A general and efficient PIFA mediated synthesis of heterocycle-fused quinolinone derivatives

Article abstract of DOI:10.1016/S0040-4020(02)00903-1

A new application of the hypervalent iodine reagent phenyliodine(III)bis(trifluoroacetate) (PIFA) has been developed for the construction of a series of N, O, S-containing heterocycle-fused quinolinone derivatives in a general and efficient way. An altern

Full text of DOI:10.1016/S0040-4020(02)00903-1

Tetrahedron 58 (2002) 8581–8589
A general and efficient PIFA mediated synthesis of
heterocycle-fused quinolinone derivatives
*
M. Teresa Herrero, Imanol Tellitu, Esther Domınguez, Susana Hernandez, Isabel Moreno
*
´
and Raul SanMartın
´
´
´
´ ´ ´
Departamento de Quımica Organica II, Facultad de Ciencias, Universidad del Paıs Vasco–Euskal Herriko Unibertsitatea (UPV/EHU),
Apdo. 644-48080 Bilbao, Spain
Received 25 March 2002; revised 13 June 2002; accepted 23 July 2002
Abstract—A new application of the hypervalent iodine reagent phenyliodine(III)bis(trifluoroacetate) (PIFA) has been developed for the
construction of a series of N, O, S-containing heterocycle-fused quinolinone derivatives in a general and efficient way. An alternative
approach to the formation of these novel tricyclic heterocycles by a PIFA mediated aryl–heteroaryl coupling reaction is also
presented. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
presence in a variety of biologically active compounds7 has
led to the design of numerous approaches towards the
construction of this skeleton.8 In particular, some naturally
occurring and synthetically produced heterocycle-fused
quinolines and quinolinones of type 1 have attracted the
interest of the research community on account of their
important activity.9 However, there is a lack of effective and
general routes for the synthesis of this kind of derivatives.
In the last decades the chemistry of hypervalent iodine
reagents has witnessed a profound progress in the field of
synthetic organic chemistry. Their low toxicity, ready
availability and easy handling have allowed their appli-
cation to a number of important transformations1 and,
besides, their environmentally friendly nature also suggests
future applications in ‘green chemistry’. Particularly,
phenyliodine(III)bis(trifluoroacetate) (PIFA), phenyl-
iodine(III)diacetate) (PIDA) and hydroxy(tosyloxy)iodo-
benzene, Koser’s reagent (HITB) have found a wide
application in the synthesis of heterocyclic compounds.2
Among them, the known PIFA-mediated biaryl coupling
reaction has been employed by us3 and by others4 for the
preparation of different synthetic and naturally occurring
products containing the biaryl moiety. By contrast, apart
from the initial results of our group,5 and despite of its
enormous potential in the area of heterocyclic chemistry, the
I(III) promoted aryl–heteroaryl coupling reaction has not
been studied. Thus, according to this strategy, we have
employed PIFA to generate aryl radical-cations, via a SET
mechanism,6 to be intramolecularly trapped by aromatic and
heteroaromatic rings giving rise to a series of phenanthri-
dines, phenanthridinones3a and phenanthrenoids5a starting
from N-arylbenzylamines, N-arylbenzamides and stil-
benoids, respectively (see Scheme 1).
The quinoline system is a prevalent topic of research. Its
Keywords: hypervalent iodine; heterocycles; cyclizations; biaryl coupling;
quinolinones.
*
Corresponding authors. Tel.: þ34-94-601-2577; fax: þ34-94-601-2748;
e-mail: qopdopee@lg.ehu.es
Scheme 1.
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00903-1

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M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
reaction between commercially available amines 4a–c and
2-thiophene-carboxaldehyde (5) gave rise to the corre-
sponding imines which, without isolation (1H NMR¼8.2–
8.6 ppm), were reduced with NaBH4 to furnish amines 6a–c
which, in turn, were trifluoroacetylated10 yielding the
corresponding amides 7a–c, in good overall yields (64–
72%). Finally, these adequately functionalized precursors
were submitted to the cyclization conditions.
The oxidative biaryl-coupling step was accomplished using
commercially available PIFA and BF3·OEt2 as the activat-
ing agent in CH2Cl2 as solvent.11 Optimization of the
experimental conditions (amounts of reagents and reaction
temperature) led to the formation of the desired tricyclic
compounds, thienobenzoazepine 8b (n¼1) and thieno-
benzoazocine 8c (n¼2), in moderate yields (47 and 20%,
respectively). However, treatment of amide 7a under a
variety of reaction conditions resulted in a complete
degradation of the starting material. Consequently, the
expected thienoquinolinone 8a (n¼0) was never detected.
Scheme 2.
Therefore, and according to the success reached in our
previous experience, we decided to expand that method-
ology to the preparation of heterocycle-fused quinoline and
quinolinone derivatives from precursors of type 2 (see
approach A in Scheme 2).
On the other hand, during the course of our investigations
several problems arisen (vide infra) and, therefore, an
alternative synthetic approach had to be evaluated (see
approach B in Scheme 2). Encouraged by the enormous
synthetic potential of hypervalent iodine reagents, con-
veniently functionalized synthons 3 containing a preformed
biaryl bond were prepared. On the residual carboxamide
group, a PIFA mediated oxidation reaction was envisaged to
perform the key cyclization step. Therefore, in this paper, a
study of the I(III) mediated synthesis of a series of
heterocycle-fused quinolinones 1 will be disclosed through
the already mentioned routes.
Inspired in our precedents for the PIFA-mediated synthesis
of phenanthridinones from N-arylbenzamides,3a we next
checked the behavior of amides of type 10 and 11 under the
cyclization conditions. Thus, according to Scheme 4,
acylation of amines 4a–c with 2-thiophenecarbonyl
chloride (9) yielded amides 10a–c which were N-methyl-
ated12 under standard conditions to afford N-methylamides
11a–c, respectively, in good overall yields (61–90%).
Unfortunately, none of the six amides 10 and 11 submitted
to the cyclization reaction under a variety of conditions
afforded the desired tricyclic derivatives of type 12. In all
cases, degradation of the starting materials to afford
complex mixtures of unidentified compounds was observed.
