Cerium(III)-catalyzed facile synthesis of dihydrobenzofuran-tethered pyridines and dihydroquinolin-5(6 H)-ones from -enaminones

Article abstract of DOI:10.1055/s-0030-1258236

A series of novel dihydrobenzofuran-tethered pyridines, dihydroquinolin-5(6H)-ones, and indeno[1,2-b]pyridin-5-ones were synthesized in very good yields by CeCl₃7H₂O-NaI catalyzed one-pot condensation of variants of the Bohlmann-Rahtz reaction, viz. -enaminones derived from 7-acetyldihydrobenzofurans, acyclic and cyclic 1,3-dicarbonyls, and ammonium acetate. The protocol offers the advantages of easily accessible substrates, shorter reaction times, and easy work-up with a readily available catalyst. Further more, dihydrobenzofuran-substituted 2-(chloromethyl)pyridine was derivatized to its synthetic hybrid by reacting with piperazine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258236

PAPER
3745
Cerium(III)-Catalyzed Facile Synthesis of Dihydrobenzofuran-Tethered
Pyridines and Dihydroquinolin-5(6H)-ones from b-Enaminones
D
ihydrobenzo
r
furan-T
e
i
thered
n
P
yridines an
i
d Dihyd
v
roquinolin-5
a
(6
H
)-oness Kantevari,*a Dinesh Addla,a Balasubramanian Sridharb
a
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500007, India
E-mail: kantevari@yahoo.com; E-mail: kantevari@gmail.com
b
Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 29 June 2010; revised 14 July 2010
can be increased in combination with sodium iodide.12
The successful utility of cerium(III) in reactions originat-
ed from 1,3-dicarbonyls12 prompted us to investigate its
applicability in the one-pot condensation of b-enaminones
Abstract: A series of novel dihydrobenzofuran-tethered pyridines,
dihydroquinolin-5(6H)-ones, and indeno[1,2-b]pyridin-5-ones
were synthesized in very good yields by CeCl3·7H2O–NaI catalyzed
one-pot condensation of variants of the Bohlmann–Rahtz reaction,
viz. b-enaminones derived from 7-acetyldihydrobenzofurans, acy- with 1,3-dicarbonyls and ammonium acetate.
clic and cyclic 1,3-dicarbonyls, and ammonium acetate. The proto-
We herein report an efficient CeCl3·7H2O–NaI catalyzed
col offers the advantages of easily accessible substrates, shorter
regioselective conversion of newly synthesized dihy-
reaction times, and easy work-up with a readily available catalyst.
drobenzofuranyl-substituted enaminones 1a,b into novel
substituted pyridines and dihydroquinolin-5(6H)-ones
tethered with a dihydrobenzofuran group through a
Michael addition, cyclodehydration, and elimination se-
quence. One-pot reaction of (E)-1-(2,3-dihydrobenzofu-
ran-7-yl)-3-(dimethylamino)prop-2-enones 1a,b, derived
from the respective commercially available 2¢-hydroxy-
acetophenones, with readily available acyclic and cyclic
1,3-dicarbonyls 2a–m and ammonium acetate in propan-
Further more, dihydrobenzofuran-substituted 2-(chloromethyl)py-
ridine was derivatized to its synthetic hybrid by reacting with piper-
azine.
