New metal-catalyzed synthesis of quinoline and chromene skeletons

Article abstract of DOI:10.1002/ejoc.200600230

Alkoxy-functionalized butadienylboronic esters have been synthesized starting from α,β-unsaturated acetals and cross-coupled with both N-protected and N-unprotected 2-bromo-and 2-iodoaniline, and with 2-iodophenol. In particular, N-tosyl-protected dienyla

Full text of DOI:10.1002/ejoc.200600230

FULL PAPER
DOI: 10.1002/ejoc.200600230
New Metal-Catalyzed Synthesis of Quinoline and Chromene Skeletons[‡]
Annamaria Deagostino,[a] Vittorio Farina,*[b] Cristina Prandi,[a] Chiara Zavattaro,[a] and
Paolo Venturello*[a]
Keywords: Quinoline / Chromene / Conjugated dienes / Conjugate elimination / Suzuki cross-coupling
Alkoxy-functionalized butadienylboronic esters have been
synthesized starting from α,β-unsaturated acetals and cross-
coupled with both N-protected and N-unprotected 2-bromo-
and 2-iodoaniline, and with 2-iodophenol. In particular, N-
tosyl-protected dienylanilines can be transformed under mild
conditions into quinolines and quinolinones, in the presence
of a PdII catalyst. Moreover, the cross-coupling reaction be-
tween butadienylboronic esters and iodophenol directly af-
fords chromenes that can be successively transformed into
chromenones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
with the development of new ligand systems, and intramo-
lecular versions have been utilized for the synthesis of het-
erocyclic compounds containing nitrogen[8] and oxygen[9].
The cyclization works well with aromatic and activated
amines (amides and sulfonamides), and this methodology
has been used to construct various nitrogen-containing het-
erocycles.[10] More recently, the applicability of Pd-catalyzed
asymmetric allylic alkylation (AAA) reaction of phenol-de-
rived allylic carbonates to the synthesis of chiral chromans
was demonstrated.[11] Finally, an expedient preparation of
chromane derivatives has been realized by employing an in-
dium-mediated intramolecular addition.[12]
Introduction
Organic molecules containing C–N and C–O bonds are
of significant importance and frequently show interesting
properties as pharmaceutically and biologically active sub-
stances, dyes and fine chemicals.[1] Quinolines and their de-
rivatives have long been developed as antimalarial agents
since the discovery of cinchona alkaloids.[2] Classical syn-
thetic routes to quinolines rely on the preparation of inter-
mediate imines that tautomerize to dienamines, and finally
undergo aromatic electrophilic cyclization, according to the
historic Combes procedure,[3] on the Skraup reaction, in
which the diketone is replaced by an α,β-unsaturated car-
bonyl compound,[4] on the Friedländer synthesis, or
others.[5]
Synthetic organic reactions catalyzed by transition-metal
complexes have progressed enormously over the last few
years, and highly regio- and stereoselective methods have
been developed in order to carry out the syntheses of com-
plicated natural products and pharmaceutically active com-
pounds, as well as functional molecules. Over the past few
years much effort has gone into developing Pd-catalyzed
reactions of aryl halides with amines[6] and alcohols.[7] Ini-
tial works were focused on the intermolecular C–N and C–
O bond constructions, and more recently, this cross-coup-
ling chemistry has undergone optimization, particularly
During the past few years, we have reported that the lith-
ium/potassium mixed base LIC-KOR (Schlosser’s su-
perbase: LIC = butyllithium, KOR = potassium tert-butox-
ide),[13] chemoselectively promotes the conversion of α,β-
unsaturated acetals into 1-alkoxybuta-1,3-dienes,[14] in-
ducing a stereoselective conjugate elimination that is initi-
ated by the metalation reaction at the γ-allylic position of
the unsaturated substrate. Moreover, the elimination prod-
uct can be further selectively metalated at its α-position by
conducting the former elimination reaction in the presence
of at least 2 equiv. of the LIC-KOR base: the produced nu-
cleophile can be finally quenched with various electrophiles,
yielding functionalized butadienyl derivatives.[15] By re-
sorting to this procedure, we have described different func-
tionalized unsaturated systems.[16] More recently, the aryl-
ation of α,β-unsaturated carbonyl compounds by a Heck
[‡] The results reported are taken from the Ph. D. Thesis of Chiara reaction has been described.[17] The reactivity of α-met-
Zavattaro
alated alkoxydienes with trialkylboranes and trialkyl bo-
[a] Dipartimento di Chimica Generale ed Organica Applicata
rates as electrophiles has also been reported.[18]
dell’Università,
Via Pietro Giuria, 7, 10125 Torino, Italy
In the course of our recent studies, we have developed a
new synthesis of quinoline and chromene systems, which
forms the subject of this paper.
