization. Substrates with b-
branched alkyl groups were tolerated as was demonstrated
by the valeric acid derived 4-quinolone 4e formed in mod-
erate yield (Table 2, entry 5). Surprisingly, we found that
ortho-amidoacetophenone 3f with a branched alkyl group
at the amide a-carbon atom did not undergo cyclization
into the desired 4-quinolone 4f (Table 2, entry 6). In sev-
eral experiments no significant conversion could be de-
tected even after several days. The starting material was
recovered quantitatively and the optical purity of 3f was
found to be unchanged (98% ee as determined by HPLC
on a chiral stationary phase). This rules out a competing
deprotonation at the amide a-carbon atom as a reason for
the failure of this cyclization. As yet, we cannot provide a
definitive explanation and can only speculate that the cy-
clization process is rather sensitive toward the steric de-
mand of the amide substituent.
R3
R3
R1
3
Entry R1
R3
R2
Product Yield (%)
1
2
H
H
H
H
H
H
H
H
H
Me
H
H
H
Ph
3a
3b
3c
3d
3e
3f
99a
90b
68b
99a
99a
86b
33c
79a
58c
82a
47b
99b
H
2-pyridyl
2-thienyl
pentyl
i-Bu
3
H
4
H
5
H
6
H
(R)-CH(Et)Ph
pentyl
pentyl
Ph
7
5-F
3g
3h
3i
8
4-CO2Me
9
4-OMe
10
11
12
H
H
H
(R)-CH(OTBS)Ph 3j
(CH2)4COMe
CH=CHMe
3k
3ld
a Method A: X = NH2, Y = Cl, py (1.1 equiv), CH2Cl2 (0.1–0.2 M),
r.t., 16 h.
b Method B: X = NH2, Y = OH, PyBroP (1.1 equiv), Et3N (1.1 equiv),
CH2Cl2 (0.1 M), r.t., 16 h.
c Method C: X = Br, Y = NH2, CuI (0.1 equiv),
MeHNCH2CH2NHMe (0.1 equiv), K2CO3 (2.0 equiv), toluene (0.3
M), 100 °C, 16 h.
d Product 3l was formed as a 2:3 mixture of the conjugated and non-
conjugated alkenes.
To test the influence of different aryl substituents on the
amidoacetophenone on the cyclization efficiency, com-
pounds 3g–i were prepared and converted into the respec-
tive 4-quinolones 4g–i. The electronic properties of the
ring substituents did not have a significant influence on
the reactivity and the expected quinolone derivatives were
obtained in yields ranging from 44–63% (Table 2, entries
7–9). Nevertheless, entries 8 and 9 (Table 2) demonstrat-
ed that methoxycarbonyl and methoxy groups were toler-
ated under the reaction conditions. Entry 9 (Table 2)
shows that not only acetophenone derivatives are suitable
reaction partners but propiophenone derivatives also pro-
vide the respective 3-alkyl-substituted quinolone 4i.
Before examining the scope of the cyclocondensation re-
action in detail we sought to further optimize the process.
Employing ortho-amidoacetophenone 3a as a model sub-
strate, we varied the solvent, the reaction temperature and
equivalents of the reagents (Et3N and TMSOTf). Howev-
er, none of these changes enhanced the efficacy of the cy-
clization. In all the experiments, full conversion of the
starting material was achieved within 48 hours but the
yield of 4-quinolone 4a was low (~40%). A major prob-
lem was the separation of the 4-quinolone from the salt tri-
ethylammonium trifluoromethanesulfonate ([Et3NH][OTf])
which was formed during the reaction. By a simple mod-
Synthesis 2011, No. 20, 3261–3266 © Thieme Stuttgart · New York

PAPER
4-Quinolones via Cyclocondensation of ortho-Amidoacetophenones
3263
Table 2 Cyclocondensation of ortho-Amidoacetophenones 3 into
4-Quinolones 4
Table 2 Cyclocondensation of ortho-Amidoacetophenones 3 into
4-Quinolones 4 (continued)
O
R2
R3
O
O
R2
R1
NH
O
HN
Et3N (3 equiv)
TMSOTf (3–5 equiv)
3
R3
O
NH
3
63 (93%)b
HN
DCE (0.05 M)
reflux
R1
7
O
3
4
F
F
3g
Entry ortho-Amidoacetophenone 4-Quinolone
Yield (%)
4g
O
O
3
NH
O
3
NH
O
HN
1
83
8
51
HN
O
O
CO2Me
3a
CO2Me
4aa
3h
4h
O
N
O
N
NH
O
NH
O
2
85
HN
HN
9
44 (62%)b
O
O
O
O
O
3b
4ba
OMe
O
OMe
3i
O
4i
S
S
NH
O
O
O
HN
TBSO
HN
3
4
5
39
NH
O
10
81
TBSO
3c
3d
3e
4ca
O
3j
O
4j (ee >95%)d
3
NH
O
3
HN
92
O
3
NH
O
3
11
26
O
HN
4da
O
O
3k
4k
NH
31 (48%)b
HN
O
NH
O
HN
12
33
4e
O
O
Et
3le
4l
NH
O
6
0
HN
a Compounds 4a–d are known.12c
Et
b Yield in parentheses based on recovered starting material.