Key words: Bohlmann–Rahtz
reaction,
dihydrobenzofuran,
CeCl3·7H2O–NaI, one-pot condensation, b-enaminone, hetero-
cycles, pyridines, quinolinones
The prevalence and diversity of polysubstituted aromatic
nitrogen heterocycles, viz. pyridine and quinolinones,
found in natural products and used in medicinal chemistry
continues to fuel the development of newer methods and
strategies for their synthesis.1 Notable natural products
and other successful synthetic drug candidates having a
2,3,6-substituted pyridine central core unit are depicted in
Figure 1.2,3 In an effort to develop a new heterocyclic li-
brary with drug-like properties, we thought to synthesize
a series of analogues containing both pyridine and dihy-
drobenzofuran moieties in one molecular frame. A prom-
ising approach for the preparation of these structurally
related pyridine-dihydrobenzofuran conjugates4,5 would
be through multicomponent reactions (MCR).6,7
CO2R
N
S
S
N
N
N
S
N
CO2Me
O
S
RO2C
N
R = H, micrococcinic acid
R = Me, methyl micrococcinate
S
N
O
MeO2C
N
Incisive work from Bagley2,8 has unveiled a remarkable
variant of the classical Bohlmann–Rahtz synthesis,8c
wherein an alkynone was combined with aminoalkenoate
to give substituted pyridine derivatives. From our
research9 as well as work from others10 it is clear that b-
enaminones could serve as Bohlmann–Rahtz variants of
polarized alkynones in the synthesis of 2,3,6-trisubstitut-
ed pyridines. In recent years, among the lanthanide cata-
lysts, cerium(III) chloride has emerged as an inexpensive,
efficient, and green reagent (in fact, it shows the same
toxicity level as sodium chloride) that is able to catalyze
various selective chemical transformations and cycliza-
tions.11 In most cases, the activity of cerium(III) chloride
O
dimethyl sulfomycinamate
F
MeO
OH
N
O
O
OH
OH
cerivastatin
RO2C
N
NH2
O
NH
lavendamycin
SYNTHESIS 2010, No. 21, pp 3745–3754
x
x.
x
x
.
2
0
1
0
Advanced online publication: 30.08.2010
DOI: 10.1055/s-0030-1258236; Art ID: Z16410SS
Figure 1 Representatives of natural and synthetic polysubstituted
pyridines and dihydroquinolinones
© Georg Thieme Verlag Stuttgart · New York

3746
S. Kantevari et al.
PAPER
2-ol in the presence of CeCl3·7H2O–NaI catalyst resulted Due to the presence of the ambident nucleophilic charac-
in the title compounds with high regioselectivity at the ter of the enamine moiety and ambident electrophilic
2,3,6-positions. Furthermore the current method is easy to character of the enone moiety, b-enaminones are useful
perform and broad in scope and generates a novel library synthetic intermediates in organic synthesis.10 A variety
of substituted dihydroquinolin-5-one motifs bearing dihy- of intra- and intermolecular reactions have been per-
drobenzofurans in the tether. Dihydrobenzofuran-substi- formed taking advantage of their electronic properties. b-
tuted 2-(chloromethyl)pyridine was also derivatized Enaminones are generally prepared by the condensation
further to a synthetic hybrid by reacting with piperazine to of the respective aryl methyl ketones with N,N-dimethyl-
give a complex drug-like structure.
formamide dimethyl acetal (DMF-DMA) in refluxing xy-
O
O
OH
O
OH
O
allyl bromide
K2CO3, 8 h
Δ
R
MIBK
R
180 °C, 5 h
R
O
O
O
O
DMF-DMA
xylene
concd H2SO4
NMe2
1,4-dioxane
100 °C, 4 h
reflux, 7 h
R
R
1a: R = 4-Me
1b: R = 5-F
Scheme 1 Preparation of enaminones 1a,b
Table 1 Optimization of the Catalyst and Reaction Conditionsa
O
OEt
O
NH4OAc
catalyst
O
O
O
O
N
NMe2
+
solvent
OEt
1a
2a
3aa
Entry
Catalyst
mol%
Time (h)
Temp (°C)
reflux
reflux
reflux
reflux
reflux
80
Solvent
i-PrOH
i-PrOH
MeOH
i-PrOH
i-PrOH
DMF
Yieldb (%)
1
2
K5CoW12O40·3H2O
K5CoW12O40·3H2O
SnCl2·2H2O
20
30
30
30
30
20
20
20
20
20
20
20
30
10
20
8.0
8.0
58
60
15
52
12
35
66
62
38
23
82
58
80
58
<1
3
24.0
24.0
24.0
5.0
4
CeCl3·7H2O
5
CeCl3 (anhyd)
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
CeCl3·7H2O–NaI
NaI
6
7
5.0
reflux
reflux
reflux
85
MeOH
MeCN
DCE
8
8.0
9
24.0
24.0
4.0
10
11
12
13
14
15
H2O
reflux
85
i-PrOH
neat
4.0
4.0
reflux
reflux
reflux
i-PrOH
i-PrOH
i-PrOH
4.0
4.0
a All reactions were performed with 1a (1.0 mmol), 2a (1.2 mmol), NH4OAc (2.0 mmol).
b Isolated yield.