[b] Department of Research and Development, Boehringer-In-
gelheim Pharmaceuticals., Inc.,
Ridgefield, CT 06877, USA
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A. Deagostino, V. Farina, C. Prandi, C. Zavattaro, P. Venturello
FULL PAPER
cross-coupling with 2-bromo- and 2-iodoaniline under dif-
ferent experimental conditions. The results obtained in or-
der to evaluate the effect of the solvent, temperature, cata-
lyst and base are reported in Table 1. Scheme 2 shows the
results obtained under the best experimental conditions
(Entry 7), using the boronates 2a and 2c and N-protected
or unprotected 2-iodoanilines.
Results and Discussion
Synthesis of Quinoline Systems
Our procedure consists of three steps: (i) the synthesis
of the dienylboronates, which starts from α,β-unsaturated
acetals in the presence of the LIC-KOR superbase; (ii) the
Suzuki cross-coupling reaction, which involves a properly
N-protected o-haloaniline; (iii) the PdII-catalyzed cycliza-
tion process.
Synthesis of the Dienyl Boronates
The dienylboronates 2a–c were synthesized starting from
the diethyl acetal of but-2-enal (1a), 3-methylbut-2-enal
(1b), and 2-methylbut-2-enal (1c), respectively, in the pres-
ence of the LIC-KOR reagent. Typically, treatment of cro-
tonaldehyde diethyl acetal (1a) at –95 °C with Schlosser’s
LIC-KOR base readily gives α-metalated 1-ethoxybuta-1,3-
diene. Subsequent reaction with triisopropyl borate leads to
immediate disappearance of the deep red color due to the
metalated diene. Aqueous workup of the reaction mixture
affords intermediate dienylboronic acid, which, in order to
address its instability, was trapped with 2,2-dimethylpro-
pane-1,3-diol to give the corresponding boronic ester 2a
(Scheme 1).
Scheme 2. Synthesis of dienylanilines by Suzuki cross-coupling.
When the coupling reaction was carried out with N-Ts-
protected aniline 3c and 3f, only (E)-arylated products were
obtained, while with N-Ac- and N-TFA-protected aniline
3d and 3e, respectively, the dienic moiety underwent partial
isomerization, and both (E)- and (Z)-arylated derivatives
were isolated.[19] The isomerization probably takes place
according to the Pd-catalyzed process proposed in
Scheme 3.[20]
The Suzuki reaction was performed on protected anilines
in order to decrease the tendency of the amino group to
form stable PdII complexes.[21] Acylation, and especially to-
sylation of amines was found to eliminate the basicity and
thus the complexation strength, therefore allowing smooth
reaction using catalytic quantities of Pd complexes. It must
be mentioned that, while the dienylboronates 2a and 2c give
the corresponding arylated derivatives 3a and 3c, substrate
2b directly affords the cyclization product 4b even in THF
at 55 °C, probably through the formation of the highly
Scheme 1. Synthesis of (1-ethoxy-1,3-butadienyl)boronates.
Suzuki Cross-Coupling
By exploiting the particular reactivity of 1,3-dienyl- stable intermediate carbocation (see Scheme 4). Traces of
boronate derivatives, we have successfully carried out their HCl are likely to be provided by the PdII catalyst.[22]
Table 1. Suzuki cross-coupling of boronate 2a with 2-bromo- and 2-iodoaniline, as a function of different experimental conditions.
Entry
Halogen
Solvent
Base ()
T [°C]
t [h]
Catalyst (%)
Yield [%]
1
2
3
4
5
6
7
Br
Br
Br
Br
Br
I
dioxane
DMSO
THF
DMSO
toluene
THF
Et3N (2 )
80
80
50
100
50
50
15
15
15
15
15
15
15
Pd(dba)3 (1.5), P(tBu)3 (3.5)
Pd(dba)3 (1.5), P(tBu)3 (3.5)
Pd(OAc)2 (5), PCy3 (10)
Pd(OAc)2 (5), dppp (0.005)
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
0
0
0
19
24
33
49
Cs2CO3 (2 )
K2CO3 (2 )
KF (2 )
K2CO3 (2 )
K2CO3 (1 )
K2CO3 (2 )
I
THF
50
Scheme 3. Pd-catalyzed (E)/(Z) isomerization of 1-ethoxy-1,3-butadienyl derivatives.