2.2. The aromatic amidation approach
2. Results and discussion
Although, as already mentioned, the synthesis of some of
the target molecules 8b,c has been accomplished, we were
not satisfied with the obtained results since the employed
procedure is far to be considered efficient and general for
our synthetic purposes. Therefore, we decided to evaluate
the alternative B shown in Scheme 2.13 In this context, we
next focused our attention on the known ability of PIFA to
generate N-acylnitrenium ions from N-alkoxyamides14
2.1. The biaryl coupling approach
In order to optimize the projected approach (A in Scheme
2), the thiophene ring was selected as the heterocyclic
partner on the basis of its demonstrated stability under
oxidative coupling conditions.5 Thus, substrates 7a–c
(n¼0,1,2) were prepared as follows (see Scheme 3). The
Scheme 3. (i) 2-Thiophenecarboxaldehyde (5), toluene, reflux; (ii) NaBH4,
MeOH, 08Crt (92% for 6a, 95% for 6b, 90% for 6c); (iii) (CF3CO)2O,
pyridine, rt (70% for 7a, 75% for 7b, 80% for 7c); (iv) PIFA, BF3·OEt2,
CH2Cl2, 2402208C (0% for 8a, 47% for 8b, 20% for 8c).
Scheme 4. (i) 2-Thiophenecarbonyl chloride (9), pyridine, CH2Cl2, 08Crt
(94% for 10a, 72% for 10b, 97% for 10c); (ii) MeI, NaH, THF, 08C rt (96%
for 11a, 84% for 11b, 90% for 11c).

M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
8583
Scheme 5.
Scheme 7. (i) HITB, MeCN, 758C (85%); (ii) DMFDMA, toluene, 608C
(92%).
which, eventually, could be trapped intramolecularly by
arene rings to afford the target quinoline skeleton in a simple
way. Kikugawa had previously employed this approach in
an electrophilic aromatic substitution reaction,15 which
involved a N-chlorination step with t-BuOCl and oxidative
cyclization using silver or zinc salts.16 Similarly, Cherest
and Lusinchi employed ferric chloride with the same
purpose.17 Later, it was found18 that limitations associated
with these protocols (i.e. solubility of silver salts or
undesired aromatic chlorination) could be overcome by
using PIFA as the cyclization reagent in a single step.
tion under basic conditions yielding the methyl ester 17a in
an excellent 87% overall yield (four steps). Next, the ester
group was hydrolyzed under basic conditions, and the
resulting free carboxylic acid 18a was transformed into the
required amide 19a by treatment of the corresponding acyl
chloride derivative with methoxylamine. When the oxi-
dative cyclization conditions were applied to amide 19a, the
desired quinolinone 20a was obtained in 37% yield. To our
delight, by using TFA instead of BF3·OEt2 as the activating
agent,20 the yield was dramatically increased to 91%.
It is accepted that N-alkoxyamides I (see Scheme 5) react
with I(III) reagents to give intermediates of type II.
Subsequently, by release of PhI, the positively charged
species generated, which is stabilized by the electron
donating alkoxy group, is trapped intra- or intermolecularly
by an aromatic group. In our case, we envisaged that starting
from a precursor with a preformed biaryl bond and a
residual carbamoyl group on the heteroaromatic ring, as in
3, would facilitate the projected heterocyclization.
To the light of the so-obtained promising results, and
searching for future SAR studies, we decided to expand our
synthetic approach to the synthesis of a series of hetero-
cycle-fused quinolinones.21 With this objective in mind,
benzoylacetate 21 was selected as the starting material on
the basis of its potentiality for the preparation of a number of
different heterocycles (see Scheme 7).22 Thus, ester 21 was
transformed into the synthetically activated tosyloxy
derivative 2223 by the action of Koser’s reagent (HITB)24
and, separately, into the enaminoester 23 by treatment with
dimethylformamide dimethyl acetal (DMFDMA).25
Face to comparative purposes, we selected again a
thiophene substituted derivative as a model to optimize
the cyclization step. The preparation of the required ester
17a started (see Scheme 6) from benzaldehyde (13), which
reacted with the commercially available Grignard reagent
14 to afford the propargylic alcohol 15. Once prepared, it
was oxidized with manganese oxide to provide the
corresponding ketone 1619 which underwent conjugate
addition with methyl thioglycolate and subsequent cycliza-
Following with our synthetic objectives (see Scheme 8),
ketoester 22 was treated independently with thioacetamide
and thiobenzamide, under Hantzsch conditions, to afford
thiazoles 17b and 17c, respectively, in good yields.26 On the
other hand, the action of hydroxylamine3d and phenyl-
hydrazine27 on enaminoester 23 resulted in the formation of
the corresponding isoxazole 17d and phenylpyrazole 17e,
respectively, in good yields.
Scheme 6. (i) THF, 1-propynylmagnesium bromide (14), 08C; (ii) MnO2,
CH2Cl2, 08C (92%, two steps); (iii) HSCH2CO2Me, THF, 08C; (iv) MeOH,
Cs2CO3, MgSO4, 08Crt (97%, two steps); (v) NaOH, MeOH, THF, H2O, rt
(97%); (vi) SOCl2, toluene, reflux; (vii) NH2OMe·HCl, pyridine, CH2Cl2,
08Crt; (viii) PIFA, TFA, CH2Cl2, 08Crt (65%, two steps).
Scheme 8. (i) MeCSNH2, DMF, 608C (75%); (ii) PhCSNH2, DMF, 608C
(86%); (iii) NH2OH·HCl, pH¼425, MeOH, 1158C, sealed tube (80%); (iv)
PhNHNH2, pH¼5–6, MeOH, reflux (91%).

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M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
and efficient way starting from a common b-ketoester
precursor 21 has been presented. Our investigations provide
preparative approaches to interesting new and complex
heterocyclic compounds with potential pharmacological
activity.
4. Experimental30
Melting points were measured in a Bu¨chi apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin–
Elmer R-1420 infrared spectrophotometer as KBr plates or
as neat liquids and peaks are reported in cm21. NMR spectra
were recorded on a Bruker ACE-250 instrument (250 MHz
1
for H and 62.83 MHz for 13C). Chemical shifts (d) were
1
measured in ppm relative to chloroform (d 7.26 for H or
77.00 for 13C) as internal standard; dimethylsulfoxide-d6
(2.49 for 1H or 39.5 for 13C) has been used when indicated.
