New heterocyclic inputs for the povarov multicomponent reaction

Article abstract of DOI:10.1055/s-0030-1260062

Oxa-, thia- and imidazolones are reactive inputs as electron-rich olefin components in Povarov reactions. On interaction with anilines and aldehydes, these substrates afford the corresponding multicomponent adducts in a regioselective manner. Intramolecular processes are also explored. Post-condensation oxidation provides convenient access to a variety of fused quinoline derivatives. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260062

SPECIAL TOPIC
2237
New Heterocyclic Inputs for the Povarov Multicomponent Reaction
H
eterocyclic In
s
P
o
t
varov
h
MCR er Vicente-García,a Rosario Ramón,a Rodolfo Lavilla*a,b
a
Barcelona Science Park, Baldiri Reixac 10–12, 08028, Barcelona, Spain
Laboratory of Organic Chemistry, Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII sn, 08028, Barcelona, Spain
Fax +34(93)4037104; E-mail: rlavilla@pcb.ub.es
b
Received 28 March 2011
Dedicated to Professor Carmen Nájera on the occasion of her 60th birthday
The reactivity of some geminally diheterosubstituted sys-
tems was also tackled. Although the putative structures re-
sulting from these MCRs are attractive, only a scattered
number of precedents can be found in databases, includ-
Abstract: Oxa-, thia- and imidazolones are reactive inputs as elec-
tron-rich olefin components in Povarov reactions. On interaction
with anilines and aldehydes, these substrates afford the correspond-
ing multicomponent adducts in a regioselective manner. Intramo-
lecular processes are also explored. Post-condensation oxidation ing ketene dithioacetals,9 dihydro-1,4-dioxines, and 1,3-
dioxoles.10
provides convenient access to a variety of fused quinoline deriva-
tives.
Key words: domino reaction, heterocycles, imines, multicompo-
nent reaction, quinolines
R2
NH2
4
R2
O
Multicomponent reactions (MCRs) constitute a useful
H
R3
O
group of transformations of growing impact in organic
chemistry. Due to their atom- and step-economy, conver-
gence and exploratory power, they have found numerous
applications in organic synthesis, combinatorial chemis-
try, and medicinal chemistry.1 On the other hand, hetero-
cycles can be found in a large number of natural products,
drugs, and bioactive compounds. Thus, the participation
of heterocycles in MCRs as reactants, with their specific
reactivity, brings novel avenues of connectivity and nicely
complements their classical role as MCR adducts.2 The
Povarov reaction ranks among the most used MCRs.3 This
transformation consists of the interaction of a carbonyl
compound, an aniline, and an activated olefin (usually
enol ethers or enamine derivatives4) to yield, under acid
catalysis, a tetrahydroquinoline adduct. The process is as-
sumed to take place in a domino fashion through the inter-
mediacy of the corresponding imine, which once activated
by the catalyst suffers the nucleophilic attack of the elec-
tron-rich olefin to give a cationic intermediate ready to be
trapped by the aromatic ring of the aniline moiety.5 In this
context, our group has reported that a variety of nitrogen
heterocycles, such as dihydropyridines6 and unsaturated
lactams,7 can be used as activated olefin inputs in this
MCR. Interestingly, the use of cyclic enol esters in
Povarov processes yields, through a mechanistic detour,
N-arylated lactams, instead of the usual tetrahydroquino-
line adducts.8
X
X
Y
5
O
Sc(OTf)3
MeCN
Y
NH
1
R3
6
X = O, NBn, NH
Y = NH, S, O
formed
bonds
Scheme 1 Povarov reactions with heterocyclic olefinic inputs
The main points to be determined were the stability and
reactivity of this class of compounds in Povarov condi-
tions, which involve the presence of water, acidic media,
and cross reactivity processes with anilines and alde-
hydes. Our attention was focused on a large family of
structures (Figure 1) with great synthetic potential as ver-
satile building blocks in a variety of transformations, par-
ticularly Diels–Alder cycloadditions.11 The scope of the
Povarov MCR was studied with heterocyclic systems 1a–e,
2a,b, and 3 (Figure 1). Only one of them was commercial-
ly available (1e) and the rest were synthesized by known
methods or modifications thereof.12 In view of the recent-
ly published participation of the 2-aminooxazole 2a in a
somewhat related process,13 we have included this aro-
matic compound together with the imidazole 2b14 in the
reactant list.
Me
O
NH2
N
In order to expand the range of the olefinic components in
this MCR, we decided to study the participation of vici-
nally heteroatom-disubstituted olefins such as 1,3-oxa-,
thia-, and imidazol-2-one and related systems (Scheme 1).
Y
X
Z
N
S
1a–e
2
3
1a: X = NH, Y = NH
1b: X = NBn, Y = O
1c: X = NH, Y = S
1d: X = NBn, Y = S
1e: X = O, Y = O
2a Z = O
2b Z = NH
SYNTHESIS 2011, No. 14, pp 2237–2246
Advanced online publication: 09.06.2011
x
x.
x
x
.
2
0
1
1
Figure 1 Novel inputs tested for Povarov MCRs
DOI: 10.1055/s-0030-1260062; Art ID: C33911SS
© Georg Thieme Verlag Stuttgart · New York

2238
E. Vicente-García et al.
SPECIAL TOPIC
Initially, all experiments were run under standard condi- perature.3,15 However, in some cases it was necessary to
tions for the Povarov reaction, in which the activated ole- use microwave activation or prolonged heating to achieve
fin interacts with an aniline-aldehyde mixture under useful yields.