c Determined by chiral HPLC analysis.
O
d Determined by derivatization with chiral carboxylic acids.
e Compound 3l was used as a 2:3 mixture of the conjugated and un-
conjugated alkenes.
3f (ee = 98%)c
4f
Synthesis 2011, No. 20, 3261–3266 © Thieme Stuttgart · New York

3264
C. Eidamshaus et al.
PAPER
The need for strong bases in the classical Camps cycliza- tion, would afford the cationic intermediate 7. Subsequent
tion does not allow the use of enantiopure starting materi- deprotonation would then lead to 8 which after elimina-
als that might undergo racemization (e.g., ortho- tion of trimethylsilanol followed by proto-desilylation of
amidoacetophenones with stereogenic centers at the the 4-hydroxy group gives the 4-quinolone derivative 4.
amide a-carbon atom). In order to examine the racemiza-
R2
tion-free synthesis of chiral quinolone derivatives starting
from enantiopure substrates using our cyclization condi-
tions, mandelic acid derived ortho-amidoacetophenone
derivative 3j was prepared and cyclized to provide the
quinolone 4j (Table 2, entry 10). The desired product was
obtained in high yield and excellent optical purity (ee
>95%, see Supporting Information). In analogy to the re-
spective pyridine derivatives, enantiopure hydroxymeth-
yl-substituted quinolones obtained from 4j might be
efficient catalysts or ligands for asymmetric transforma-
tions.16
O
R3
O
R2
R1
NH
O
HN
R3
R1
4
3
OTMS
N
R2 OTMS
The striking differences in the reactivity of 3f and 3j
might be caused by different conformations of the amido
side chain. An internal hydrogen bond between the N–H
proton and the tert-butyldimethylsilyloxy (OTBS) group
in 3j hampers free rotation around the C1–C2 bond and
fixes the molecule in an eclipsed conformation. This
would make the C1 atom more accessible to nucleophilic
attack and therefore facilitate the reaction. However, as
the mechanism of the cyclization is not yet fully under-
stood and various pathways are conceivable (see below)
we cannot provide a precise explanation for the reaction
outcome and other factors cannot be excluded.
R3
R2
R1
OTMS
path B
N
path A
R3
OTMS
R1
5
8
+ H
– H
R2 OTMS
R3
OTMS
R2
R1
NH OTMS
HN
R3
OTMS
R1
Other functional groups including ketones and olefins
were also tolerated in this cyclization reaction, however
6
7
the yields of the respective 4-quinolones 4k and 4l were Scheme 2 Proposed mechanism for the TMSOTf-induced cycliza-
tion of ortho-amidoacetophenones 3 to 4-quinolones 4
rather low (Table 2, entries 11 and 12). Presumably, with
substrates 3k and 3l, side reactions occur under the Lewis
acidic reaction conditions limiting the efficiency of the
cyclization process.
To further increase the flexibility of the substitution pat-
tern of the prepared quinolone derivatives, compounds 4d
and 4j were subjected to our previously reported protocols
for O-selective nonaflation [using perfluoro-1-butane-
sulfonyl fluoride (NfF)] or O-selective methylation
(Scheme 3). We have already reported various applica-
tions for pyrid-4-yl nonaflates in palladium-catalyzed
cross-couplings such as Suzuki, Sonogashira and Heck re-
actions.13e,17 Under standard conditions nonaflate 9 fur-
nished Suzuki coupling product 10 in very good yield.