Coupling constants, J, are reported in Hertz. DEPT
experiments were used to assist with the assignation of the
signals. Combustion analyses were performed on a Perkin–
Elmer 2400 CHN apparatus, and HRMS spectra were
recorded at the University of Vigo on a VG Autospec M
instrument.
4.1. Typical procedure for the synthesis of amines 6a–c
4.1.1. Synthesis of N-(3,4-dimethoxyphenyl)-N-[(2-thi-
enyl)methyl]amine (6a). A suspension of 2-thiophene-
carboxaldehyde (5) (1.0 g, 8.8 mmol) and 3,4-
dimethoxyaniline (4a) (1.5 g, 9.7 mmol) in toluene
Scheme 9. (i) NaOH, H2O, MeOH, rt (87% for 18b, 93% for 18c, 85% for
18e); (ii) HCl, H2O, MeOH, reflux (85%); (iii) SOCl2, toluene, reflux;
(iv) NH2OMe·HCl, pyridine, CH2Cl2, 08Crt (79% for 19b, 80% for 19c,
68% for 19d, 82% for 19e); (v) PIFA, BF3·OEt2 or TFA, CH2Cl2,
2402208C (90% for 20b, 97% for 20c, 61% for 20d, 63% for 20e).
˚
(30 mL) was heated at reflux in the presence of 4 A
molecular sieves for 12 h under argon. Then, the mixture
was allowed to rise to rt, the solids were filtered, and the
solvent was distilled under vacuum. The so-obtained oil was
dissolved in MeOH (30 mL), NaBH4 (2.0 g, 52.5 mmol)
was added in three portions at 08C, and the mixture was
stirred at rt until total conversion of the starting material.
Water (20 mL) was added, the solution was extracted with
CH2Cl2 (3£20 mL) and dried over sodium sulfate. After
evaporation of the solvent, the resulting solid was crystal-
lized from MeOH to afford amine 6a as a pale brown
solid (92%). Mp 56–578C (MeOH); 1H NMR (CDCl3), 3.81
(s, 3H, OMe), 3.82 (s, 3H, OMe), 4.47 (s, 2H, CH2), 6.22
(dd, J¼8.4, 2.3 Hz, 1H, Harom), 6.31 (d, J¼2.3 Hz, 1H,
Harom), 6.75 (d, J¼8.4 Hz, 1H, Harom), 6.94–7.00 (m,
2H, Harom), 7.22 (d, J¼4.8 Hz, 1H, Harom); 13C NMR
(CDCl3), 43.2, 54.6, 55.6, 98.5, 102.8, 112.4, 123.5, 123.9,
125.9, 140.8, 141.9, 142.8, 149.0. Anal. calcd for
C13H15NO2S: C, 62.62; H, 6.06; N, 5.62. Found: C, 62.33;
H, 5.99; N, 5.40.
Transformation of esters 17b–e into the required methoxy-
amides 19b–d could not be achieved directly following
previously reported procedures.28 Therefore (see Scheme
9), esters 17 were first hydrolyzed under basic or acidic29
conditions to afford the corresponding carboxylic acids
18b–e which, by previous activation as carbonyl chlorides,
were successfully transformed into the desired amides
19b–d in good overall yields (59–70%, three steps).
Finally, application of the cyclization conditions on the
so-obtained amides 19 resulted in the formation of the target
quinolinone-fused heterocycles 20b–d. This final step had
to be optimized with respect to the employed activating
agent. In fact, it was observed that, whereas no difference
was observed in the formation of quinolinone 20e by using
either BF3·OEt2 or TFA (61 vs. 60% yield), boron trifluoride
was the reagent of choice in the formation of quinolinones
20b (90 vs. 75% yield) and 20c (97 vs. 90% yield).
Conversely, TFA afforded a better result in the formation of
quinolinone 20d (61 vs. 40% yield).
4.1.2. N-(3,4-Dimethoxybenzyl)-N-[(2-thienyl)methyl]-
amine (6b). According to the typical procedure amine 6b
was obtained from benzylamine 4b in 95% yield as an
orange oil. 1H NMR (CDCl3), 1.66 (br s, 1H, NH), 3.78 (s,
2H, CH2), 3.87 (s, 3H, OMe), 3.89 (s, 3H, OMe), 3.99 (s,
2H, CH2), 6.80–6.88 (m, 2H, Harom), 6.91–6.98 (m, 3H,
Harom), 7.22 (dd, J¼5.0, 1.4 Hz, 1H, Harom); 13C NMR
(CDCl3), 46.7, 51.7, 55.0, 55.1, 110.2, 110.6, 119.5, 123.6,
124.1, 125.9, 132.0, 143.7, 147.3, 148.2; HRMS calcd for
C14H17NO2S 263.0980, found 263.0980.
3. Conclusion
In summary, new synthetic uses of the hypervalent iodine
reagent PIFA for the construction of a series of N, O,
S-containing heterocycle-fused quinolinones in a general

M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
8585
4.1.3. N-(3,4-Dimethoxyphenethyl)-N-[(2-thienyl)methyl]-
amine (6c). According to the typical procedure amine 6c
was obtained from phenethylamine 4c in 90% yield as an
orange oil. 1H NMR (CDCl3), 1.53 (br s, 1H, NH), 2.77 (t,
J¼6.6 Hz, 2H, CH2), 2.91 (t, J¼6.6 Hz, 2H, CH2), 3.85 (s,
3H, OMe), 3.86 (s, 3H, OMe), 3.99 (s, 2H, CH2), 6.72–6.81
(m, 3H, Harom), 6.89–6.95 (m, 2H, Harom), 7.20 (dd, J¼5.0,
1.0 Hz, 1H, Harom); 13C NMR (CDCl3), 34.6, 47.1, 49.3,
54.4, 54.5, 110.2, 110.9, 119.4, 123.0, 123.4, 125.3, 131.4,
143.3, 146.2, 147.7; HRMS calcd for C15H19NO2S
277.1137, found 277.1142.