Sc(OTf)3 catalysis in the presence of 4 Å molecular
sieves, with acetonitrile as the solvent and at room tem-
Table 1 Scope of the Povarov MCR with 1-Heterosubstituted 3-Azol-2-ones
R2
O
O
X
X
Sc(OTf)3
MeCN
O
H
H
O
X
R2
R2
Y
H
Y
H
+
+
+
R3
Y
H
R3
N
R3
N
1
4
NH2
5
H
H
6
6'
Entry
1
4
5
6/6¢
Conditions
50 °C, 12 h
Isomer
ratio (6/6¢) (%)
Yield
O
NH
O
O
H
HN
H
1
1:1
1:1
3:1
1:0
2:1
1:2
81
58
42
35
72
44
H
CO2Et
HN
NH
NH2
4a
EtO2C
N
H
5a
5a
1a
6a/6a¢
O
NH
H
O
OHC
HN
H
2
3
4
5
6
MW, 10 min
HN
NH
NH2
CF3
CF3
Cl
N
H
4b
1a
F3C
6b/6b¢
O
Bn
N
O
H
O
O
H
Bn
r.t., 12 h
O
N
H
CO2Et
NH2
EtO2C
N
4a
5a
1b
H
6c/6c¢
O
Bn
H
N
O
OHC
MeO
O
OMe
H
Bn
r.t., 12 h
O
N
NH2
N
H
4b
5b
1b
F3C
6d
O
NH
O
H
O
S
H
MW, 10 min
S
NH
H
CO2Et
NH2
EtO2C
N
H
4a
5a
5a
1c
6e/6e¢
O
NH
H
O
OHC
S
H
50 °C, 5 da
S
NH
NH2
N
H
4c
1c
Cl
6f/6f¢
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

SPECIAL TOPIC
Heterocyclic Inputs for Povarov MCR
2239
Table 1 Scope of the Povarov MCR with 1-Heterosubstituted 3-Azol-2-ones (continued)
R2
O
O
X
X
Sc(OTf)3
MeCN
O
H
H
O
X
R2
R2
Y
H
Y
H
+
+
+
R3
Y
H
R3
N
R3
N
1
4
NH2
5
H
H
6
6'
Entry
1
4
5
6/6¢
Conditions
Isomer
Yield
ratio (6/6¢) (%)
O
NH
O
H
OHC
S
O
7
MW, 30 min
1:2
48
H
S
NH
NH2
N
H
4d
5a
1c
O
6g/6g¢
O
NH
H
O
O
O
OHC
S
H
8
9
50 °C, 5 d
2:1
5:1b
2:1
55
53
84
S
NH
NH2
NH2
NH2
CF3
N
H
5a
5a
5a
4b
1c
F3C
6h/6h¢
O
Bn
N
H
O
S
H
MW, 10 min
Bn
S
N
H
CO2Et
EtO2C
N
4a
1d
H
6i/6i¢
O
Bn
H
N
OHC
S
Bn
H
10
MW, 10 min
S
N
CF3
N
H
4b
1d
F3C
6j/6j¢
a Two equivalents of components 4 and 5.
b Isomer ratio assigned by analogy with related compounds.
The scope of the reaction was studied by screening all isomer could be detected, 6c/6c¢ being produced as the
components: the activated olefin input (1a–d, Table 1), usual stereoisomeric mixture (3:1, 42%, entry 3) and in
the aniline, and the aldehyde reactants. 1H-Imidazol- the case of the interaction with the aromatic aldehyde
2(3H)-one (1a) reacted with ethyl glyoxalate (4a) and p- (Table 1, entry 4), only one racemate was obtained (6d,
toluidine (5a) to give the expected adducts 6a/6a¢ as a 35%). Next, the reactivity of thiazol-2(3H)-one (1c) was
nearly equimolecular mixture of stereoisomers in 81% tested. Thanks to the easier access to this heterocycle, its
yield (Table 1, entry 1). As expected, the ring fusion was convenient storage and reluctance to suffer hydrolytic
cis, and there was lack of stereoselectivity, which is the degradation, a broad panel of aldehydes and anilines were
usual outcome in this type of MCR. Analogously, the in- reacted against this input. Although requiring different re-
teraction of 1a with aromatic aldehyde 4b and aniline 5a action conditions, all kinds of aldehydes gave raise to pro-
afforded tetrahydroquinolines 6b/6b¢ in 58% yield ductive transformations. The reaction was again highly
(Table 1, entry 2). In the case of N-benzyloxazolone 1b, regioselective, and when ethyl glyoxalate was used, a suit-
the reaction was also productive with aromatic and elec- able yield of the adduct (6e/6e¢, 72%, Table 1, entry 5)
trophilic aldehydes, and with activated anilines (4-Me and was obtained. Similar results were observed with aromatic
4-MeO, 5a and 5b, respectively). Remarkably, the reac- and heteroaromatic aldehydes, ranging from highly acti-
tion displayed a good regioselectivity and only one regio- vated (4-CF3, 4b, entry 8) to less electrophilic derivatives
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

2240
E. Vicente-García et al.
SPECIAL TOPIC
(4-Cl, 4c, entry 6; furfural, 4d, entry 7). The benzylated
derivative 1d also gave satisfactory results, again with
high regioselectivities (entries 9 and 10). Interestingly, in
the former case, although detected by NMR methods, the
crude mixture of adducts 6i/6i¢ could not be isolated, as
they underwent spontaneous oxidation to the correspond-
ing quinoline derivative 11f during column chromatogra-
phy.
R2
R2
R1
R1
N+
O
N
Y
O
NH
N
1
Y
LA
R3
R3
regioselective
attack
R2
The structural assignment of these scaffolds was per-
formed by NMR methods (1H, 13C, COSY, HMBC,
HSQC, NOESY), among which the NOE correlations
were of diagnostic value and allowed the stereochemical
features and regioselectivity of the process to be estab-
lished (Figure 2). Optimized geometries to crosscheck the
observed results were calculated with molecular mechan-
ics, semiempirical, and DFT methods.
R1
N
R1 = Bn, H
Y = NH, S, O
H
O
NH
Y
H
R3
6
Scheme 2 Mechanistic proposal for the Povarov MCR
sensitive to hydrolysis and did not result in productive
MCRs.
No useful reactivity arose from 1,3-dioxol-2-one (1e),
presumably because of its lability towards hydrolysis.
Even when performing the reaction under mild conditions
and with preformed imines we were unable to detect the
desired adducts or by-products derived from them. Re-
markably, 1,3-dioxoles lacking the carbonyl moiety con-
necting the heterocyclic oxygens have been reported as
productive inputs in Povarov processes.10 Similarly, 2-
aminooxazole (2a) has been tested in analogous MCRs,13
although this compound, together with imidazole 2b,14
were not productive when reacted under standard condi-
tions in Povarov reactions. Nevertheless, in some cases
the formation of the MCR adduct was detected in minute
amounts (NMR/MS evidence).
In this context, the reactivity of 2-methylenebenzothiazo-
line 3 (Scheme 3) was studied next. After some experi-
mentation, it was decided to promote the Povarov reaction
with the preformed imines, due to the instability of the ac-
tivated olefin 3 in the presence of water, and also the liter-
ature precedents on the reactivity of this kind of
compounds 3 with aldehydes to form styrylmethylben-
zothiazolium salts.16 Therefore, 2,3-dimethylbenzothiaz-
olium iodide was treated with n-butyllithium at low
temperature to generate in situ the methylenebenzothiaz-
oline 3, which was reacted with imine 7 using microwave
activation conditions. Interestingly, the spiro compound B
(Scheme 3) was not detected, in sharp contrast with the re-
activity described for the structurally similar ketene
dithioacetals.9 The major product in this reaction was the
stilbazolium vinylogous salt 8 (43%). Its formation could
be the result of the expected addition of the nucleophilic
enamine moiety upon the electrophilic imine to generate
the putative intermediate A, followed by the formal elim-
ination of aniline. To confirm this hypothesis, the reaction
between the 4-fluorobenzaldehyde and 2,3-dimethylben-
zothiazolium iodide17 was performed in acetic anhydride
as described,16 to nicely afford compound 8, thus confirm-
ing the initial hypothesis.