After selective O-methylation, product 11 was converted
into the enantiopure secondary alcohol 12 in excellent
yield.
Typically the reaction times for the cyclocondensation re-
actions ranged between 16–48 hours, however, in some
cases, only partial conversion was detected even after
three days. In these examples the reactions were stopped
and the yields based on recovered starting material are
given in parentheses (Table 2). Attempts were made to
shorten the reaction times by increasing the amount of
TMSOTf or varying the equivalents of base, but without
success. Also higher boiling chlorinated solvents were in-
vestigated (e.g. 1,2-dichlorobenzene) and the cyclization
was conducted in a microwave oven. Unfortunately, these
modifications did not lead to significant improvements in
the reaction rates.
In summary, we have shown that Et3N in combination
with TMSOTf can successfully replace metal alkoxides in
the base-promoted cyclocondensation of ortho-amidoace-
tophenones leading to 4-quinolone derivatives. The de-
scribed procedure is fairly tolerant of many functional
groups and allows for the selective preparation of 2-alkyl-
substituted 4-quinolones. Moreover, enantiomerically
pure starting materials can be employed to afford, without
racemization, enantiopure 4-quinolone derivatives with
chiral side chains. In one example it was demonstrated
that a quinolin-4-yl nonaflate was an excellent partner in
A proposed mechanism for the cyclization is depicted in
Scheme 2. In analogy to the proposed mechanism for the
cyclization of b-ketoenamides, the disilylated species 5 is
likely to be formed in the first step. From here two differ-
ent pathways are possible (A and B). Intermediate 5 can
either cyclize directly via a formal 6p-electrocyclization
to give the dihydroquinoline intermediate 8, or after N-
protonation leading to 6, a similar cyclization, which can
also be regarded as an intramolecular Mannich-type reac-
Synthesis 2011, No. 20, 3261–3266 © Thieme Stuttgart · New York

PAPER
4-Quinolones via Cyclocondensation of ortho-Amidoacetophenones
3265
ponents were then removed under reduced pressure before the resid-
ual material was partitioned between EtOAc (50 mL) and NaOH (2
M, 30 mL). The organic layer was separated and washed with
NaOH (2 M, 2 × 30 mL) to completely remove [HNEt3][OTf] (the
extraction process can be monitored by TLC, Rf [HNEt3][OTf] ~0.3
(5% MeOH in CH2Cl2, KMnO4 stain). The aq layer was back-ex-
tracted with EtOAc (2 × 30 mL), and the combined organic layer
dried over Na2SO4, filtered and the solvent removed under reduced
pressure. The crude residue was purified by flash column chroma-
tography (SiO2, 5% MeOH in CH2Cl2) to afford 4a. The analytical
data were in agreement with those reported in the literature.12c
3
3
N
N
a
b
4d
ONf
9, 98%
10, 85%
Yield: 158 mg (83%); yellow solid; mp >230 °C.
TBSO
HO
N
1H NMR (400 MHz, CDCl3–CD3OD, 1:1): d = 6.54 (s, 1 H, 3-H),
7.31–7.39 (m, 1 H, ArH), 7.47–7.55 (m, 3 H, ArH), 7.59–7.66 (m,
1 H, ArH), 7.71 (mc, 3 H, ArH), 8.27 (mc, 1 H, ArH).
13C NMR (101 MHz, CDCl3–CD3OD): d = 107.5 (d, C-3), 118.2 (s,
Ar), 123.8, 124.4, 124.8, 128.7, 130.0, 132.0, 133.9 (7 d, Ar), 140.3,
151.4, 151.6 (3 s, Ar and C-2), 179.1 (s, C-4).
N
d
c
4j
OMe
OMe
11, 80%
12, 92%
HRMS: m/z [M + H]+ calcd for C15H12NO: 222.0919; found:
222.0907.