4.2.4. 8,9-(Dimethoxy)-5-trifluoroacetyl-5,6-dihydro-4H-
thieno[2,3-d][2]benzoazepine (8b). A solution of PIFA
(270 mg, 0.63 mmol) and BF3·OEt2 (0.10 mL, 0.83 mmol)
in CH2Cl2 (13 mL) was added to a solution of amide 7b
(150 mg, 0.42 mmol) in 8.5 mL of the same solvent. After
1 h, the solvent was removed in vacuo and the residue was
subjected to flash chromatography (hexanes/EtOAc, 7:3) to
yield benzoazepine 8b (47%) as an oil which was crystal-
lized from hexanes (rotamer mixture 62:38). Mp 119–
1
1218C (hexanes); H NMR (CDCl3), 3.94 (s, 6H, OMe),
4.42 and 4.49 (s, total 2H, CH2), 4.60 and 4.64 (s, total 2H,
CH2), 6.88 and 6.98 (s, total 1H, Harom), 7.02 (s, 1H, Harom),
7.25 (d, J¼5.2 Hz, 1H, Harom), 7.35 (d, J¼5.2 Hz, 1H,
Harom); 13C NMR (CDCl3), 43.5, 48.4, 56.0, 110.0, 110.2,
112.2, 113.6, 116.5 (q, J¼287 Hz), 116.6 (q, J¼287 Hz),
124.9, 125.1, 125.6, 127.2, 127.4, 128.8, 129.0, 130.1,
130.5, 141.0, 141.2, 148.4, 148.5, 149.2, 149.4, 155.0 (q,
J¼36 Hz), 155.2 (q, J¼36 Hz); IR (KBr) 1685. Anal. calcd
for C16H14F3NO3S: C, 53.78; H, 3.95; N, 3.92. Found: C,
53.66; H, 3.79; N, 3.82.
4.2. Typical procedure for the synthesis of N-trifluoro-
acetamides 7a–c
4.2.1. Synthesis of N-(3,4-dimethoxyphenyl)-N-[(2-thi-
enyl)methyl]-trifluoroacetamide (7a). Trifluoroacetic
anhydride (2.8 mL, 20.1 mmol) was added to a solution of
amine 6a (2.0 g, 8.0 mmol) in pyridine (20 mL) at 08C, and
the mixture was stirred for 1 h. Then, water (20 mL) and
EtOAc (20 mL) was added and the mixture was washed
with 5% aq HCl (1£20 mL), water (1£20 mL), brine
(1£20 mL), and the organic phase was dried over sodium
sulfate. After distillation of the solvent, the resulting solid
was crystallized from hexanes to afford amide 7a as a pale
brown solid (70% yield). Mp 53–558C (hexanes); 1H NMR
(CDCl3), 3.75 (s, 3H, OMe), 3.88 (s, 3H, OMe), 5.00 (br s,
2H, CH2), 6.51 (d, J¼1.6 Hz, 1H, Harom), 6.66 (dd, J¼8.3,
1.6 Hz, 1H, Harom), 6.80–6.93 (m, 3H, Harom), 7.27 (d,
J¼5.2 Hz, 1H, Harom); 13C NMR (CDCl3), 49.4, 55.3, 55.4,
110.2, 111.1, 116.0 (q, J¼289 Hz), 120.4, 126.1, 126.2,
128.3, 130.5, 136.6, 148.5, 149.1, 156.2 (q, J¼36 Hz); IR
(neat) 1694. Anal. calcd for C15H14F3NO3S: C, 52.17; H,
4.09; N, 4.06. Found: C, 52.26; H, 4.33; N, 4.12.
4.2.5. 9,10-(Dimethoxy)-5-trifluoroacetyl-4,5,6,7-tetra-
hydrothieno[2,3-e][3]benzoazocine (8c). A solution of
PIFA (175 mg, 0.40 mmol) and BF3·OEt2 (0.07 mL,
0.54 mmol) in CH2Cl2 (25 mL) was added to a solution of
amide 7c (100 mg, 0.27 mmol) in 8.5 mL of the same
solvent at 2408C. After 12 h, the solvent was removed in
vacuo and the residue was subjected to flash chromato-
graphy (hexanes/EtOAc, 7:3) yielding the benzoazocine 8c
in 20% yield as an oil which was crystallized from hexanes.
1
Mp 148–1508C (hexanes); H NMR (CDCl3), 2.37–2.42
(m, 1H, H-7), 2.99–3.07 (m, 1H, H-7), 3.22–3.27 (m, 1H,
H-6), 3.56 (d, J¼14.3 Hz, 1H, H-4), 3.89 (s, 3H, OMe), 3.93
(s, 3H, OMe), 4.24–4.32 (m, 1H, H-6), 5.22 (d, J¼14.3 Hz,
1H, H-4), 6.76 (s, 1H, Harom), 6.85 (s, 1H, Harom), 7.05 (d,
J¼5.2 Hz, 1H, Harom), 7.30 (d, J¼5.2 Hz, 1H, Harom); 13C
NMR (CDCl3), 35.2, 44.1, 48.4, 48.5, 55.9, 111.9, 112.6,
116.3 (q, J¼287 Hz), 125.3 127.4, 127.9, 130.7, 131.8,
140.5, 147.5, 148.8, 155.7 (q, J¼36 Hz); IR (KBr) 1688.
Anal. calcd for C17H16F3NO3S: C, 54.98; H, 4.34; N, 3.77.
Found: C, 55.00; H, 4.59; N, 3.88.
4.2.2. N-(3,4-Dimethoxybenzyl)-N-[(2-thienyl)methyl]-
trifluoroacetamide (7b). According to the typical pro-
cedure amide 7b was obtained from amine 6b in 75% yield
(rotamer mixture 46:54) as an orange oil. 1H NMR (CDCl3),
3.85 (s, 3H, OMe), 3.88 and 3.89 (s, total 3H, OMe), 4.53 (s,
2H, CH2), 4.62 (s, 2H, CH2), 6.71–7.02 (m, 5H, Harom),
7.33 (d, J¼5.2 Hz) and 7.26 (d, J¼5.2 Hz, total 1H, Harom);
13C NMR (CDCl3), 42.5, 43.7, 47.1, 48.9, 55.2, 110.0,
110.6, 110.8, 111.0, 116.2 (q, J¼288 Hz), 119.9, 120.6,
125.8, 126.0, 126.2, 127.2, 127.5, 136.5, 148.4, 148.6,
148.8, 149.0, 156.1 (q, J¼36 Hz), 156.3 (q, J¼36 Hz); IR
(neat) 1690; HRMS calcd for C16H16NO3F3S 359.0803,
found 359.0806.