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New Metal-Catalyzed Synthesis of Quinoline and Chromene Skeletons
FULL PAPER
be reoxidized to PdII by CuII, benzoquinone, or air, in order
to promote the reaction once again.[10a,10b,18c,25] In the pres-
ent case, on the contrary, the reaction proceeds without the
need for a re-oxidation. This is due to the fact that interme-
diate C can re-add HPdX to the exocyclic double bond with
opposite regiochemistry D, and finally directly generate the
quinoline skeleton through elimination of Pd(OAc)Ts,
which restarts the catalytic cycle without requiring any re-
oxidation process (Scheme 6).[26]
This is rendered possible by the excellent leaving group
characteristics of the sulfinate ion. It is now apparent why
amides do not participate in this reaction, as expulsion of
an acyl anion is extremely unfavorable. Thus, the judicious
combination of reaction conditions and suitable N-protect-
ing/activating groups allows this novel tandem annulation
reaction to proceed under facile conditions without the
need for complex Pd re-oxidation schemes.
Scheme 4. Direct synthesis of cyclic derivative 4b through the for-
mation of a stable carbocation.
Cyclization Reaction
The cyclization step has been investigated on the dienyl-
anilines 3c–3f in DMF at 80 °C using Pd(OAc)2 as a cata-
lyst, under an inert gas. The cyclization step takes place
only on N-Ts-protected derivatives 3c and 3f, whereas the
dienylanilines 3d and 3f do not react, because the Ac and
TFA groups are not reactive enough, for reasons that will
become apparent upon examination of Scheme 6 (poorer
leaving groups). The protected dienylanilines cyclize to af-
ford quinoline-type skeletons (Scheme 5).
Synthesis of Chromene-Type Skeletons
Two chromenes have been synthesized starting from di-
enylboronates and 2-iodophenol in the presence of a Pd cat-
alyst, as shown in Scheme 7.
Scheme 5. Pd-catalyzed synthesis of quinoline-type skeletons.
Similar results concerning the synthesis of nitrogen het-
erocycles by the Pd-catalyzed cross-coupling of 2-alkenylan-
ilines with vinylic triflates and halides have been reported
recently.[23]
Scheme 7. Pd-catalyzed synthesis of chromene-type skeletons.
It was impossible to isolate the cross-coupling intermedi-
The first step of the mechanistic pathway involves proba-
bly the formation a π-complex A between PdII and the di- ate, because the cyclization to the chromene skeleton occurs
enyl fragment. The π-complex successively undergoes heter- readily. It is uncertain whether the latter is Pd- or acid-
ocyclization and conversion to the σ-complex B. According catalyzed. Derivative 6b was smoothly hydrolyzed to 2,2-
to the information reported in the literature for similar reac- dimethylchroman-4-one (7b), which is known to be an im-
tions, the cyclization process can be terminated by a β-elim- portant building block for the synthesis of many pharma-
inative step to afford HX and Pd0.[24] The latter could then ceutically important structures.[27]
Scheme 6. Proposed mechanism for the novel Pd-catalyzed cyclization.
Eur. J. Org. Chem. 2006, 3451–3456
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A. Deagostino, V. Farina, C. Prandi, C. Zavattaro, P. Venturello
FULL PAPER
= 7.7, 1 H; superimposed on δ = 7.22–7.15 ppm (m, 1 H)], 6.80–
6.70 (m, 2 H), 6.18 (dt, J = 16.9, 10.5 Hz, 1 H), 5.69 (d, J =
10.5 Hz, 1 H), 5.09 (dd, J = 16.9, 1.8 Hz, 1 H), 4.81 (dd, J = 10.5,
1.8 Hz, 1 H), 3.93 (q, J = 7.0 Hz, 2 H), 1.56 (br. s, 2 H), 1.33 (t, J
= 7.0 Hz, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 156.3,
144.6, 133.7, 131.0, 129.8, 120.8, 117.9, 115.8, 112.5, 105.1, 63.4,
Conclusion
We have developed a tandem Suzuki coupling/cyclization
between dienylboronates and o-haloanilines derivatives or
o-halophenols, which leads to the direct formation of sub-
stituted quinoline and chromenes, respectively. Additional
studies are necessary to further assess the general synthetic
utility of our new annulation protocol.
14.7 ppm. MS: m/z (%) = 189 (42) [M+], 188 (18), 160 (100) [M+
–
29], 144 (27), 132 (44), 120 (29). C12H15NO (189.25): calcd. C
76.16, H 7.99, N 7.40; found C 77.01, H 7.80, N 7.15.