Synthesis 2010, No. 21, 3745–3754 © Thieme Stuttgart · New York

PAPER
Dihydrobenzofuran-Tethered Pyridines and Dihydroquinolin-5(6H)-ones
3747
lene.10h,i Although the method is readily adopted, there is promote the condensation of enaminone 1a with ethyl
no synthetic protocol for the preparation of 2,3-dihy- acetoacetate (2a). Screening various solvents (DMF,
drobenzofuran-7-ylenaminones 1a,b. The required start- MeOH, i-PrOH, MeCN, H2O, and neat) and reaction con-
ing compound, (2,3-dihydrobenzofuran-7-yl)ethanone,13 ditions resulted optimum yield (82%; entry 11) of 3aa in
was prepared by following the reaction sequence depicted propan-2-ol at reflux temperature.
in Scheme 1. It was then converted into b-enaminones
After screening the reaction parameters, we next exam-
ined the broader scope of the reaction with various acyclic
1a,b by refluxing with N,N-dimethylformamide dimethyl
acetal in xylene [overall yields 1a (39%) and 1b (44%)].
1,3-dicarbonyls 2a–h and ammonium acetate under opti-
1
The products 1a and 1b were fully characterized by H
mal conditions [CeCl3·7H2O–NaI (20 mol%), i-PrOH, re-
and 13C NMR and mass spectral analysis.
flux]. All the acyclic 1,3-dicarbonyls except 2g and 2h
On the basis of our previous work,9 initially, b-enaminone reacted well with both the enaminones 1a and 1b and the
1a (a polarized variant of a Bohlmann–Rahtz alkynone) corresponding dihydrobenzofuran-tethered 2,3,6-trisub-
was selected to react with ethyl acetoacetate (2a) and am- stituted pyridines 3 were obtained in very good yields
monium acetate in the presence of 20 mol% of potassium (Table 2). However, the cerium(III)-catalyzed condensa-
dodecatungstocobaltate (K5CoW12O40·3H2O) catalyst. tion of enaminone 1a with the trifluoromethyl analogues
The target product ethyl 6-(2,4-dimethyl-2,3-dihydroben- of 1,3-dicarbonyls 2g,h and ammonium acetate (entries 7
zofuran-7-yl)-2-methylnicotinate (3aa) was obtained in and 8) was sluggish resulting in the formation of several
58% yield. In order to improve the reaction efficiency, the unidentified byproducts. The structures of dihydrobenzo-
reaction conditions were optimized (Table 1). A study de- furan-conjugated 2,3,6-trisubstituted pyridines 3 were
signed to optimize yields showed CeCl3·7H2O–NaI (20 clearly assigned from their IR, 1H and 13C NMR, ESI-MS,
mol%) to be superior to K5CoW12O40·3H2O. The reaction and HRMS analysis. Further the structures of 3aa and 3ae
was facile only when CeCl3·7H2O in combination with so- were unambiguously confirmed by single crystal X-ray
dium iodide was used and no reaction took place with so- diffraction analysis (Figures 2 and 3).
dium iodide alone. In the absence of sodium iodide, the
Encouraged by the good results acquired from acyclic 1,3-
reaction with CeCl3·7H2O requires 24 hours to give prod-
dicarbonyls in the generation of pyridine scaffolds, we
uct 3aa in 52% yield (entry 4). The results described here
then proceeded to investigate scope of this reaction with
cyclic 1,3-dicarbonyls 2i–m. An array of dihydrobenzo-
furan-appended quinolinones (Scheme 2) with structural
established that the water associated with the cerium(III)
salt plays a role in the ability of the CeCl3·7H2O–NaI to
Table 2 Cerium(III)-Catalyzed One-Pot Synthesis of Dihydrobenzofuranyl Nicotinates 3aa–3bba
O
R3
NH4OAc
CeCl3⋅7H2O-NaI
O
O
O
O
O
N
R2
R2
R3
NMe2
+
i-PrOH
reflux
R1
1,3-dicarbonyl
R1
3aa–bd
2a–f
1a: R1 = 4-Me
1b: R1 = 5-F
Entry
Enaminone
1,3-Dicarbonyl
R2
Time (h)
Product
Yieldb (%)
R3
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
Me
Me
Me
Me
CH2Cl
Pr
OEt
Me
2a
2b
2c
2d
2e
2f
4.0
4.0
3aa
3ab
3ac
3ad
3ae
3af
82
78
60
85
83
64
<1
<1
80
82
3
Ot-Bu
OMe
OEt
OEt
OEt
OCF3
OEt
OMe
4.0
4
4.0
5
6.0
6
6.0
7
CF3
Me
Me
Me
2g
2h
2a
2b
12.0
12.0
4.0
3ag
3ah
3ba
3bb
8
9
10
4.0
a Reaction conditions: 1a,b (1.0 mmol), 2a–h (1.2 mmol), NH4OAc (2.0 mmol), i-PrOH, reflux.