4.3. Typical procedure for the synthesis of amides 10a–c
4.3.1. Synthesis of N-(3,4-dimethoxyphenyl)-2-thio-
phene-carboxamide (10a). Pyridine (1.3 mL, 16.3 mmol)
was added to a solution of commercially available
2-thiophenecarbonyl chloride (9) (1.0 g, 6.8 mmol) and
amine 4a (1.91 g, 3.80 mmol) in CH2Cl2 (30 mL) at 08C,
and the mixture was stirred at rt until total consumption of
the starting material (tlc, Hex/EtOAc, 1:1, 12 h). Then, the
crude mixture was washed with a saturated solution of
CuSO4 (3£10 mL) and water (2£10 mL). The organic phase
was dried over sodium sulfate and the solvent was distilled
under vacuum to afford amide 10a as a white solid which
was purified by crystallization from MeOH (94% yield). Mp
4.2.3. N-(3,4-Dimethoxyphenethyl)-N-[(2-thienyl)-
methyl]-trifluoroacetamide (7c). According to the typical
procedure amide 7c was obtained from amine 4c in 80%
1
yield (rotamer mixture 50:50) as an orange oil. H NMR
(CDCl3), 2.74–2.89 (m, 2H, CH2), 3.52–3.61 (m, 2H,
CH2), 3.86 (s, 6H, OMe), 4.48 and 4.73 (s, total 2H, CH2),
6.65–6.72 (m, 2H, Harom), 6.80–6.83 (m, 1H, Harom), 6.92–
7.00 (m, 2H, Harom), 7.28–7.31 (m, 1H, Harom); 13C NMR
(CDCl3), 31.6, 34.0, 44.0, 45.7, 47.5, 47.7, 54.9, 110.7,
110.8, 111.1, 111.2, 115.9 (q, J¼289 Hz), 120.0, 125.6,
125.7, 126.0, 126.3, 126.9, 127.0, 129.1, 130.0, 136.6,
136.8, 147.1, 147.3, 148.3, 148.4, 155.3 (q, J¼36 Hz), 156.1
(q, J¼36 Hz); IR (neat) 1690; HRMS calcd for
C17H18F3NO3S 373.0957, found 373.0959.
1
175–1778C (MeOH); H NMR (DMSO-d6), 3.73 (s, 3H,
OMe), 3.75 (s, 3H, OMe), 6.93 (d, J¼8.8 Hz, 1H, Harom),
7.19–7.23 (m, 1H, Harom), 7.27 (dd, J¼8.8, 2.3 Hz, 1H,
Harom), 7.39 (d, J¼2.3 Hz, 1H, Harom), 7.83 (d, J¼4.6 Hz,
1H, Harom), 7.98 (d, J¼3.8 Hz, 1H, Harom), 10.1 (br s, 1H,
NH); 13C NMR (DMSO-d6), 55.4, 55.7, 105.5, 111.9, 112.5,
128.2, 128.8, 131.7, 132.3, 140.4, 145.3, 148.5, 159.7; IR

8586
M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
(KBr) 1633. Anal. calcd for C13H13NO3S: C, 59.30; H, 4.98;
N, 5.32. Found: C, 59.26; H, 4.73; N, 5.22.
4.4.3. N-(3,4-Dimethoxyphenethyl)-N-methyl-2-thio-
phenecarboxamide (11c). According to the typical
procedure amide 11c was obtained from amide 10c in
90% yield as a brownish oil. 1H NMR (CDCl3 at 428C), 2.88
(t, J¼7.3 Hz, 2H, CH2), 3.10 (s, 3H, NMe), 3.73 (t,
J¼7.3 Hz, 2H, CH2), 3.82 (s, 3H, OMe), 3.83 (s, 3H,
OMe), 6.70–6.81 (m, 3H, Harom), 7.00 (dd, J¼5.2, 4.0 Hz,
1H, Harom), 7.24 (d, J¼4.0 Hz, 1H, Harom), 7.40 (dd, J¼5.2,
1.2 Hz, 1H, Harom); 13C NMR (CDCl3), 32.9, 35.8, 51.0,
55.2, 55.3, 111.4, 112.0, 120.2, 125.9, 127.7, 128.0, 130.6,
137.4, 147.3, 148.6, 163.4; IR (neat) 1615; HRMS calcd for
C16H19NO3S 305.1085, found 305.1096.
4.3.2. N-(3,4-Dimethoxybenzyl)-2-thiophenecarboxa-
mide (10b). According to the typical procedure amide
10b was obtained from benzylamine 4b in 72% yield as a
1
white solid. Mp 118–1198C (MeOH); H NMR (CDCl3),
3.65 (s, 3H, OMe), 3.71 (s, 3H, OMe), 4.39 (d, J¼5.6 Hz,
2H, CH2), 6.62–6.76 (m, 3H, Harom), 6.92 (dd, J¼4.8,
3.9 Hz, 1H, Harom), 7.37 (d, J¼4.8 Hz, 1H, Harom), 7.56 (t,
J¼5.6 Hz, 1H, NH), 7.61 (d, J¼3.9 Hz, 1H, Harom); 13C
NMR (CDCl3), 43.4, 55.4, 55.5, 110.7, 110.8, 119.9, 127.4,
127.9, 129.9, 130.5, 138.8, 148.0, 148.6, 161.8; IR (KBr)