2-[(E)-1-Ethoxy-2-methylbuta-1,3-dienyl]-N-tosylbenzeneamine (3c):
1
Yield 0.0.27 g (75%) as a yellow-brown oil. H NMR (200 MHz,
Experimental Section
CDCl3): δ = 7.75 (d, J = 8.7 Hz, 1 H), 7.54 (d, J = 8.7 Hz, 2 H),
7.3–7.2 (m, 1 H), 7.1–7.0 (m, 4 H), 5.65 (dd, J = 17.4, 10.6, 1 H),
5.00 (dd, J = 17.4, 1.4, 1 H), 4.72 (dd, J = 10.6, 1.4, 1 H), 4.50 (br.
s, 1 H), 3.41 (q, J = 6.6, 2 H), 2.33 (s, 3 H), 1.84 (s, 3 H), 1.17 (t,
J = 6.6, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 149.0, 147.4,
143.6, 136.1, 135.4, 132.2, 129.3, 127.1, 126.3, 125.7, 124.1, 121.9,
113.4, 112.3, 65.4, 21.4, 14.9, 10.6 ppm. MS: m/z (%) = 357 (8)
[M+], 342 (100), 174 (19), 159 (10), 155 (31), 91 (30). C20H23NO3S
(357.47): calcd. C 67.20, H 6.49, N 3.92; found C 67.80, H 6.75, N
3.20.
General Remarks: Flasks and all equipment used for the generation
and reaction of moisture-sensitive compounds were flame-dried un-
der argon. Where a temperature of –95 °C is indicated, a slush bath
of liquid nitrogen/acetone was used; room temp. stands for 25 °C.
THF was distilled from benzophenone ketyl prior to its use. BuLi
(1.6  solution in hexanes) was obtained from Aldrich. tBuOK was
sublimed in vacuo (0.1 Torr) prior to use. All commercially ob-
tained reagents were used as received. All the acetals and ethoxydi-
enes were prepared as described previously. Products were purified
by preparative column chromatography on Merck silica gel 60 with
light petroleum ether (boiling range 40–60 °C)/diethyl ether as elu-
N-{2-[(E)-1-Ethoxybuta-1,3-dienyl]phenyl}acetamide (3d): Yield
0.107 g (63%) of white solid [(E) isomer: see ref.[19]] and 0.037 g
(22%) of a yellow oil [(Z) isomer: see ref.[19]]. 1H NMR [200 MHz,
CDCl3, (E) isomer]: δ = 8.31 (d, J = 7.8 Hz, 1 H), 7.82 (br. s, 1 H),
7.38 (td, J = 7.8, 1.6, 1 H), 7.27 (dd, J = 7.8, 1.6, 1 H), 7.11 (t, J
= 7.8, 1 H), 6.11 (dt, J = 16.8, 10.6 Hz, 1 H), 5.76 (d, J = 10.6 Hz,
1 H), 5.15 (dd, J = 16.8, 1.8 Hz, 1 H), 4.88 (dd, J = 10.6, 1.8 Hz,
1 H), 3.97 (q, J = 7.0 Hz, 2 H), 2.13 (s, 3 H), 1.40 (t, J = 7.0 Hz,
3 H) ppm. 13C NMR (50.3 MHz, CDCl3, mixture of isomers): δ =
154.8, 154.0 153.4, 151.6, 133.9, 133.5, 132.2, 131.2, 130.3, 129.9,
129.8, 129.5, 125.8, 125.6, 125.5, 125.3, 121.4, 120.4, 120.1, 118.7,
118.0, 115.2, 112.9, 106.9, 67.0, 63.9, 14.6, 14.2 ppm. MS: m/z (%)
1
ent. H NMR spectra were recorded at 200 MHz in CDCl3, using
TMS as internal standard. Coupling constants (J) are given in Hz
and coupling patterns are described by abbreviations: s (singlet), d
(doublet), t (triplet), q (quartet), br. s (broad singlet). 13C NMR
spectra were recorded at 50.2 MHz in CDCl3, and chemical shifts
were determined relative to the residual solvent peak (δ =
77.0 ppm). GC-MS spectra were obtained with a mass-selective de-
tector HP-5970B instrument operating at an ionizing voltage of
70 eV connected to an HP-5890GC cross-linked methyl silicone
capillary column (25 m×0.2 mm×0.33 µm film thickness).