Scheme 3 O-Selective nonaflation and O-selective methylation of
4-quinolones 4d and 4j, and subsequent cross-coupling to give 10 or
deprotection to afford 12. Reagents and conditions: (a) NaH, NfF, py-
ridine–THF–DMF (1:10:1), r.t., 3.5 h; (b) PhB(OH)2, Pd(PPh3)4,
K2CO3, DMF, 90 °C, 6 h; (c) MeI, K2CO3, DMF, r.t., 24 h; (d) TBAF
(1 M in THF), THF, r.t., 2 h.
Anal. Calcd for C15H11NO: C, 81.43; H, 5.01; N, 6.33. Found: C,
81.41; H, 5.19; N, 6.31.
2-Pentylquinolin-4-yl Nonaflate (9)
To a soln of 4d (100 mg, 0.46 mmol) in a mixture of THF (2 mL),
py (0.2 mL) and DMF (0.2 mL) was added NaH (60% wt in mineral
oil, 56 mg, 1.39 mmol). The resulting soln was stirred at r.t. for 30
min and then treated with NfF (0.25 mL, 1.4 mmol). Stirring at r.t.
was continued for 3.5 h before the reaction was quenched by addi-
tion of H2O. The organic layer was separated and the aq layer ex-
tracted with EtOAc (3 × 15 mL). The combined organic layers were
dried over Na2SO4, filtered and the solvent removed under reduced
pressure. The crude residue was purified by flash column chroma-
tography (SiO2, hexane–EtOAc, 9:1) to afford the title compound 9.
a palladium-catalyzed cross-coupling reaction. Hence, li-
braries of quinoline derivatives should be easily accessi-
ble via this method.
Reactions were generally performed under argon in flame-dried
flasks. Solvents and reagents were added via syringe. Solvents were
purified using the MB SPS-800-dry solvent system. Et3N was dis-
tilled from CaH2 and stored over KOH under an atmosphere of ar-
gon. Pyridine was stored over KOH under an atmosphere of argon.
Other reagents were purchased and used as received unless other-
wise stated. The products were purified by flash chromatography on
SiO2 (230–400 mesh, Merck or Fluka). Unless otherwise stated,
yields refer to analytically pure samples. Melting points were mea-
sured with a Reichert apparatus (Thermovar) and are uncorrected.
Optical rotations were determined with a Perkin–Elmer 241 pola-
rimeter at the temperatures given. IR spectra were obtained using a
Nicolet 5 SXC FT-IR spectrometer or with a Nexus FT-IR spec-
trometer fitted with a Nicolet Smart DuraSample IR ATR. NMR
spectra were recorded using Bruker AC 250, AC 500, AV-III 700
and JOEL ECX 400, Eclipse 500 instruments. Chemical shifts are
reported relative to residual solvent signals or TMS [1H: d = 0.00
(TMS), d = 7.26 (CDCl3); 13C: d = 77.0 (CDCl3); 19F: d = –162
(C6F6)]. Integrals are in accordance with assignments and coupling
constants (J) are given in Hz. All 13C NMR spectra are proton-de-
coupled. For detailed signal assignments 2D spectra were recorded
(COSY, HMQC, HMBC). The 13C NMR signals of the CF3(CF2)3
group are not given as unambiguous assignments were not possible
due to strong splitting through coupling with the 19F nuclei. HRMS
analyses were performed with an Agilent 6210 ESI–TOF instru-
ment. Elemental analyses were carried out with a CHN-Analyzer
2400 (Perkin–Elmer), a Vario EL or a Vario EL III.
Yield: 225 mg (98%); colorless oil.
IR (ATR): 2980–2860 (=C–H), 1655–1595 (C=C) cm–1.
1H NMR (500 MHz, CDCl3): d = 0.91 (t, J = 7.0 Hz, 3 H, 5¢-H),
1.31–1.49 (m, 4 H, 4¢-H, 3¢-H), 1.81–1.87 (m, 2 H, 2¢-H), 3.02 (t,
J = 7.9 Hz, 2 H, 1¢-H), 7.31 (s, 1 H, 3-H), 7.60–7.68 (m, 1 H, ArH),
7.79–7.82 (m, 1 H, ArH), 8.03 (mc, 1 H, ArH), 8.12 (mc, 1 H, ArH).