1629. Anal. calcd for C14H15NO3S: C, 60.63; H, 5.45; N,
5.05. Found: C, 60.36; H, 5.53; N, 5.32.
4.4.4. Ethyl 2-(N,N-dimethylaminomethyliden)benzoyl-
acetate (23). DMFDMA (0.9 mL, 6.37 mmol) was added
dropwise to a solution of commercially available ketoester
21 (1.0 g, 5.78 mmol) in 7 mL of toluene, and the mixture
was stirred at 608C for 24 h. After cooling, solvent was
evaporated in vacuo, and the resulting oil was column
chromatographed (hexanes/EtOAc, 6:4) to afford ester 23
which was crystallized from hexanes (92%) as a yellowish
4.3.3. N-(3,4-Dimethoxyphenethyl)-2-thiophenecarboxa-
mide (10c). According to the typical procedure amide 10c
was obtained from phenethylamine 4c in 97% yield as a
yellowish solid. Mp 95–978C (hexanes); 1H NMR (CDCl3),
2.87 (t, J¼6.7 Hz, 2H, CH2), 3.62–3.70 (m, 2H, CH2), 3.84
(s, 3H, OMe), 3.87 (s, 3H, OMe), 6.04 (br s, 1H, NH), 6.74–
6.84 (m, 3H, Harom), 7.05 (dd, J¼5.0, 4.0 Hz, 1H, Harom),
7.41 (d, J¼4.0 Hz, 1H, Harom), 7.45 (d, J¼5.0 Hz, 1H,
Harom); 13C NMR (CDCl3), 34.9, 41.2, 55.3, 55.4, 110.9,
111.5, 120.3, 127.3, 127.7, 129.7, 131.1, 138.9, 147.1, 148.4,
161.9; IR (KBr) 1628. Anal. calcd for C15H17NO3S: C, 61.83;
H, 5.88; N, 4.81. Found: C, 61.63; H, 5.70; N, 4.62.
1
solid. Mp 26–298C (hexanes); H NMR (CDCl3), 0.91 (t,
J¼7.1 Hz, 3H, CMe), 3.01 (br s, 6H, NMe2), 3.98 (q,
J¼7.1 Hz, 2H, CH2), 7.38–7.48 (m, 3H, Harom), 7.57–7.81
(m, 3H, H–Cv, Harom); 13C NMR (CDCl3), 13.5, 41.0,
45.5, 59.2, 99.1, 127.5, 128.4, 131.2, 140.6, 155.5, 168.2,
193.6; IR (KBr) 1684, 1631; HRMS calcd for C14H17NO3
247.1208, found 247.1203.
4.4. Typical procedure for the synthesis of N-methyl-
amides 11a–c
4.4.5. 1-Phenylbut-2-yn-1-one (16).19 1-Propynylmag-
nesium bromide (14) (20.8 mL, 0.5 M in THF,
10.4 mmol) was added to a solution of benzaldehyde (13)
(1 g, 9.4 mmol) in 50 mL of THF at 08C. The mixture was
stirred at the same temperature until the conversion was
complete (NMR, 90 min). Then, a saturated solution of
NH4Cl (20 mL) was added and the aqueous phase was
extracted with EtOAc (3£20 mL). The combined extracts
were dried (Na2SO4) and evaporated to yield alcohol 15.
Without isolation, crude alcohol 15 was dissolved in 10 mL
of CH2Cl2 and added to a suspension of MnO2 (28.2 g,
324 mmol) in CH2Cl2 (25 mL). The mixture was stirred
for 1 h at 08C, filtered through a pad of celite and MgSO4,
and concentrated in vacuo to yield ketone 16 (92%, two
steps).
4.4.1. Synthesis of N-(3,4-dimethoxyphenyl)-N-methyl-2-
thiophenecarboxamide (11a). A solution of MeI (1.9 mL,
30.4 mmol) and amide 10a in THF (60 mL) was added to a
suspension of NaH (228 mg, 9.5 mmol) in 15 mL of the
same solvent at 08C. After stirring for 20 min, temperature
was raised to rt and stirring was continued during 3 h. Then,
water (60 mL) was added, decanted, and the aqueous layer
was extracted with EtOAc (3£25 mL). The combined
organic extracts were dried over sodium sulfate and the
solvent was distilled under vacuum. The resulting residue
was crystallized from hexanes to afford amide 11a as a pale
1
brown powder (96% yield). Mp 120–1228C (hexanes); H
NMR (CDCl3), 3.42 (s, 3H, NMe), 3.82 (s, 3H, OMe), 3.92
(s, 3H, OMe), 6.74 (d, J¼2.0 Hz, 1H, Harom), 6.79–6.88 (m,
4H, Harom), 7.30 (dd, J¼4.8, 1.2 Hz, 1H, Harom); 13C NMR
(CDCl3), 38.9, 55.7, 55.8, 111.0, 120.1, 126.4, 130.4, 131.9,
136.6, 137.7, 148.6, 149.3, 162.3; IR (KBr) 1624. Anal.
calcd for C14H15NO3S: C, 60.63; H, 5.45; N, 5.05. Found:
C, 60.36; H, 5.74; N, 5.19.
4.4.6. 2-Methoxycarbonyl-5-methyl-3-phenylthiophene
(17a). Methyl thioglycolate (0.74 mL, 8.3 mmol) was
added over a cold (08C) solution of crude ketone 16
(1.2 g, 8.3 mmol) in 30 mL of THF. After stirring for 2 h,
MeOH (8.3 mL) and Cs2CO3/MgSO4 (8.3 g, 1:2) were
added and stirring was continued for 15 min at the same
temperature and for 2 h at rt. Then, the mixture was poured
onto an ice-cooled 2N aq NaH2PO4 solution (150 mL) and
EtOAc. The aqueous phase was extracted with EtOAc
(3£25 mL). The combined extracts were dried (Na2SO4)
and evaporated in vacuo to afford ester 17a as an oil that
was crystallized from hexanes (97%). Mp 95–978C
4.4.2. N-(3,4-Dimethoxybenzyl)-N-methyl-2-thiophene-
carboxamide (11b). According to the typical procedure
amide 11b was obtained from amide 10b in 84% yield as an
1
orange oil. H NMR (CDCl3 at 428C), 3.10 (s, 3H, NMe),
3.86 (s, 3H, OMe), 3.87 (s, 3H, OMe), 4.70 (s, 2H, CH2),
6.82–6.88 (m, 3H, Harom), 6.99–7.03 (m, 1H, Harom), 7.34
(d, J¼3.6 Hz, 1H, Harom), 7.43 (d, J¼4.8 Hz, 1H, Harom);
13C NMR (CDCl3), 35.2, 52.8, 55.7, 110.9, 111.5, 119.6,
126.4, 128.5, 129.1, 137.6, 148.4, 149.2, 164.2; IR (neat)
1617; HRMS calcd for C15H17NO3S 291.0929, found
291.0930.