Figure 2 Diagnostic NOESY correlations for 6f/6f¢; comparison
with optimized geometries
Taking into account the stepwise nature of the most ac-
cepted mechanism for the Povarov reaction (Scheme 2),
the low degree of stereoselectivity could be attributed to
the feasibility of both facial orientations between the
imine and olefin inputs. On the other hand, the regiocon-
trol seemed to arise from the higher activation exerted by
the nitrogen towards its b-carbon, with respect to the cor-
responding effect of the oxygen or sulfur atoms. Studies
to determine the nature of these phenomena are currently
being addressed by computational methods. Interestingly,
when trying to deactivate the heterocyclic nitrogen in 1c
by acylation, the generated thiazolone proved to be very
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

SPECIAL TOPIC
Heterocyclic Inputs for Povarov MCR
2241
Me
calculated optimized geometries. The origin of such stereo-
selection, which reverses the natural tendency observed in
the intermolecular processes, is under study.
F
N
+
O
N
S
Me
3
7
Finally, the MCR adducts were successfully oxidized to
the corresponding quinolines through DDQ treatment
(Table 2).19,20 As usual, moderate yields (50–69%) were
obtained in these transformations. On other hand, the in-
tramolecular adduct 10¢ was successfully oxidized in 51%
yield to the corresponding fused quinoline system 12
(Scheme 5).
Sc(OTf)3
MeCN
MW, 10 min, 80 °C
Me
O
Me
O
S
N+
S
S
+
N
Me
N
Br
NH
Br
I–
Me
X
NH
Me
H
H
S
N
S
N
DDQ
O
O
NH
N
CDCl3, MeOH
r.t., 24 h
F
F
F
H
A
8
B
(43%)
Scheme 3 Reactivity study of 2-methylenebenzothiazolines
10'
12 (51%)
Scheme 5 Oxidation of the intramolecular Povarov adduct
In order to reverse the observed regiochemistry, it was de-
cided to tackle an intramolecular version of these
MCRs.18 Thus, the olefin-aldehyde input 9, whose reac-
tive moieties are tethered by a methylene group, was re-
acted with aniline 5c (Scheme 4). After unsuccessful
attempts at room temperature and reflux conditions, the
activation was productive through microwave irradiation,
allowing the isolation of the desired pentacyclic products
in moderate yield (56%, 10/10¢, 1:100).
Table 2 Oxidation of the Povarov Adducts 6/6¢
R2
R2
R1
R1
H
H
N
N
DDQ
O
O
CHCl3
r.t., 24 h
NH
N
Y
Y
R3
R3
11
Remarkably, the reaction proceeded with high stereocon-
trol, with the all-cis relative stereochemistry predominat-
ing. The stereochemistry of both adducts was determined
through the analysis of the diagnostic coupling constants
(Scheme 4), which matched the expected values for the
6–6'
Entry Substrate Y
R1
R2
R3
Product
(Yield, %)
1
2
3
4
5
6
7
6a/6a¢
NH
H
Me
Me
CO2Et
11a (65)
6b/6b¢ NH
H
4-CF3C6H4 11b (50)
6d
O
S
S
S
S
Bn
H
OMe 4-CF3C6H4 11c (61)
6e/6e¢
6g/6g¢
6i/6i¢
6j/6j¢
Me
Me
Me
Me
CO2Et
2-furyl
CO2Et
11d (55)
H
11e (40)
Bn
Bn
11f (quant)a
4-CF3C6H4 11g (69)
a The Povarov adducts 6i/6i¢ were oxidized spontaneously during pu-
rification by silica gel chromatography.
In conclusion, a new class of reactive inputs for the
Povarov reaction has been described with satisfactory re-
sults. A suitable range of heteroatom-substituted olefins
participate in the process in a regioselective manner. Re-
markably, the intramolecular process involving the thia-
zolone residue linked to the aldehyde moiety by its
nitrogen atom leads to a clean reversal of the natural regio-
selectivity, affording the tetrahydroquinoline adduct 10¢
with high stereocontrol. The obtained MCR adducts were
conveniently oxidized to yield the corresponding quino-
Scheme 4 Intramolecular Povarov reaction
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

2242
E. Vicente-García et al.
SPECIAL TOPIC
Ethyl (3aRS,4SR,9bRS)-8-Methyl-2-oxo-2,3,3a,4,5,9b-hexahy-
dro-1H-imidazo[4,5-c]quinoline-4-carboxylate (6a¢)
Following the general procedure A, method B (12 h), the reaction
of 1a, p-toluidine, and ethyl glyoxalate afforded compounds 6a/6a¢
(81%, 6a/6a¢, 1:1). This mixture was purified by flash chromatog-
raphy to afford pure 6a¢ as a white powder. Yield: 47 mg (41%).
lines. This transformation notably expands the structural
variability of tetrahydroquinolines and quinolines, which
are ubiquitous scaffolds in natural products, biologically
active compounds, and drugs.21,22
Unless stated otherwise, all reactions were carried out under argon
atmosphere in dried glassware. Commercially available reactants
were used without further purification. TLC was performed on pre-
coated Merck silica gel 60 F254 plates, developed with hexanes–
EtOAc (1:1) or CH2Cl2–MeOH (95:5) mixtures, and visualized un-
der a UV lamp. 1H and 13C NMR spectra were recorded on a Varian
Mercury 400 or Bruker 500 spectrometer. Unless otherwise quoted,
NMR spectra were recorded in CDCl3 solution with TMS as an in-
ternal reference. Data for 1H NMR spectra are reported as follows:
chemical shift (d ppm), multiplicity, coupling constants (Hz) and in-
tegration. Data for 13C NMR spectra are reported in terms of chem-
ical shift (d ppm). Signals were assigned by means of two-
dimensional NMR spectroscopy: 1H–1H-COSY, 1H–13C-COSY
(HSQC: Heteronuclear Single Quantum Coherence) and long-range
1H–13C-COSY (HMBC: Heteronuclear Multiple Bond Connectivi-
ty). IR spectra were recorded using a Thermo Nicolet Nexus spec-
trometer and are reported in frequency of absorption (cm–1). High-
resolution mass spectrometry was performed by the University of
Barcelona Mass Spectrometry Service.
IR (KBr): 3135, 3001, 2968, 2846, 1713, 1668, 1559, 1463, 1392,
1251, 1187, 1040, 822, 669 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 6.90–6.86 (m, 1 H), 6.81 (dd,
J = 8.1, 1.3 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 6.68 (d, J = 4.4 Hz,
1 H), 6.42–6.37 (m, 1 H), 5.39 (s, 1 H), 4.73–4.68 (m, 1 H), 4.44–
4.38 (m, 1 H), 4.24–4.09 (m, 2 H), 3.87–3.81 (m, 1 H), 2.15 (s, 3 H),
1.24 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 169.6, 162.4, 141.9, 129.6,
128.2, 126.3, 122.8, 115.3, 60.9, 56.2, 53.8, 50.5, 20.3, 13.9.
HRMS (ESI+): m/z calcd for C14H17N3O3 + Na (M + Na+):
298.1162; found: 298.1160.