b Yields refer to pure isolated products after column chromatography.
Synthesis 2010, No. 21, 3745–3754 © Thieme Stuttgart · New York

3748
S. Kantevari et al.
PAPER
Figure 2 ORTEP representation of compound 3aa with thermal dis-
placement ellipsoids drawn at the 30% probability14
Figure 3 ORTEP representation of compound 3ae with thermal dis-
placement ellipsoids drawn at the 30% probability14
diversity was synthesized in an effort to generate novel
analogues of lavendamycin-like compounds (lavendamy-
cin is an anticancer drug). For example, the reaction of b-
enaminone 1a with cyclohexane-1,3-dione (2i) and am-
monium acetate in the presence of CeCl3·7H2O–NaI under
optimized conditions afforded 2-(2,4-dimethyl-2,3-
dihydrobenzofuran-7-yl)-7,8-dihydroquinolin-5(6H)-one
(4ai) in 85% yield (Scheme 2). In a similar fashion, b-
enaminones 1a,b reacts with 4,4-dimethylcyclohexane-
1,3-dione (2k) regioselectively to give 6,6-dimethyl-7,8-
dihydroquinolin-5(6H)-ones 4ak and 4bk, respectively,
as the sole product in 76% and 72% yields. Other cyclic
1,3-diketones such as dimedone (2j) and cycloheptane-
O
O
O
O
O
N
2i
N
O
4ai (85%)
4bi (79%)
F
O
O
O
O
O
2j
O
N
N
4aj (82%)
4bj (76%)
F
O
O
O
O
O
O
O
NH4OAc
2k
CeCl3⋅7H2O-NaI
O
NMe2
N
N
i-PrOH
reflux
4ak (76%)
R
4bk (72%)
F
1a: R = 4-Me
1b: R = 5-F
O
O
O
2l
O
4al (58%)
N
O
O
O
2m
O
O
O
N
N
F
4bm (62%)
4am (68%)
Scheme 2 Synthesis of 2-(2-methyl-2,3-dihydrobenzofuran-7-yl)-7,8-dihydroquinolin-5(6H)-ones and indeno[1,2-b]pyridin-5-ones
Synthesis 2010, No. 21, 3745–3754 © Thieme Stuttgart · New York

PAPER
Dihydrobenzofuran-Tethered Pyridines and Dihydroquinolin-5(6H)-ones
3749
OEt
H
N
O
O
O
pyridine
OEt
O
N
+
N
DMAP
MeCN
6 h, r.t.
77%
N
N
N
Cl
5
3ae
Scheme 3 Synthesis of ethyl 6-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)-2-[(4-phenylpiperazin-1-yl)methyl]nicotinate (5)
1,3-dione (2l) also proceeded efficiently to afford 7,8-di- dration–elimination sequence using the reaction of enam-
hydroquinolin-5(6H)-ones 4aj, 4bj, and 4al. On the other inone 1a and ethyl acetoacetate (2a) as an example is
hand, to achieve further diversity, b-enaminones 1a,b shown in Scheme 4. At first cerium-activated reaction of
were condensed with indane-1,3-dione 2m under the stan- 1,3-dicarbonyl 2a with ammonium acetate would occur
dard one-pot protocol resulting in novel analogues of in- provide an amine. This amine, further undergoes cerium-
deno[1,2-b]pyridin-5-ones 4am and 4bm in very good assisted regioselective Michael addition on the polarized
yields. The structures of all the products were fully char- b-enaminone 1a followed by cyclodehydration. Aromati-
1
acterized by IR, H and 13C NMR, ESI-MS, and HRMS zation leading to the pyridine ring with elimination of
analysis.
dimethylamine completes the catalytic cycle.