General Procedure for the Synthesis of Butadienylboronic Esters:[28]
To a cooled solution (–95 °C) of tBuOK (1.4 g, 12.5 mmol) in anhy-
drous THF (10 mL) acetal 1a–c (5.0 mmol) and BuLi (7.8 mL,
12.5 mmol) were consecutively added dropwise whilst stirring. Af-
ter 2 h, the purple-red solution was treated with triisopropyl borate
(10.0 mmol, 2.4 mL). The solution was warmed to room temp. and
then quenched with saturated aqueous NH4Cl (10 mL). The or-
ganic phase was diluted with Et2O and then washed with brine.
After drying (Na2SO4) and evaporation of the solvent, the crude
product was diluted with toluene (30 mL) and treated with 2,2-
dimethyl-1,3-propanediol (5 mmol, 0.52 g). The mixture was stirred
at room temp. under an inert gas overnight. The organic phase was
diluted with Et2O and washed with H2O. Drying (Na2SO4) and
removal of the solvent gave the crude reaction product, which was
then purified by column chromatography.
1
= 231 (46) [M+], 202 (14), 188 (27), 160 (100), 146 (38). H NMR
[200 MHz, CDCl3, (Z) isomer]: δ = 8.55 (br. s, 1 H), 8.47 (d, J =
8.2 Hz, 1 H), 7.4–7.3 (m, 2 H), 7.18 (t, J = 7.4, 1 H), 7.17 (dt, J =
16.8, 10.2 Hz, 1 H), 5.80 (d, J = 10.6 Hz, 1 H), 5.32 (dd, J = 16.8,
1.8 Hz, 1 H), 5.16 (dd, J = 9.8, 1.6 Hz, 1 H), 3.61 (q, J = 7.0 Hz,
2 H), 2.15 (s, 3 H), 1.26 (t, J = 7.0 Hz, 3 H) ppm. MS: m/z (%) =
231 (57) [M+], 202 (16), 188 (29), 160 (100), 146 (42). C14H17NO2
(231.29): calcd. C 72.70, H 7.41, N 6.06; found C 71.01, H 6.95, N
6.40.
N-{2-[(E)-1-Ethoxybuta-1,3-dienyl]phenyl}2,2,2-trifluoroacetamide
(3e): Yield 0.193 g (68%) of a mixture of (E) and (Z) isomers (5:1
ratio), that were not separated, as a yellow oil. 1H NMR [200 MHz,
CDCl3, mixture of (E)* and (Z) isomer]: δ = 9.80 (br. s, 1 H), 8.96*
(br. s, 1 H), 8.31 (d, J = 8.2 Hz, 1 H), 8.17* (d, J = 8.4 Hz, 1 H),
8.09 (dd, J = 8.2, 1.6 Hz, 1 H), 7.74 (dd, J = 8.2, 1.6 Hz, 1 H),
7.33* (td, J = 8.0, 1.8 Hz, 1 H), 7.25* (dd, J = 8.0, 1.8 Hz, 1 H),
7.18* (dd, J = 8.0, 1.8 Hz, 1 H), 7.14 (td, J = 8.0, 1.8 Hz, 1 H),
6.88 (td, J = 8.2, 1.6 Hz, 1 H), 6.77 (td, J = 16.8, 10.2 Hz, 1 H),
6.07* (td, J = 16.8, 10.5 Hz, 1 H), 5.81 (d, J = 10.2 Hz, 1 H), 5.70*
(d, J = 10.5 Hz, 1 H), 5.23 (dd, J = 16.8, 1.5 Hz, 1 H), 5.10* [dd,
J = 16.8, 1.5 Hz, 1 H; superimposed on 1 H of the minor (Z)
isomer], 4.83* (dd, J = 10.5, 1.5 Hz, 1 H), 3.90* (q, J = 7.0 Hz, 2
H), 3.61 (q, J = 7.0 Hz, 2 H), 1.30* (t, J = 7.0 Hz, 3 H), 1.18 (t, J
= 7.0 Hz, 1 H) ppm. 13C NMR [50.3 MHz, CDCl3, major (E) iso-
General Procedure for the Synthesis of Dienylbenzeneamines 3a, 3c–
3f: Boronate [0.210 g (2a), 0.224 g (2c), 1 mmol], 2-iodoaniline
(0.219 g, 1 mmol), and (PPh3)2PdCl2 (0.035 g, 5% mol) were added
to a solution of THF (10.0 mL) and 2  aqueous K2CO3 (1.0 mL),
which had been previously degassed with argon for 10 min. The
resulting orange solution was heated to 50 °C overnight, then co-
oled to room temp., H2O (10 mL) was then added to the mixture
which was extracted with Et2O (2 × 10 mL). The collected organic
layers were washed with brine (2 × 10 mL) and dried (K2CO3), and
the solvent was removed. The reaction product was purified by
column chromatography on deactivated SiO2 (Et3N, 1%; light pe-
troleum ether/Et2O, 9:1).