(3aRS,4RS,9bSR)-8-Methyl-4-[4-(trifluoromethyl)phenyl]-
3,3a,4,5-tetrahydro-1H-imidazo[4,5-c]quinolin-2(9bH)-one
(6b¢)
Following the general procedure A, method C (1 cycle of 10 min),
the reaction of 1a, p-toluidine, and 4-(trifluoromethyl)benzalde-
hyde afforded compounds 6b/6b¢ (58%, 6b/6b¢, 1:1). This mixture
was purified by flash chromatography to afford pure 6b¢ as a white
powder. Yield: 94 mg (29%).
Povarov Multicomponent Reaction; General Procedure A
Molecular sieves 4Å (ca. 2 g) and Sc(OTf)3 (0.2 mmol) were added
to a solution of aldehyde (1 mmol) and aniline (1 mmol) in anhyd
MeCN (4 mL), and the mixture was stirred at r.t. After 5 min, a so-
lution of the olefin (1 mmol) in anhyd MeCN (3 mL) was added.
The different reaction conditions are listed below as separate meth-
ods. Sat. aq NaHCO3 (10 mL) was added, and the resulting mixture
was extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and the solvent was removed in
vacuo. The residue was purified by flash chromatography (hex-
anes–EtOAc) to give the desired products.
IR (KBr): 3455, 3263, 3192, 3122, 3077, 2904, 167, 1617, 1508,
1418, 1264, 1168, 1130, 1066, 1014, 829 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.70 (s, 4 H), 7.02–7.00 (m, 1 H),
6.91 (dd, J = 8.2, 1.6 Hz, 1 H), 6.71 (d, J = 8.1 Hz, 1 H), 5.00 (d,
J = 9.2 Hz, 1 H), 4.42 (dd, J = 9.1, 2.6 Hz, 1 H), 4.37 (d, J = 2.6 Hz,
1 H), 2.25 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 165.8, 145.9, 145.1, 130.98 (q,
J = 32.2 Hz), 130.6, 130.1, 129.8, 129.3, 127.1, 126.5 (q, J = 3.9
Hz), 124.4, 124.1, 121.7, 117.1, 60.1, 59.9, 53.6, 20.7.
Method A: The reaction mixture was stirred at r.t. and the progress
of the reaction was controlled by TLC or HPLC until the starting
material completely disappeared or no further evolution was ob-
served (if needed, an additional 5% catalyst was added every 24 h).
HRMS (ESI+): m/z calcd for C18H17F3N3O (M + H+): 348.1318;
found: 348.1315.
Ethyl (3aRS,4SR,9bSR)-1-Benzyl-8-methyl-2-oxo-1,2,3a,4,5,9b-
hexahydrooxazolo[5,4-c]quinoline-4-carboxylate (6c)
Following the general procedure A, method A (12 h), the reaction
of 1b, p-toluidine, and ethyl glyoxalate afforded compounds 6c/6c¢
(42%, 6c/6c¢, 3:1). This mixture was purified by flash chromatogra-
phy to afford pure 6c as a white powder. Yield: 81 mg (32%).
Method B: The reaction mixture was stirred at 50 °C and the
progress of the reaction was controlled by TLC or HPLC until the
starting material completely disappeared or no further evolution
was observed (if needed, an additional 5% catalyst was added every
24 h).
Method C: Sc(OTf)3 (0.2 mmol) were added to a solution of alde-
hyde (1 mmol) and aniline (1 mmol) in anhyd MeCN (1–1.5 mL),
and the mixture was stirred at r.t. After 5 min, a solution of the ole-
fin (1 mmol) in anhyd MeCN (0.5–1 mL) was added. The reaction
vessel was introduced in a microwave apparatus (Discover CEM),
and the reaction run at 80 °C and 100 W with Power Max option se-
lected. Cycles of 10 min were carried out until the starting materials
completely disappeared or no further evolution was observed.
IR (KBr): 3365, 3321, 2975, 2917, 1738, 1508, 1431, 1360, 1341,
1232, 1155, 1098, 1053 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.41–7.21 (m, 5 H), 6.99 (dd,
J = 1.6, 8.0 Hz, 1 H), 6.73–6.68 (m, 2 H), 5.41 (dd, J = 9.5, 2.6 Hz,
1 H), 4.75 (d, J = 15.7 Hz, 1 H), 4.69 (d, J = 9.5 Hz, 1 H), 4.41–4.27
(m, 2 H), 3.75 (d, J = 2.6 Hz, 1 H), 3.61 (d, J = 15.7 Hz, 1 H), 2.25
(s, 3 H), 1.35 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 168.1, 157.2, 144.09, 135.9,
130.7, 130.5, 129.2, 128.9, 127.9, 127.9, 119.3, 116.71, 75.8, 62.3,
60.2, 54.1, 45.2, 20.7, 14.3.
Oxidation of MCR Adducts to Quinolines; General Procedure
B
HRMS (ESI+): m/z calcd for C21H23N2O4 (M + H+): 367.1652;
found: 367.165.
To a solution of compound 6/6¢ or 10¢ (1 mmol) in CHCl3 (15 mL)
was added DDQ (2 mmol), and the mixture was stirred 24 h in an
open vessel at r.t. Sat. aq NaHCO3 (10 mL) was added, and the re-
sulting mixture was extracted with CHCl3 (3 × 10 mL). The com-
bined organic layers were dried (Na2SO4), filtered, and concentrated
in vacuo. The reaction mixture was purified with flash chromatog-
raphy (hexanes–EtOAc) to afford the desired product.
(3aRS,4RS,9bSR)-1-Benzyl-8-methoxy-4-[4-(trifluorometh-
yl)phenyl]-1,4,5,9b-tetrahydrooxazolo[5,4-c]quinolin-2(3aH)-
one (6d)
Following the general procedure A, method A (12 h), the reaction
of 1b, 4-methoxyaniline, and 4-(trifluoromethyl)benzaldehyde af-
forded compound 6d (35%). This crude mixture was purified by
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

SPECIAL TOPIC
Heterocyclic Inputs for Povarov MCR
2243
flash chromatography to afford pure 6d as a pale yellow powder.
Yield: 153 mg (35%).
6.66 (d, J = 8.2 Hz, 1 H), 6.01 (br s, 1 H), 5.01 (d, J = 7.0 Hz, 1 H),
4.78–4.73 (m, 1 H), 4.67–4.61 (m, 1 H), 2.19 (s, 3 H).
IR (KBr): 3428, 3333, 3071, 3026, 2923, 2832, 1719, 1508, 1431,
1322, 1258, 1117, 1066, 1014 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 171.9, 142.2, 140.2, 132.3,
128.9, 128.5, 128.4, 128.3, 126.4, 120.9, 115.4, 55.1, 53.9, 53.7,
20.3.
HRMS (ESI+): m/z calcd for C17H16ClN2OS (M + H+): 331.0666;
found: 331.067.