Further to generate more complex pharmacophoric deriv- In summary, we have developed an efficient cerium(III)-
atives, ethyl 2-(chloromethyl)-6-(2,4-dimethyl-2,3-dihy- catalyzed protocol for one-pot regioselective synthesis of
drobenzofuran-7-yl)nicotinate (3ae) was treated with novel dihydrobenzofuran-tethered pyridines and dihydro-
pyridine, 4-(dimethylamino)pyridine, and N-phenylpiper- quinolin-5(6H)-ones employing b-enaminones 1a,b and
azine in acetonitrile at room temperature (Scheme 3). Eth- acyclic and cyclic 1,3-dicarbonyls as novel variants of the
yl 6-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)-2-[(4- Bohlmann–Rahtz substrate, and ammonium acetate in re-
phenylpiperazin-1-yl)methyl]nicotinate (5) was obtained fluxing propan-2-ol. Mechanistically, the reaction pro-
in 77% yield and it was fully characterized by IR, 1H and ceeds
through
sequential
Michael
addition,
13C NMR, ESI-MS, and HRMS analysis. A plausible cyclodehydration, and elimination reactions. The method
mechanism for the tandem Michael addition–cyclodehy- appears to be very general and reactive with respect to
O
O
CeCl3⋅7H2O
NMe2
NaI
O
Me2NH
CeCl3I–Na+⋅nH2O
OEt
N
Ce(III)
O
O
NMe2 OH
OEt
O
Ce(III)Cl3
I-Na+
Me2N
N
O
OEt
Ce(III)
H2O
OEt
NMe2
NH2
O
O
Ce(III)
NMe2
O
NH4OAc
H2N
O
OEt
OEt
Ce(III)Cl3⋅I–Na+
O
N
O
O
H
Ce
(III)
O
Scheme 4 Plausible mechanism for the formation of 2,3,6-trisubstituted pyridines and dihydroquinolin-5(6H)-ones
Synthesis 2010, No. 21, 3745–3754 © Thieme Stuttgart · New York

3750
S. Kantevari et al.
PAPER
2.71 (dd, J = 7.3, 8.0 Hz, 1 H), 2.55 (s, 3 H), 2.24 (s, 3 H), 1.52 (d,
J = 6.2 Hz, 3 H).
city will make it attractive for the construction of a library 13C NMR (75 MHz, CDCl3): d = 196.9, 159.6, 140.3, 128.0, 127.6,
121.4, 118.4, 80.4, 35.3, 30.8, 22.0, 19.2.
of compounds.
starting materials. It is likely that the efficiency and nov-
elty of this method combined with its operational simpli-
3-(Dimethylamino)-1-(2,4-dimethyl-2,3-dihydrobenzofuran-7-
yl)propenone (1a); Typical Procedure
All reactions were monitored by TLC (recoated silica plates and vi-
sualizing under UV light). Air-sensitive reagents were transferred
by syringe or a double-ended needle. Evaporation of solvents was
performed at reduced pressure on a Buchi rotary evaporator. 1H and
13C NMR spectra of samples in CDCl3 were recorded on Bruker
UXNMR FT-300 MHz (Avance) spectrometer and Varian FT-500
MHz (Inova) relative to an internal standard TMS. Mass spectra
were recorded under EI conditions at 70 eV on a LC-MSD (Agilent
technologies) spectrometer. All HRMS were recorded on a QSTAR
XL hybrid MS/MS system (Applied Biosystems/MDS sciex),
equipped with an ESI source (IICT, Hyderabad). Column chroma-
tography was performed on silica gel (60–120 mesh) supplied by
Acme Chemical Co., India. TLC was performed on Merck 60 F-254
silica gel plates. Optical rotations were measured with a Jasco DIP-
370 polarimeter at 25 °C. Commercially available anhyd solvents
CH2Cl2, THF, and EtOAc were used as such without further purifi-
cation. Methyl isobutyl ketone = MIBK.