2
mer]: δ = 154.4 (q, JC,F = 36.96 Hz), 153.4, 133.5, 132.2, 131.2,
130.3, 125.8, 125.3, 121.4, 115.7 (q, 1JC,F = 289.1 Hz), 115.2, 106.9,
63.9, 14.2 ppm. MS: (E) isomer: m/z (%) = 285 (100) [M+], 257
(15), 242 (27), 238 (23), 216 (52); (Z) isomer: m/z (%) = 285 (17)
[M+], 271 (16), 270 (100), 242 (93), 145 (17). C14H14F3NO2
2-[(E)-1-Ethoxybuta-1,3-dienyl]benzeneamine (3a): Yield 0.093 g
1
(49%) of a yellow oil. H NMR (200 MHz, CDCl3): δ = 7.18 [d, J
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New Metal-Catalyzed Synthesis of Quinoline and Chromene Skeletons
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(285.26): calcd. C 58.95, H 4.95, N 4.91; found C 58.01, H 4.85,
N 4.70.
(1.0–1.5 mg) was added, and the mixture was stirred. After 4.5 h,
the chromene reagent disappeared (GC control). Amberlyst-15®
was filtered off and the solvent evaporated, then the crude quinoli-
none was purified by column chromatography on SiO2 (petroleum
2-[(E)-1-Ethoxybuta-1,3-dienyl]phenyl-N-tosylbenzenamine
(3f):
Yield 0.32 g (94%) of 3d as a yellow oil. 1H NMR (200 MHz,
CDCl3): δ = 7.58 (d, J = 8.4 Hz, 1 H), 7.43 (d, J = 8.7 Hz, 2 H),
7.3–7.1 (m, 1 H), 7.1–7.0 (m, 4 H), 5.55 (dt, J = 16.6, 10.4 Hz, 1
H), 5.40 (d, J = 10.4, Hz, 1 H), 4.90 (dd, J = 16.6, 2.2 Hz, 1 H),
4.61 (dd, J = 10.4, 2.2 Hz, 1 H), 4.12 (br. s, 1 H), 3.73 (q, J =
7.0 Hz, 2 H), 2.18 (s, 3 H), 1.24 (t, J = 6.8 Hz, 1 H) ppm. 13C
NMR (50.3 MHz, CDCl3): δ = 153.6, 143.6, 135.9, 134.8, 132.2,
131.0, 129.7, 129.4, 127.0, 126.8, 124.5, 122.5, 113.6, 106.5, 63.6,
21.2, 14.3 ppm. MS: m/z (%) = 343 (3) [M+], 329 (23), 328 (100),
160 (15), 155 (32). C19H21NO3S (343.44): calcd. C 66.45, H 6.16,
N 4.08; found C 67.01, H 6.85, N 3.95.
1
ether/Et2O, 9:1) to give pure 5b (0.25 g, 90%) as a yellow oil. H
NMR (200 MHz, CDCl3): δ = 7.96 (d, J = 7.8 Hz, 1 H), 7.72 (t, J
= 7.8 Hz, 1 H), 7.63 (t, J = 7.8 Hz, 1 H), 7.43 [d, J = 8.1 Hz, 2 H,
superimposed on δ = 7.4–7.3 ppm (m, 1 H)], 7.24 (d, J = 8.1, 2 H),
2.40 (s, 3 H), 2.28 (s, 2 H), 1.45 (s, 6 H) ppm. 13C NMR (50.3 MHz,
CDCl3): δ = 194.1, 144.1, 142.7, 138.2, 134.1, 130.4, 129.9, 128.6,
127.2, 126.9, 126.4, 60.4, 48.9, 28.3, 21.5 ppm. MS: m/z (%) = 329
(11) [M+], 274 (14), 265 (41), 174 (100), 155(17), 91 (46).
C18H19NO3S (329.41): calcd. C 65.63, H 5.81, N 4.25; found C
66.20, H 5.05, N 4.80.