1H NMR (400 MHz, DMSO-d6): d = 7.80 (d, J = 8.2 Hz, 2 H), 7.72
(d, J = 8.1 Hz, 2 H), 7.34 (t, J = 7.3 Hz, 2 H), 7.27 (t, J = 7.2 Hz, 1
H), 7.20 (d, J = 7.2 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 1 H), 6.76 (dd,
J = 8.7, 2.7 Hz, 1 H), 6.55 (d, J = 2.6 Hz, 1 H), 5.80 (s, 1 H), 5.23–
5.13 (m, 1 H), 4.85 (d, J = 9.3 Hz, 1 H), 4.56 (d, J = 16.3 Hz, 1 H),
4.29–4.23 (m, 1 H), 3.92 (d, J = 16.2 Hz, 1 H), 3.63 (s, 3 H).
(3aRS,4RS,9bRS)-4-(Furan-2-yl)-8-methyl-1,4,5,9b-tetrahy-
drothiazolo[5,4-c]quinolin-2(3aH)-one (6g¢)
Following the general procedure A, method C (3 cycles of 10 min),
the reaction of 1c, p-toluidine, and 2-furaldehyde afforded com-
pounds 6g/6g¢ (48%, 6g/6g¢, 1:2). This mixture was purified by
flash chromatography to afford pure 6g¢ as a brown powder. Yield:
67 mg (32%).
13C NMR (100 MHz, DMSO-d6): d = 156.7, 152.2, 152.1, 143.3,
142.3, 142.2, 136.2, 128.9, 128.5, 128.2 (q, J = 31.7 Hz), 127.2,
126.9, 124.9 (q, J = 3.7 Hz), 124.3 (q, J = 272.1 Hz), 119.8, 117.5,
117.5, 115.4, 114.4, 77.3, 77.3, 60.3, 60.2, 55.3, 54.2, 44.7.
HRMS (ESI+): m/z calcd for C25H22F3N2O3 (M + H+): 455.1577;
found: 455.1574.
IR (KBr): 3429, 3135, 3096, 2962, 2924, 1668, 1585, 1553, 1502,
1457, 1367, 1265, 1175, 1028, 899, 816, 733 cm–1.
Ethyl (3aRS,4SR,9bRS)-8-Methyl-2-oxo-1,2,3a,4,5,9b-hexahy-
drothiazolo[5,4-c]quinoline-4-carboxylate (6e)
Following the general procedure A, method C (1 cycle of 10 min),
the reaction of 1c, p-toluidine, and ethyl glyoxalate afforded com-
pounds 6e/6e¢ (72%, 6e/6e¢, 2:1). This mixture was purified by flash
chromatography to afford pure 6e as a pale yellow powder. Yield:
100 mg (48%).
1H NMR (400 MHz, CD3OD): d = 7.51–7.47 (m, 1 H), 7.02–6.98
(m, 1 H), 6.91 (dd, J = 8.2, 1.8 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H),
6.43–6.38 (m, 2 H), 5.09 (d, J = 7.3 Hz, 1 H), 4.87 (d, J = 2.5 Hz, 1
H), 4.79 (d, J = 2.4 Hz, 1 H), 2.23 (s, 3 H).
13C NMR (100 MHz, CD3OD): d = 177.0, 154.9, 143.5, 142.9,
130.2, 130.0, 129.8, 122.6, 117.1, 111.4, 107.6, 55.5, 52.9, 52.7,
20.7.
IR (film): 3334, 3193, 3077, 2917, 2866, 1732, 1694, 1662, 1508,
1329, 1245, 1015, 816 cm–1.
HRMS (ESI+): m/z calcd for C15H15N2O2S (M + H+): 287.0849;
found: 287.0849.
1H NMR (400 MHz, CDCl3): d = 6.99 (dd, J = 8.2, 1.7 Hz, 1 H),
6.92–6.89 (m, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 5.96 (br s, 1 H), 4.98
(d, J = 6.2 Hz, 1 H), 4.40 (br s, 1 H), 4.29 (q, J = 7.1 Hz, 2 H), 4.10
(d, J = 10.1 Hz, 1 H), 3.95 (ddd, J = 10.1, 6.2, 0.5 Hz, 1 H), 2.25 (s,
3 H), 1.34 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.5, 170.0, 140.4, 130.7, 129.8,
129.2, 117.4, 116.2, 62.4, 56.7, 54.1, 45.5, 20.6, 14.3.
(3aRS,4RS,9bSR)-8-Methyl-4-[4-(trifluoromethyl)phenyl]-
1,4,5,9b-tetrahydrothiazolo[5,4-c]quinolin-2(3aH)-one (6h)
Following the general procedure A, method B (5 d), the reaction of
1c, p-toluidine, and 4-(trifluoromethyl)benzaldehyde afforded com-
pounds 6h/6h¢ (55%, 6h/6h¢, 2:1). This mixture was purified by
flash chromatography to afford pure 6h as a yellow powder. Yield:
92 mg (37%).
HRMS (ESI+): m/z calcd for C14H17N2O3S (M + H+): 293.0954;
found: 293.0953.
IR (KBr): 3397, 3186, 3071, 2917, 2879, 1706, 1617, 1508, 1322,
1258, 1168, 1130, 1066, 1002, 829 cm–1.
(3aRS,4RS,9bSR)-4-(4-Chlorophenyl)-8-methyl-1,4,5,9b-tet-
rahydrothiazolo[5,4-c]quinolin-2(3aH)-one (6f)
Following the general procedure A, method B (5 d), the reaction of
1c, p-toluidine, and 4-chlorobenzaldehyde afforded compounds 6f/
6f¢ (44%, 6f/6f¢, 1:2). This mixture was purified by flash chromatog-
raphy to afford pure 6f as a yellow powder. Yield: 64 mg (15%).
1H NMR (400 MHz, DMSO-d6): d = 8.63 (br s, 1 H), 7.76 (d, J = 8.3
Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.03–7.07 (m, 1 H), 6.91 (dd,
J = 8.2, 1.7 Hz, 1 H), 6.65 (d, J = 8.2 Hz, 1 H), 6.33 (s, J = 14.9 Hz,
1H ), 4.94 (d, J = 6.0 Hz, 1 H), 4.23 (d, J = 10.4 Hz, 1 H), 4.00 (dd,
J = 10.4, 6.0 Hz, 1 H), 2.19 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 170.4, 145.5, 142.9, 130.8,
129.7, 129.4, 128.7 (d, J = 31.7 Hz), 125.4, 125.1 (d, J = 3.6 Hz),
124.2 (d, J = 272.0 Hz), 117.0, 114.9, 57.7, 54.6, 49.9, 20.2.