1
(hexanes); H NMR (CDCl3), 2.52 (s, 3H, Me), 3.74 (s,
3H, OMe), 6.78 (s, 1H, H-4), 7.37–7.43 (m, 5H, Harom); 13
C
NMR (CDCl3), 15.3, 51.4, 123.8, 127.4, 127.5, 128.9,
130.1, 135.6, 145.1, 148.8, 162.1; IR (KBr) 1718. Anal.
calcd for C13H12O2S: C, 67.21; H, 5.21. Found: C, 67.41; H,
5.44.

M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
8587
4.4.7. 2-Carboxy-5-methyl-3-phenylthiophene (18a).
4.6. Typical procedure for the synthesis quinolinones
20a–e
Sodium hydroxide (12.0 g, 310 mmol) was added to a
solution of ester 17a (1.8 g, 7.8 mmol) in 40 mL of a
mixture of MeOH/THF/H2O (6.5:2.0:1.5) and the mixture
was stirred until total consumption of the starting material.
Then, the solution was treated with HCl (5% aq) and
extracted with EtOAc (3£20 mL). The organic extracts
were dried over sodium sulfate and the solvent was
evaporated under reduced pressure to afford carboxylic
acid 18a as an oil that was crystallized from Et2O
4.6.1. Synthesis of N-methoxy-2-methylthieno[2,3-c]-
quinolin-4-one (20a). A solution of PIFA (1.03 mmol)
and the activating agent (BF3·OEt2 for 20a–c and TFA for
20d,e, 3.0 mmol) in 15 mL of CH2Cl2 was added at 08C (at
2208C for 20b–e) to a solution of amide 19a (1.0 mmol) in
10 mL of the same solvent. The mixture was stirred at the
same temperature during 1 h and then treated with Na2CO3
(aq), decanted and dried over sodium sulfate. The oil
obtained after solvent evaporation was column chromato-
graphed (Hex/EtOAc, 3:7) and crystallized from hexanes to
afford quinolinone 20a as a pale brown solid in 91% yield.
1
(97%). Mp 181–1828C (Et2O); H NMR (MeOH-d4), 2.47
(s, 3H, Me), 6.77 (s, 1H, H-4), 7.28–7.36 (m, 5H, Harom);
13C NMR (DMSO-d6), 15.4, 126.2, 128.6, 128.7, 130.2,
131.6, 137.4, 146.8, 150.3, 165.1; IR (KBr) 1677. Anal.
calcd for C12H10O2S: C, 66.03; H, 4.62. Found: C, 66.33; H,
4.40.
1
Mp 130–1328C (hexanes); H NMR (CDCl3), 2.67 (s, 3H,
Me), 4.14 (s, 3H, NOMe), 7.29–7.36 (m, 1H, Harom), 7.40
(s, 1H, H-1), 7.54–7.60 (m, 1H, Harom), 7.69 (d, J¼8.3 Hz,
1H, Harom), 7.92 (d, J¼7.9 Hz, 1H, Harom); 13C NMR
(CDCl3), 16.3, 63.0, 112.7, 117.0, 120.4, 122.8, 124.2,
128.6, 129.2, 136.2, 141.7, 149.1, 153.7; IR (KBr) 1656.
Anal. calcd for C13H11NO2S: C, 63.65; H, 4.52; N, 5.71.
Found: C, 63.73; H, 4.44; N, 5.65.
4.5. Typical procedure for the synthesis of amides 19
4.5.1. Synthesis of N-methoxycarbamoyl-5-methyl-3-
phenylthiophene (19a). Thionyl chloride (0.86 mL,
11.7 mmol) was added to a solution of acid 18a (1.7 g,
7.8 mmol) in 60 mL of toluene and the mixture was heated
to reflux for 4 h. Then, the mixture was cooled to rt and the
solvent was evaporated under reduced pressure. The so-
obtained oil was dissolved in 60 mL of CH2Cl2 and
NH2OMe·HCl (716 mg, 8.6 mmol) and pyridine (1.26 mL,
15.6 mmol) were added. The new mixture was stirred at rt
until total consumption of the starting material (1H NMR).
Then, the solution was treated with a saturated aqueous
solution of CuSO4 (3£20 mL). The organic phase was dried
over sodium sulfate and the solvent was evaporated under
reduced pressure. The resulting residue was column
chromatographed (Hex/EtOAc, 7:3) to afford amide 19a
as an oil which was crystallized from Et2O as a white
4.6.2. N-Methoxy-2-methylthiazolo[5,4-c]quinolin-4-one
(20b). According to the typical procedure, quinolinone 20b
was obtained from amide 19b13 in 90% yield as a brown
solid. Mp 184–1868C (hexanes); 1H NMR (CDCl3), 2.91 (s,
3H, Me), 4.15 (s, 3H, OMe), 7.37–7.44 (m, 1H, Harom),
7.62–7.73 (m, 2H, Harom), 8.40–8.43 (m, 1H, Harom); 13C
NMR (CDCl3), 20.2, 63.2, 112.4, 116.5, 123.3, 124.7,
130.4, 136.6, 153.5, 154.4, 173.6; IR (KBr) 1656. Anal.
calcd for C12H10N2O2S: C, 58.52; H, 4.09; N, 11.37. Found:
C, 58.73; H, 4.10; N, 11.15.
4.6.3. N-Methoxy-2-phenylthiazolo[5,4-c]quinolin-4-one
(20c). According to the typical procedure, quinolinone 20c
was obtained from amide 19c13 in 97% yield as a white
1
powder (65%). Mp 102–1048C (Et2O); H NMR (CDCl3),
2.50 (s, 3H, Me), 3.66 (s, 3H, OMe), 6.70 (s, 1H, H-4),
7.38–7.45 (m, 5H, Harom), 7.98 (br s, 1H, NH); 13C NMR
(CDCl3), 15.2, 64.0, 127.8, 128.3, 128.5, 128.7, 128.9,
135.2, 142.9, 144.1, 161.1; IR (KBr) 3189, 1649. Anal.
calcd for C13H13NO2S: C, 63.13; H, 5.30; N, 5.66. Found:
C, 63.33; H, 5.15; N, 5.29.