General Procedure for the Synthesis of Quinolines 4c and 4f:
Pd(OAc)2 (0.0056 g, 5%mol) and dienylaniline [0.18 g (3c), 0.17 g
(3f), 0.50 mmol] were consecutively added to a solution of DMF
(3.0 mL) and 2  aqueous K2CO3 (1.0 mL), which had been pre-
viously degassed with argon for 10 min. The mixture was heated to
80 °C for 5 h. After that period, the mixture was cooled to room
temperature and filtered through Celite, then the solvent was evap-
orated to afford the crude reaction product, that was purified by
column chromatography on deactivated SiO2 (Et3N, 1%, light pe-
troleum ether/EtOAc, 6:1).
General Procedure for the Synthesis of Chromenes 6a and 6b: Bo-
ronate [0.27 g (2a), 0.29 g (2b), 1.3 mmol] and 2-bromophenol
(0.17 g, 1.0 mmol) were added to THF (10 mL) which had been
degassed with argon for 10 min, then Pd(PPh3)4 (0.058 g, 5% mol)
and K2CO3 (0.21 g, 1.5 mmol) were consecutively added. The re-
sulting solution was stirred at 80 °C overnight, and then cooled to
room temperature. H2O (10 mL) was added, the mixture extracted
with Et2O (2×10 mL), and then washed with 10% aqueous NaOH
(2×10 mL); the collected organic layers were treated with charcoal,
filtered and dried (K2CO3). After evaporation of the solvent, the
crude reaction product was purified by column chromatography on
neutral Al2O3 (light petroleum ether/Et2O, 9:1).
4-Ethoxy-2-methylquinoline (4f): Yield 0.045·g (48%) as a colorless
oil. 1H NMR (200 MHz, CDCl3): δ = 8.17 (d, J = 7.8 Hz, 1 H),
7.95 (d, J = 7.8 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8,
1 H), 6.61 (s, 1 H), 4.25 (q, J = 7.0 Hz, 2 H), 2.70 (s, 3 H), 1.57 (t,
J = 7.0 Hz, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 161.6,
160.1, 148.7, 129.7, 127.9, 124.6, 121.7, 119.9, 101.0, 63.9, 29.7,
14.5 ppm. MS: m/z (%) = 187 (76) [M+], 159 (100), 130 (24), 120
(9). C12H13NO (187.24): calcd. C 76.98, H 7.00, N 7.48; found C
78.01, H 6.85, N 6.70.
Ethoxy-2-methyl-2H-chromene (6a): Yield 0.091 g (48%) as a yel-
1
low-green oil. H NMR (200 MHz, CDCl3): δ = 7.36 (dd, J = 7.8,
1.6 Hz, 1 H), 7.06 (td, J = 7.8, 1.6 Hz, 1 H), 6.80 (td, J = 7.8,
1.6 Hz, 1 H), 6.72 (dd, J = 7.8, 1.6 Hz, 1 H), 4.99 (qd, J = 6.4,
3.0 Hz 1 H), 4.52 (d, J = 3.0 Hz, 1 H), 3.79 (q, J = 7.0 Hz, 2 H),
1.43–1.26 (m, 6 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 154.6,
149.2, 129.8, 122.0, 120.6, 115.7, 110.1, 95.2, 72.2, 62.7, 22.4,
14.4 ppm. MS: m/z (%) = 190 (25) [M+], 175 (68), 161 (17), 147
(100). C12H14O2 (190.24): calcd. C 75.76, H 7.42; found C 74.85,
H 7.95.
4-Ethoxy-2,3-dimethylquinoline (4c): The crude reaction product
was purified by column chromatography on deactivated SiO2
(Et3N, 1%, light petroleum ether/EtOAc, 6:1) to give pure 4c
(0.065 g, 65%). 1H NMR (200 MHz, CDCl3): δ = 8.01 (d, J = 8.1,
1 H), 7.62 (t, J = 8.1, 1 H), 7.46 (t, J = 8.1, 1 H), 7.26 (d, J = 8.1,
1 H), 4.10 (q, J = 6.6 Hz, 2 H), 2.70 (s, 3 H), 2.38 (s, 3 H) 0.88 (t,
4-Ethoxy-2,2-dimethyl-2H-chromene (6b): (0.075 g, 36%) as a yel-
1
low-green oil. H NMR (200 MHz, CDCl3): δ = 7.37 (dd, J = 7.6,
J = 6.6 Hz, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 160.6, 1.6 Hz, 1 H), 7.08 (td, J = 7.6, 1.6 Hz, 1 H), 6.80 (td, J = 7.6,
159.8, 147.6, 128.9, 126.7, 125.2, 122.8, 121.7, 121.3, 70.1, 24.1,
1.6 Hz, 1 H), 6.71 (dd, J = 7.6, 1.6 Hz, 1 H), 4.53 (s, 1 H), 3.79 (q,
15.7, 12.3 ppm. MS: m/z (%) = 201 (100) [M+], 173 (78), 144 (52), J = 6.8 Hz, 2 H), 1.38 (s, 6 H), 1.36 (t, J = 6.8 Hz, 3 H) ppm. 13C
130 (16), 77 (17). C13H15NO (201.26): calcd. C 77.58, H 7.51, N
6.96; found C 76.20, H 8.01, N 6.02.