IR (KBr): 3385, 3161, 3071, 2911, 1668, 1617, 1501, 1476, 1341,
1258, 1194, 1085, 1008, 835 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.59 (br s, 1 H), 7.52–7.42 (m,
4 H), 7.05–7.02 (m, 1 H), 6.89 (dd, J = 8.3, 1.8 Hz, 1 H), 6.64 (d,
J = 8.2 Hz, 1 H), 6.25 (br s, 1 H), 4.92 (d, J = 6.1 Hz, 1 H), 4.12 (d,
J = 10.5 Hz, 1 H), 3.92 (dd, J = 10.4, 6.0 Hz, 1 H), 2.18 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 170.5, 143.0, 139.8, 132.6,
130.7, 130.6, 129.3, 128.2, 125.3, 117.0, 114.95, 57.4, 54.6, 50.1,
20.2.
HRMS (ESI+): m/z calcd for C18H16F3N2OS (M + H+): 365.093;
found: 365.0929.
(3aRS,4RS,9bSR)-1-Benzyl-8-methyl-4-[4-(trifluorometh-
yl)phenyl]-1,4,5,9b-tetrahydrooxazolo[5,4-c]quinolin-2(3aH)-
one (6j)
Following the general procedure A, method C (1 cycle of 10 min),
the reaction of 1d, p-toluidine, and 4-(trifluoromethyl)benzalde-
hyde afforded compounds 6j/6j¢ as a diastereomeric mixture (75
mg, overall yield 84%, 6j/6j¢, 2:1). This mixture could not be sepa-
rated and was directly oxidized to quinoline 11g following proce-
dure B (see below).
1H NMR (400 MHz, CDCl3): d (diagnostic signals from the mix-
ture) = 7.64 (d, J = 8.2 Hz, 2 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.43–7.27
(m, 5 H), 6.99 (dd, J = 8.0, 1.5 Hz, 1 H), 6.94 (br s, 1 H), 6.66 (d,
J = 8.0 Hz, 1 H), 5.20 (d, J = 15.6 Hz, 1 H), 4.95 (d, J = 8.1 Hz, 1
H), 4.59 (d, J = 3.1 Hz, 1 H), 4.44 (dd, J = 8.1, 3.1 Hz, 1 H), 4.06
(d, J = 15.6 Hz, 1 H), 2.27 (s, 3 H).
HRMS (ESI+): m/z calcd for C17H16ClN2OS (M + H+): 331.0666;
found: 331.0669.
(3aRS,4SR,9bSR)-4-(4-Chlorophenyl)-8-methyl-1,4,5,9b-tet-
rahydrothiazolo[5,4-c]quinolin-2(3aH)-one (6f¢)
In the above process, on further elution, compound 6f¢ was obtained
as a yellow powder. Yield: 125 mg (29%).
IR (KBr): 3385, 3160, 3071, 2911, 1617, 1476, 1341, 1258, 1194,
1085, 1008, 835, 669 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.76 (d, J = 1.3 Hz, 1 H), 7.52–
7.43 (m, 4 H), 7.06–7.02 (m, 1 H), 6.86 (dd, J = 8.2, 1.4 Hz, 1 H),
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

2244
E. Vicente-García et al.
SPECIAL TOPIC
(E)-2-(4-Fluorostyryl)-3-methylbenzo[d]thiazol-3-ium Iodide
(8)
Following the general procedure A, method C (1 cycle of 10 min),
the reaction of 3 and (E)-N-(4-fluorobenzylidene)-4-methoxy-
aniline afforded compound 8 (43%). The compound precipitated
out as a brown powder from the reaction media, was collected by
filtration, and washed with Et2O (20 mL). Yield: 85 mg (43%).
1H NMR (400 MHz, DMSO-d6): d = 12.5 (br s, 1 H), 11.04 (br s, 1
H), 7.93 (d, J = 8.8 Hz, 1 H), 7.91–7.88 (m, 1 H), 7.50 (dd, J = 8.8,
1.9 Hz, 1 H), 4.46 (q, J = 7.1 Hz, 2 H), 2.51 (s, 3 H), 1.38 (t, J = 7.1
Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 164.1, 154.9, 141.2, 137.5,
132.3, 130.3, 129.9, 129.8, 122.8, 119.8, 115.31, 61.2, 21.6, 14.3.
HRMS (ESI+): m/z calcd for C14H14N3O3 (M + H+): 272.103; found:
272.1028.
IR (KBr): 3423, 3045, 2994, 1617, 1591, 1508, 1450, 1418, 1328,
1232, 1155, 829, 752 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.45 (d, J = 7.8 Hz, 1 H), 8.29–
8.21 (m, 2 H), 8.20–8.13 (m, 2 H), 8.03 (d, J = 15.9 Hz, 1 H), 7.93–
7.86 (m, 1 H), 7.84–7.76 (m, 1 H), 7.44 (t, J = 8.8 Hz, 1 H), 4.37 (s,
3 H).
8-Methyl-4-[4-(trifluoromethyl)phenyl]-1H-imidazo[4,5-
c]quinolin-2(3H)-one (11b)
Following the general procedure B, the oxidation of 6b¢ afforded
compound 11b as a pale yellow powder. Yield: 5 mg (50%).
13C NMR (100 MHz, DMSO-d6): d = 171.9, 165.6, 163.1, 147.1,
142.0, 132.3, 132.3, 130.8, 129.4, 128.5, 127.9, 124.3, 116.9, 116.5,
116.3, 113.9, 36.5.
HRMS (ESI+): m/z calcd for C16H13FNS (M + H+): 270.0747;
found: 270.0747.
IR (KBr): 2893, 1713, 1655, 1629, 1437, 1367, 1322, 1168, 1098,
1066, 893, 662 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 12.10 (br s, 1 H), 11.32 (br s,
1 H), 8.17 (d, J = 8.1 Hz, 2 H), 7.90 (dd, J = 12.0, 8.4 Hz, 4 H), 7.48
(dd, J = 8.8, 1.7 Hz, 1 H), 2.51 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 155.8, 142.4, 141.6, 139.9,
136.2, 132.0, 130.2, 129.8, 129.7, 129.5 (q, J = 31.7 Hz), 125.9 (q,
J = 3.9 Hz), 120.7, 120.3, 114.7, 102.8, 21.9.
HRMS (ESI+): m/z calcd for C18H13N3O (M + H+): 344.1005;
found: 344.1000.
(4bRS,4b1SR,12bSR)-3-Bromo-4b1,8,12b,13-tetrahydrodiben-
zo[b,h]thiazolo[5,4,3de][1,5]naphthyridin-6(4bH)-one (10)
Following the general procedure A, method C (1 cycle of 15 min),
the reaction of 9 (see Supporting Information) and 4-bromoaniline
afforded compounds 10/10¢ (56%, 10/10¢, 1:100). The precipitated
major stereoisomer 10¢ was filtered and washed with Et2O (20 mL)
to afford 10¢ as a white powder. Yield: 7 mg (1%).
1-Benzyl-8-methoxy-4-[4-(trifluoromethyl)phenyl]oxazolo[5,4-
c]quinolin-2(1H)-one (11c)
Following the general procedure B, the oxidation of 6d afforded
compound 11c as a white powder. Yield: 30 mg (61%).