1
solid. Mp 183–1858C (Et2O); H NMR (CDCl3), 4.19 (s,
3H, OMe), 7.43 (t, J¼7.9 Hz, 1H, Harom), 7.53–7.55 (m,
3H, Harom), 7.64–7.75 (m, 2H, Harom), 8.14–8.17 (m, 2H,
Harom), 8.56 (d, J¼7.9 Hz, 1H, Harom); 13C NMR (CDCl3),
63.2, 112.3, 116.6, 123.2, 124.5, 124.8, 127.2, 128.9, 130.3,
131.5, 132.5, 136.6, 153.5, 155.0, 174.0; IR (KBr) 1668.
Anal. calcd for C17H12N2O2S: C, 66.22; H, 3.92; N, 9.08.
Found: C, 66.33; H, 3.79; N, 9.10.
4.5.2. 4-(N-Methoxycarbamoyl)-5-phenylisoxazole (19d).
According to the typical procedure amide 19d was obtained
from acid 18d31 in 68% yield as a pale brown solid. Mp
1
109–1118C (Et2O); H NMR (CDCl3), 3.69 (s, 3H, OMe),
4.6.4. N-Methoxyisoxazolo[4,5-c]quinolin-4-one (20d).
According to the typical procedure quinolinone 20d was
obtained from amide 19d in 61% yield as a white.
Mp.2008C (hexanes); 1H NMR (CDCl3), 4.12 (s, 3H,
OMe), 7.39–7.45 (m, 1H, Harom), 7.69–7.76 (m, 2H,
Harom), 8.10–8.13 (m, 1H, Harom), 8.92 (s, 1H, H-3); 13C
NMR (CDCl3), 63.4, 108.7, 110.4, 113.2, 123.4, 123.7,
133.1, 137.4, 147.4, 153.3, 165.6; IR (KBr) 1684. Anal.
calcd for C11H8N2O3: C, 61.11; H, 3.73; N, 12.96. Found: C,
61.23; H, 3.69; N, 13.00.
7.39–7.43 (m, 3H, Harom), 7.84–7.87 (m, 2H, Harom), 8.52
(s, 1H, H-3); 13C NMR (CDCl3), 64.2, 108.3, 125.9, 128.2,
128.7, 131.4, 149.8, 159.8, 169.9; IR (KBr) 3201, 1655.
Anal. calcd for C11H10N2O3: C, 60.55; H, 4.62; N, 12.84.
Found: C, 60.65; H, 4.69; N, 13.01.
4.5.3. 1,5-Diphenyl-4-(N-methoxycarbamoyl)pyrazole
(19e). According to the typical procedure pyrazole 19e
was obtained from ester 18e32 in 82% yield as a pale brown
solid. Mp 173–1758C (hexanes); 1H NMR (CDCl3), 3.67 (s,
3H, OMe), 7.14–7.38 (m, 10H, Harom), 8.11 (s, 1H, H-3),
8.56 (br s, 1H, NH); 13C NMR (CDCl3), 64.3, 114.6, 125.0,
127.9, 128.4, 128.7, 128.8, 129.7, 130.1, 138.8, 140.8,
142.1, 161.7; IR (KBr) 3236, 1643. Anal. calcd for
C17H15N3O2: C, 69.61; H, 5.15; N, 14.33. Found: C,
69.66; H, 5.39; N, 14.40.
4.6.5. N-Methoxy-1-phenylpyrazolo[4,5-c]quinolin-4-
one (20e). According to the typical procedure, quinolinone
20e was obtained from amide 19e in 63% yield as a white
solid. Mp 192–1948C (hexanes); 1H NMR (CDCl3), 4.10 (s,
3H, OMe), 6.98–7.22 (m, 2H, Harom), 7.50–7.69 (m, 7H,
Harom), 8.41 (s, 1H, H-3); 13C NMR (CDCl3), 62.8, 110.2,

8588
M. T. Herrero et al. / Tetrahedron 58 (2002) 8581–8589
(b) Oshiro, Y.; Sakurai, Y.; Sato, S.; Kurahashi, N.; Tanaka,
T.; Kikuchi, T.; Tottori, K.; Uwahodo, Y.; Miwa, T.; Nishi, T.
J. Med. Chem. 2000, 43, 177–189. (c) Michael, J. P. Nat.
Prod. Rep. 1995, 12, 77–89. (d) Michael, J. P. Nat. Prod. Rep.
1995, 12, 465–475.
113.1, 113.8, 122.4, 122.8, 126.8, 129.7, 129.9, 130.3,
136.5, 138.2, 138.6, 139.8, 154.1; IR (KBr) 1678. Anal.
calcd for C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found:
C, 70.22; H, 4.39; N, 14.20.
8. (a) Toomey, J. E.; Murigan, R. Progress in Heterocyclic
Chemistry; Elsevier: Oxford, 1996; Vol. 8. pp 214–216.
(b) Comins, D. L.; O’Connor, S. Progress in Heterocyclic
Chemistry; Elsevier: Oxford, 1997; Vol. 9. pp 231–234.
9. Heterocycle-fused quinolines, including thienoquinolines, are
reported to possess significant antiinflammatory, antitumor
and antibacterial properties. See for example: (a) Mekheimer,
R. A.; Ahmed, E. K.; El-Fahham, H. A.; Kamel, L. H.
Synthesis 2001, 97–102, and references cited therein. See
also: (b) Mekheimer, R. A. Synthesis 2000, 2078–2084.
(c) Toche, R. B.; Jachak, M. N.; Sabnis, R. W.; Kappe, T.
J. Heterocycl. Chem. 1999, 36, 467–471, and references cited
therein.
Acknowledgements
Financial support from the University of the Basque
Country (UPV 170.310-G37/98) and Basque Government
(PI 53/96) is gratefully acknowledged. The Ministerio de
Educacion y Cultura (Spain) is also acknowledged for a
fellowship granted to M. T. H. and for additional financial
support (PB 0600-97).
´
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