To a soln of 1-(2,4-dimethyl-2,3-dihydrobenzofuran-7-yl)ethanone
(2.0 g, 10.52 mmol) in xylene (20 mL) was added DMF-DMA (2.94
mL, 21.05 mmol) under N2 and the mixture was refluxed for 7 h
(TLC monitoring). Xylene was then removed by distillation and the
crude residue was triturated with hexane. The solid residue thus
formed was filtered to give 1a (1.8 g, 70%) as a pure light brown
solid; mp 139 °C.
IR (KBr): 2908, 1635, 1545, 1360, 1259, 1232, 1081, 905, 877
cm–1.
1H NMR (500 MHz, CDCl3): d = 7.71 (d, J = 12.2 Hz, 1 H), 7.63 (d,
J = 7.1 Hz, 1 H), 6.65 (d, J = 7.1 Hz, 1 H), 6.02 (d, J = 12.2 Hz, 1
H), 4.96–5.03 (m, 1 H), 3.23 (dd, J = 9.1, 6.1 Hz, 1 H), 3.01 (br s, 6
H), 2.71 (dd, J = 7.1, 7.1 Hz, 1 H), 2.23 (s, 3 H), 1.52 (d, J = 6.1 Hz,
3 H).
13C NMR (75 MHz, CDCl3): d = 186.2, 157.7, 153.4, 137.6, 128.3,
126.8, 121.2, 79.7, 44.7, 35.4, 22.0, 19.0.
1-[2-(Allyloxy)-4-methylphenyl]ethanone; Typical Procedure
To a soln of 2¢-hydroxy-4¢-methylacetophenone (31.53 g, 0.21 mol)
in MIBK (470 mL) was added anhyd K2CO3 (29.0 g, 0.21 mol) fol-
lowed by allyl bromide (32 mL, 0.25 mol). The mixture was re-
fluxed for 8 h and then it was filtered, the residue was washed with
MIBK (3 × 25 mL), and the combined solvent was evaporated to
dryness. The crude residue was redissolved in CHCl3 (175 mL),
washed with H2O (3 × 50 mL) and brine (50 mL), dried (Na2SO4),
and concentrated under vacuum. Purification by column chroma-
tography (silica gel, hexane–EtOAc, 9:1) yielded the product (37.1
g, 93%) as a white solid; mp 48 °C (Lit.1 48–49 °C).
MS (ESI): m/z = 246 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C15H20NO2: 246.1494; found:
246.1497.
1-[2-(Allyloxy)-5-fluorophenyl]ethanone
Following the typical procedure for 1-[2-(allyloxy)-4-methylphe-
nyl]ethanone using 5¢-fluoro-2¢-hydroxyacetophenone (27.8 g, 0.18
mol), MIBK (400 mL), anhyd K2CO3 (24.9 g, 0.18 mol), and allyl
bromide (18.8 mL, 0.21 mol); washing with MIBK (3 × 30 mL), re-
dissolved in CHCl3 (150 mL), washed with H2O (3 × 50 mL) and
brine soln (50 mL), column chromatography (silica gel, hexane–
EtOAc, 9:1) yielded the product (33.6 g, 96%) as a low melting
white solid; mp 38 °C.
1H NMR (300 MHz, CDCl3): d = 7.64 (d, J = 7.7 Hz, 1 H), 6.77 (d,
J = 7.7 Hz, 1 H), 6.69 (s, 1 H), 6.01–6.14 (m, 1 H), 5.29–5.46 (m, 2
H), 4.62 (dt, J = 5.2, 1.5 Hz, 2 H), 2.58 (s, 3 H), 2.38 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 7.43 (dd, J = 3.1, 5.7 Hz, 1 H),
7.07–7.11 (m, 1 H), 6.87 (dd, J = 3.9, 5.2 Hz, 1 H), 6.01–6.09 (m, 1
H), 5.41 (dd, J = 1.3, 1.3 Hz, 1 H), 5.32 (dd J = 1.3, 1.0 Hz, 1 H),
4.60 (d, J = 5.2 Hz, 2 H), 2.60 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.2, 158.2, 155.0, 132.3, 120.0,
119.7, 118.3, 116.5, 114.2, 69.9, 31.7.