The resulting filtrate was concentrated and the residual solid was
purified by flash chromatography to afford 10 as a white powder.
Yield: 762 mg (55%).
IR (KBr): 3519, 3417, 3116, 3007, 2936, 2834, 1764, 1604, 1559,
1508, 1476, 1444, 1322, 1232, 1162, 1117, 1066, 1027, 1002, 938,
854 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.52 (d, J = 8.1 Hz, 2 H), 8.01
(dd, J = 8.8, 2.1 Hz, 3 H), 7.49 (d, J = 7.4 Hz, 2 H), 7.39 (t, J = 7.4
Hz, 2 H), 7.37–7.32 (m, 2 H), 7.06 (d, J = 2.7 Hz, 1 H), 5.63 (s, 2
H), 3.63 (s, 3 H).
13C NMR (125 MHz, DMSO-d6): d = 157.6, 154.3, 140.9, 138.8,
136.3, 135.9, 134.6, 132.5, 131.8, 129.6 (q, J = 31.8 Hz), 129.0,
128.7, 127.8, 126.0, 125.7 (q, J = 3.4 Hz), 124.2 (q, J = 272.1 Hz),
121.7, 115.7, 99.4, 55.5, 46.7.
IR (KBr): 3429, 3372, 2930, 2846, 1649, 1482, 1450, 1405, 1328,
1245, 1213, 822, 752, 733, 662, 547 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.78–7.76 (m, 1 H), 7.39–7.25
(m, 5 H), 6.99 (d, J = 8.6 Hz, 1 H), 6.82 (br s, 1 H), 5.50 (d, J = 5.50
Hz, 1 H), 5.05 (d, J = 17.5 Hz, 1 H), 4.48–4.40 (m, 2 H), 3.98 (dd,
J = 7.1, 9.8 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 170.4, 144.6, 134.1, 132.5,
131.5, 131.3, 127.2, 126.6, 126.2, 125.0, 120.65, 118.6, 108.8, 57.8,
47.8, 44.0, 41.0.
HRMS (ESI+): m/z calcd for C17H14BrN2OS (M + H+): 373.0005;
found: 373.0014.
HRMS (ESI+): m/z calcd for C25H18F3N2O3 (M + H+): 451.1264;
found: 451.126.
(4bRS,4b1SR,12bRS)-3-Bromo-4b1,8,12b,13-tetrahydrodiben-
zo[b,h]thiazolo[5,4,3-de][1,5]naphthyridin-6(4bH)-one (10¢)
IR (KBr): 3423, 3308, 3064, 3026, 2962, 2911, 2859, 1649, 1597,
1482, 1437, 1380, 1296, 1258, 1162, 931, 809, 758, 713, 630 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.50–7.27 (m, 5 H), 7.13 (dd,
J = 2.3, 8.6 Hz, 1 H), 6.65 (dd, J = 1.7, 8.6 Hz, 1 H), 6.04 (br s, 1
H), 5.26 (d, J = 7.38 Hz, 1 H), 4.66 (d, J = 17.4 Hz, 1 H), 4.51 (d,
J = 17.4 Hz, 1 H), 4.41 (dt, J = 1.8, 7.42 Hz, 1 H), 4.39–4.36 (m, 1
H).
13C NMR (100 MHz, DMSO-d6): d = 170.2, 143.7, 133.8, 132.2,
131.7, 130.3, 129.7, 128.6, 126.9, 126.8, 124.5, 117.1, 108.5, 57.8,
52.1, 44.9, 41.6.
HRMS (ESI+): m/z calcd for C17H14BrN2OS (M + H+): 373.0005;
found: 373.0003.
Ethyl 8-Methyl-2-oxo-1,2-dihydrothiazolo[5,4-c]quinoline-4-
carboxylate (11d)
Following the general procedure B, the oxidation of 6e afforded
compound 11d as a white powder. Yield: 28 mg (55%).
IR (KBr): 3135, 3000, 2968, 2846, 1713, 1668, 1559, 1463, 1392,
1251, 1187, 1040, 822, 771, 669 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 13.13 (br s, 1 H), 8.11–8.08
(m, 1 H), 8.01 (d, J = 8.7 Hz, 1 H), 7.66 (dd, J = 8.8, 1.8 Hz, 1 H),
4.48 (q, J = 7.1 Hz, 2 H), 2.53 (s, 1 H), 1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 172.5, 164.6, 143.4, 140.6,
138.9, 138.7, 132.3, 129.9, 120.9, 115.8, 115.5, 62.1, 21.6, 14.1.
HRMS (ESI+): m/z calcd for C14H13N2O3S (M + H+): 289.0641;
found: 289.064.
Ethyl 8-Methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinoline-
4-carboxylate (11a)
Following the general procedure B, the oxidation of 6a¢ afforded
compound 11a as a yellow powder. Yield: 34 mg (65%).
4-(Furan-2-yl)-8-methylthiazolo[5,4-c]quinolin-2(1H)-one(11e)
Following the general procedure B, the oxidation of 6g¢ afforded
compound 11e as a brown powder. Yield: 10 mg (40%).
IR (KBr): 3432, 3130, 2913, 2847, 1665, 1581, 1556, 1502, 1363,
1183, 1074, 1014, 899, 815, 728 cm–1.
IR (KBr): 3385, 3135, 2975, 2923, 2853, 2750, 1700, 1674, 1629,
1476, 1341, 1296, 1226, 1200, 1111, 1066, 989, 822 cm–1.
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

SPECIAL TOPIC
Heterocyclic Inputs for Povarov MCR
2245
1H NMR (400 MHz, DMSO-d6): d = 13.14 (br s, 1 H), 8.08 (d,
J = 20.0 Hz, 2 H), 7.92 (d, J = 8.6 Hz, 1 H), 7.62 (dd, J = 8.6, 1.3
Hz, 1 H), 7.34 (d, J = 3.0 Hz, 1 H), 6.83–6.77 (m, 1 H), 2.51 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 171.7, 151.9, 145.3, 144.1,
140.5, 139.9, 136.2, 132.0, 128.8, 121.0, 119.1, 114.4, 112.8, 111.1,
21.4.
Acknowledgment
This work was supported by DGICYT
– Spain (project
BQUCTQ2009-07758), Generalitat de Catalunya (project
2009SGR 1024), and Barcelona Science Park. Grupo Ferrer (Barce-
lona, Spain) is thanked for financial support. We thank Prof. Janina
Kabatc (University of Technology and Life Sciences, Bydgoszcz,
Poland) for useful comments.
HRMS (ESI+): m/z calcd for C15H8N2O3S (M + H+): 283.0536;
found: 283.0536.
References
Ethyl 1-Benzyl-8-methyl-2-oxo-1,2-dihydrothiazolo [5,4-
c]quinoline-4-carboxylate (11f)
(1) For an overview, see: Multicomponent Reactions; Zhu, J.;
Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005.
(2) For reviews, see: (a) Isambert, N.; Lavilla, R. Chem. Eur. J.