NMR (50.3 MHz, CDCl3): δ = 153.6, 148.1, 129.5, 121.9, 120.2,
119.2, 116.1, 99.6, 77.3, 62.6, 29.2 (2 C), 14.5 ppm. MS: m/z (%) =
204 (19) [M+], 189 (79), 161 (100), 121 (10). C13H16O2 (204.26):
calcd. C 76.44, H 7.90; found C 76.99; H,7.45.
Typical Procedure for the Synthesis of 4-Ethoxy-1,2-dihydro-2,2-di-
methyl-1-tosylquinoline (4b): Boronate 2b (0.58 g, 2.6 mmol) and 2-
iodo-N-tosylaniline (0.720 g, 1.93 mmol), and PdCl2(PPh3)2
(0.068 g, 5% mol) were used. The reaction then was carried out as
above reported for quinoline 4a, to afford pure 4b (0.38 g, 55%) as
a white solid (m.p. 104–106 °C). 1H NMR (200 MHz, CDCl3): δ =
7.65 (dd, J = 7.8, 1.6 Hz, 1 H), 7.44 (td, J = 7.8, 1.6 Hz, 1 H), 7.70
(td, J = 7.8, 1.6 Hz, 1 H), 7.2–7.1 (m, 3 H), 7.07 (d, J = 8.1, 2 H),
4.24 (s, 1 H), 3.31 (q, J = 6.7 Hz, 2 H), 2.36 (s, 3 H), 1.48 (s, 6 H),
1.20 (t, J = 6.7 Hz, 3 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ =
149.7, 142.6, 137.9, 136.8, 129.8, 128.7, 128.2, 128.0, 127.5, 126.7,
121.8, 104.0, 62.5, 58.61, 29.2, 21.3, 14.2 ppm. MS: m/z (%) = 187
(68), 159 (100), 158 (13), 130 (22), 77 (12). C20H23NO3S (357.47):
calcd. C 67.20, H 6.49, N 3.92; found C 68.05, H 5.99, N 4.08.
Typical Procedure for the Synthesis of 2,3-Dihydro-2,2-dimeth-
ylchromen-4-one (7b): Chromene 6b (0.045 g, 0.22 mmol) was dis-
solved in CHCl3, then a catalytic quantity of Amberlyst-15® (1.0–
1.5 mg) was added, and the mixture was stirred. After 2 h, the
chromene reagent disappeared (GC control). The resin was filtered
off and the solvent evaporated, then the crude chromenone was
purified by column chromatography on SiO2 (petroleum ether/
Et2O, 9:1) to give pure 7b (0.029 g, 75%) as a yellow oil. 1H NMR
(200 MHz, CDCl3): δ = 7.79 (d, J = 7.8 Hz, 1 H), 7.40 (t, J =
7.8 Hz, 1 H), 6.92 (t, J = 7.8 Hz, 1 H), 6.86 (d, J = 7.8 Hz, 1 H),
2.66 (s, 2 H), 1.36 (s, 6 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ
= 192.6, 159.9, 136.1, 126.5, 120.6, 120.2, 118.3, 79.1, 48.9, 26.7 (2
Typical Procedure for the Synthesis of 2,3-Dihydro-2,2-dimethyl-1- C) ppm. MS: m/z (%) = 176 (59) [M+], 161 (100), 121 (52), 120
tosylquinolin-4(1H)-one (5b): Quinoline 4b (0.30 g, 0.84 mmol) was
(51), 93 (10), 92 (40). C11H12O2 (176.21): calcd. C 74.98, H 6.86;
found C 75.75, H 7.10.
dissolved in CHCl3, then a catalytic quantity of Amberlyst-15®
Eur. J. Org. Chem. 2006, 3451–3456
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3455

A. Deagostino, V. Farina, C. Prandi, C. Zavattaro, P. Venturello
FULL PAPER
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using 3a in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzo-
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Received: March 15, 2006
Published Online: May 22, 2006
3456
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3451–3456