1-(3-Allyl-2-hydroxy-4-methylphenyl)ethanone; Typical Proce-
dure
1-[2-(Allyloxy)-4-methylphenyl]ethanone (15.92 g, 83.78 mmol)
was heated neat at 180 °C for 5 h (TLC monitoring). The mixture
was then cooled to r.t. and purified by column chromatography (sil-
ica gel, hexane–EtOAc, 9:1) to give the product (14.64 g, 92%) as
a light yellow syrup.
1H NMR (300 MHz, CDCl3): d = 12.6 (s, 1 H), 7.46 (d, J = 8.1 Hz,
1 H), 6.64 (d, J = 8.1 Hz, 1 H), 5.80–5.93 (m, 1 H), 4.88–4.97 (m, 2
H), 3.42 (d, J = 6.0 Hz, 2 H), 2.58 (s, 3 H), 2.31 (s, 3 H).
1-(3-Allyl-5-fluoro-2-hydroxyphenyl)ethanone
Following the typical procedure for 1-(3-allyl-2-hydroxy-4-meth-
ylphenyl)ethanone using 1-[2-(allyloxy)-5-fluorophenyl]ethanone
(30.1 g, 0.155 mol) gave the product (27.1 g, 90%) as a light yellow
syrup.
1H NMR (300 MHz, CDCl3): d = 12.27 (s, 1 H), 7.22 (dd, J = 3.0,
5.4 Hz, 1 H), 7.08 (dd, J = 3.0, 5.4 Hz, 1 H), 5.86–5.99 (m, 1 H),
5.07–5.12 (m, 2 H), 3.39 (d, J = 6.8 Hz, 2 H), 2.59 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 204.0, 160.4, 146.2, 135.0, 128.2,
126.6, 122.3, 120.6, 114.6, 29.5, 26.3, 19.9.
1-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)ethanone;Typical
Procedure
To a soln of 1-(3-allyl-2-hydroxy-4-methylphenyl)ethanone (10 g,
52.63 mmol) in 1,4-dioxane (225 mL) was added concd H2SO4 (29
mL) at 0 °C with stirring over 10 min. The mixture was heated to
100 °C for 4 h and then it was cooled to r.t. and neutralized (sat. aq
Na2CO3). The soln was taken in a separating funnel and EtOAc (80
mL) was added; the combined organic layer was separated, washed
with H2O (3 × 30 mL) and brine (25 mL), dried (Na2SO4), and con-
centrated. Column chromatography (silica gel, hexane–EtOAc, 9:1)
gave the product (6.50 g, 65%) as a white solid; mp 75 °C (Lit.13 73–
74 °C).
1-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)ethanone
Following the typical procedure for 1-(2,4-dimethyl-2,3-dihy-
drobenzofuran-7-yl)ethanone using 1-(3-allyl-5-fluoro-2-hydroxy-
phenyl)ethanone (9.34 g, 48.14 mmol), 1,4-dioxane (225 mL), and
concd H2SO4 (25.6 mL); workup used EtOAc (100 mL) and H2O
(3 × 50 mL) and brine (25 mL). Column chromatography (silica gel,
hexane–EtOAc, 9:1) gave the product (6.53 g, 70%) as a thick syr-
up.
1H NMR (300 MHz, CDCl3): d = 7.27 (d, J = 9.8 Hz, 1 H), 6.96 (d,
J = 7.1 Hz, 1 H), 4.98–5.08 (m, 1 H), 3.32 (dd, J = 7.7, 7.9 Hz, 1 H),
1H NMR (300 MHz, CDCl3): d = 7.57 (d, J = 8.0 Hz, 1 H), 6.64 (d,
J = 8.0 Hz, 1 H), 4.99–5.08 (m, 1 H), 3.24 (dd, J = 9.1, 6.2 Hz, 1 H),
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Dihydrobenzofuran-Tethered Pyridines and Dihydroquinolin-5(6H)-ones
3751
2.81 (dd, J = 7.5, 7.3 Hz, 1 H), 2.54 (d, J = 3.9 Hz, 3 H), 1.52 (dd,
J = 3.2, 3.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 195.7, 158.2, 155.1, 131.2, 129.3,
117.4, 112.8, 81.1, 36.3, 30.8, 21.6.