2008, 14, 8444. (b) Jiang, B.; Rajale, T.; Wever, W.; Tu, S.
J.; Li, G. Chem. Asian J. 2010, 5, 2318. (c) Sunderhaus, J.
D.; Martin, S. F. Chem. Eur. J. 2009, 15, 1300.
(d) Synthesis of Heterocycles via Multicomponent
Reactions, Vol. I and II (Topics in Heterocyclic Chemistry,
Vol. 23 and 25); Orru, R. V. A.; Ruitjer, E., Eds.; Springer:
Heidelberg, 2010.
(3) (a) Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656.
(b) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721.
(c) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. Rev.
2008, 77, 137. (d) Bello, D.; Ramón, R.; Lavilla, R. Curr.
Org. Chem. 2010, 14, 332.
Following the general procedure A, method C (1 cycle of 10 min),
the reaction of 1c, p-toluidine, and ethyl glyoxalate afforded com-
pounds 6i/6i¢ (6i/6i¢, 5:1). This mixture was purified by flash chro-
matography to afford pure 11f as a yellow powder. Yield: 109 mg
(53%).
IR (film): 3064, 2984, 2911, 1706, 1674, 1553, 1495, 1444, 1424,
1367, 1264, 1053, 829, 713 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.17 (d, J = 8.7 Hz, 1 H), 7.89 (s,
1 H), 7.50 (dd, J = 8.7, 1.5 Hz, 1 H), 7.41–7.33 (m, 2 H), 7.32–7.22
(m, 3 H), 5.73 (s, 2 H), 4.63 (q, J = 7.1 Hz, 2 H), 2.36 (s, 3 H), 1.54
(t, J = 7.1 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 173.4, 165.4, 145.4, 140.9, 139.4,
139.2, 135.4, 131.7, 131.7, 129.4, 128.1, 125.8, 120.7, 117.1, 115.7,
63.2, 49.0, 22.3, 14.5.
(4) (a) Batey, R. A.; Simoncic, P. D.; Lin, D.; Smyj, R. P.;
Lough, A. J. Chem. Commun. 1999, 651. (b) Batey, R. A.;
Powell, D. A. Chem. Commun. 2001, 2362. (c) Powell, D.
A.; Batey, R. A. Org. Lett. 2002, 4, 2913.
HRMS (ESI+): m/z calcd for C21H19N2O3S (M + H+): 379.1111;
found: 379.1106.
(5) For alternative trappings of the cationic intermediate, see:
Jiménez, O.; de la Rosa, G.; Lavilla, R. Angew. Chem. Int.
Ed. 2005, 44, 6521.
(6) (a) Carranco, I.; Díaz, J. L.; Jiménez, O.; Vendrell, M.;
Albericio, F.; Royo, M.; Lavilla, R. J. Comb. Chem. 2005, 7,
33. (b) Lavilla, R.; Bernabeu, M. C.; Carranco, I.; Díaz, J. L.
Org. Lett. 2003, 5, 717.
1-Benzyl-8-methyl-4-[4-(trifluoromethyl)phenyl]thiazolo[5,4-
c]quinolin-2(1H)-one (11g)
Following the general procedure B, the oxidation of 6j afforded
compound 11g as a white powder. Yield: 25 mg (69%).
IR (film): 3340, 3026, 2911, 1681, 1540, 1495, 1399, 1162, 1123,
1066, 841, 726 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.06 (dd, J = 8.3, 5.5 Hz, 3 H),
7.87 (s, 1 H), 7.82 (d, J = 8.2 Hz, 2 H), 7.48 (dd, J = 8.6, 1.7 Hz, 1
H), 7.42–7.36 (m, 2 H), 7.34–7.28 (m, 3 H), 5.74 (s, 2 H), 2.36 (s, 3
H).
(7) Vicente-García, E.; Catti, F.; Ramón, R.; Lavilla, R. Org.
Lett. 2010, 12, 860.
(8) Isambert, N.; Cruz, M.; Arévalo, M. J.; Gómez, E.; Lavilla,
R. Org. Lett. 2007, 9, 4199.
(9) Cheng, D.; Zhou, J.; Saiah, E.; Beaton, G. Org. Lett. 2002,
4, 4411.
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Staehele, W.; Amendt, C.; Emde, U.; Zenke, F. PCT Int.
Appl. WO2006002726, 2006; Chem. Abstr. 2006, 144,
128981.
13C NMR (100 MHz, CDCl3): d = 171.3, 150.1, 146.3, 142.5, 139.8,
137.2, 135.4, 131.7 (q, J = 32.7 Hz), 131.5, 130.9, 129.4, 128.8,
128.1, 124.1 (q, J = 272.4 Hz), 126.1 (q, J = 3.7 Hz), 125.9, 120.7,
115.6, 113.43, 49.4, 29.5.
HRMS (ESI+): m/z calcd for C25H18F3N2OS (M + H+): 451.1086;
found: 451.1084.
(11) Matsunaga, H.; Ishizuka, T.; Kunieda, T. Tetrahedron 2005,
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3-Bromodibenzo[b,h]thiazolo[5,4,3-de][1,5]naphthyridin-
6(8H)-one (12)
Following the general procedure B, the oxidation of 10¢ afforded
compound 12 as a brownish solid. Yield: 66 mg (51%).
(12) (a) Cornwell, S. P.; Kaye, P. T.; Kent, A. G.; Meakins, G. D.
J. Chem. Soc., Perkin Trans. 1 1981, 2340. (b) Hoshimoto,
S.; Matsunaga, H.; Kunieda, T. Chem. Pharm. Bull. 2000,
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2008, 64, 204. (d) Rokach, J.; Hamel, P. J. Chem. Soc.,
Chem. Commun. 1979, 786. (e) Fei, J.; Basu, A.; Xue, F.;
Palmore, G. T. R. Org. Lett. 2006, 8, 3. (f) Matsuura, T.;
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1995, 51, 5891. (j) Fearnley, S. P.; Thongsornkleeb, C.
J. Org. Chem. 2010, 75, 933.
IR (KBr): 3051, 2923, 1706, 1585, 1495, 1463, 1341, 1296, 1258,
1207, 1066, 950, 816, 790, 720 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.51 (d, J = 7.0 Hz, 1 H), 8.14
(d, J = 2.0 Hz, 1 H), 8.02 (d, J = 8.9 Hz, 1 H), 7.84–7.79 (m, 1 H),
7.63–7.49 (m, 3 H), 5.35 (s, 2 H).
13C NMR: The 13C NMR spectrum could not be recorded due to the
extreme insolubility of compound 12 in all solvents tested.
HRMS (ESI+): m/z calcd for C17H9BrN2OS (M + H+): 368.9692;
found: 368.9696.
(13) Powner, M. W.; Sutherland, J. D.; Szostak, J. W. J. Am.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York

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(18) (a) For intramolecular Povarov processes, see examples in
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Synthesis 2011, No. 14, 2237–2246 © Thieme Stuttgart · New York