13C NMR (101 MHz, CDCl3): d = 13.9 (q, C-5¢), 22.5 (t, C-4¢), 29.3
(t, C-3¢), 31.5 (t, C-2¢), 39.3 (t, C-1¢), 111.8 (d, C-3), 119.7 (s, Ar),
120.5, 127.4, 129.0, 131.0 (4 d, Ar), 149.9 (s, Ar), 153.2 (s, C-2),
164.1 (s, C-4).
19F NMR (376 MHz, CDCl3): d = –127.7, –122.6, –110.6, –82.5.
HRMS: m/z [M + H]+ calcd for C18H17F9NO3S: 498.0780; found:
498.0807.
(R)-2-[(tert-Butyldimethylsiloxy)(phenyl)methyl]-4-methoxy-
quinoline (11)
To a soln of quinolone 4j (248 mg, 0.68 mmol) in DMF (3.5 mL)
was added K2CO3 (282 mg, 2.04 mmol) and MeI (115 mg, 0.81
mmol). The resulting suspension was stirred for 24 h at r.t. before
H2O (15 mL) and EtOAc (15 mL) were added. The organic layer
was separated and the aq layer extracted with EtOAc (2 × 20 mL).
The combined organic layers were washed with brine (1 × 20 mL),
dried over Na2SO4, filtered and the solvent removed under reduced
pressure. The crude residue was purified by flash column chroma-
tography (SiO2, hexane–EtOAc, 9:1) to afford quinoline 11.
2-Phenylquinolin-4(1H)-one (4a); Typical Procedure
To a soln of ortho-amidoacetophenone 3a (200 mg, 0.86 mmol) in
DCE (8.5 mL) was added Et3N (0.36 mL, 2.6 mmol) followed by
TMSOTf (1.12 g, 5.14 mmol). The resulting soln was heated to 95
°C under argon for 3 d. After cooling to r.t., the remaining TMSOTf
was quenched by slow addition of MeOH (5 mL). All volatile com-
Yield: 206 mg (80%); colorless oil; [a]D22 +171 (c 0.5, CHCl3).
IR (ATR): 3065–2850 (=C–H, C–H), 1620–1510 (C=C) cm–1.
Synthesis 2011, No. 20, 3261–3266 © Thieme Stuttgart · New York

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C. Eidamshaus et al.
PAPER
1H NMR (500 MHz, CDCl3): d = –0.01 (s, 3 H, SiCH3), 0.10 (s, 3
H, SiCH3), 0.97 [s, 9 H, C(CH3)3], 3.99 (s, 3 H, OCH3), 6.03 (s, 1 H,
CHPh), 7.03 (s, 1 H, 3-H), 7.18–7.22 (m, 1 H, ArH), 7.27–7.31 (m,
2 H, ArH), 7.45 (mc, 1 H, ArH), 7.55–7.60 (m, 2 H, ArH), 7.66 (mc,
1 H, ArH), 8.01 (mc, 1 H, ArH), 8.13 (mc, 1 H, ArH).
13C NMR (101 MHz, CDCl3): d = –4.9 (q, SiCH3), –4.8 (q, SiCH3),
18.3 [s, C(CH3)3], 25.8 [q, C(CH3)3], 55.5 (q, OCH3), 78.3 (d,
CHPh), 97.0 (d, C-3), 120.8, 121.6, 125.2, 125.8, 127.4, 128.1,
128.6 (7 d, Ar), 129.6 (s, Ar), 143.4 (s, Ar), 148.1 (s, Ar), 162.7 (s,
C-2), 165.7 (s, C-4).
(5) Lucero, B. d'A; Gomes, C. R. B.; Frugulhetti, I. C. de P. P.;
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HRMS: m/z [M + H]+ calcd for C23H30NO2Si: 380.2040; found:
380.2048.
Anal. Calcd for C23H29NO2Si: C, 72.78; H, 7.70; N, 3.69. Found: C,
72.89; H, 7.93; N, 3.74.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
Support of this work by the Deutsche Forschungsgemeinschaft, the
Studienstiftung des Deutschen Volkes (Ph.D. fellowship to C.E.)
and Bayer Schering Pharma AG is most gratefully acknowledged.
We also thank Dr. R. Zimmer for help during the preparation of this
manuscript.
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Synthesis 2011, No. 20, 3261–3266 © Thieme Stuttgart · New York