MS (ESI): m/z = 312 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.1599; found:
312.1597.
1-[6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methylpyri-
din-3-yl]ethanone (3ab)
Yield: 78%; mp 110 °C.
3-(Dimethylamino)-1-(5-fluoro-2,3-dihydrobenzofuran-7-
yl)propenone (1b)
Following the typical procedure for 1a using 1-(2,4-dimethyl-2,3-
dihydrobenzofuran-7-yl)ethanone (2.50 g, 12.8 mmol), xylene (30
mL), and DMF-DMA (3.60 mL, 25.7 mmol) gave 1b (2.34 g, 73%)
as a pure light brown solid; mp 78 °C.
IR (KBr): 2926, 2853, 1740, 1580, 1419, 1359, 1244, 1189, 1152,
1032, 903, 821, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.05 (q, 2 H), 7.97 (d, J = 8.3 Hz,
1 H), 6.75 (d, J = 8.3 Hz, 1 H), 5.00–5.08 (m, 1 H), 3.28 (dd, J = 9.0,
6.0 Hz, 1 H), 2.80 (s, 3 H), 2.76 (dd, J = 7.5, 7.54 Hz, 1 H), 2.57 (s,
3 H), 2.27 (s, 3 H), 1.54 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 199.9, 164.1, 157.6, 137.6, 136.5,
135.3, 129.6, 128.0, 121.9, 120.1, 114.2, 79.9, 35.7, 25.3, 22.1,
19.0, 14.3.
IR (KBr): 2926, 1634, 1552, 1438, 1364, 1255, 1171, 1103, 1037,
972, 800, 741 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.73 (d, J = 12.7 Hz, 1 H), 7.39
(dd, J = 2.9, 6.8 Hz, 1 H), 6.87 (dd, J = 2.9, 3.9 Hz, 1 H), 6.00 (d,
J = 12.7 Hz, 1 H), 4.95–5.02 (m, 1 H), 3.29 (dd, J = 6.8, 8.8 Hz, 1
H), 3.02 (br s, 6 H), 2.80 (dd, J = 7.8, 7.8 Hz, 1 H), 1.50 (d, J = 6.8
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 184.4, 158.6, 155.5, 153.8, 129.7,
129.6, 123.6, 114.8, 113.7, 80.2, 44.7, 36.7, 21.8.
MS (ESI): m/z = 282 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO2: 282.1494; found:
282.1501.
MS (ESI): m/z = 250 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C14H17NO2F: 250.1243;
tert-Butyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-
methylnicotinate (3ac)
found: 250.1249.
Yield: 60%.
IR (neat): 2924, 1714, 1584, 1457, 1370, 1281, 1145, 1079, 909,
786 cm–1.
2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-7,8-dihydroquin-
olin-5(6H)-one (4ai); Typical Procedure
1H NMR (300 MHz, CDCl3): d = 8.10 (d, J = 8.3 Hz, 1 H), 8.02 (d,
J = 7.5 Hz, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 6.73 (d, J = 7.5 Hz, 1 H),
5.01–5.08 (m, 1 H), 3.27 (dd, J = 6.7, 7.5 Hz, 1 H), 2.83 (s, 3 H),
2.74 (dd, J = 6.7, 8.3 Hz, 1 H), 2.26 (s, 3 H), 1.59 (s, 9 H), 1.52 (d,
J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.1, 158.5, 157.5, 155.9, 138.5,
136.0, 128.1, 126.6, 124.1, 121.8, 120.2, 118.4, 79.6, 51.2, 35.7,
27.8, 22.6, 18.9, 14.0.
To a mixture of 1a (0.245 g, 1.0 mmol), dione 2i (0.13 g, 1.2 mmol),
and NH4OAc (0.15 g, 2.0 mmol) in i-PrOH (5 mL) was added
CeCl3·7H2O (75 mg, 0.2 mmol) and NaI (30 mg, 0.2 mmol) and the
mixture was refluxed for 4 h (TLC monitoring). The mixture was
cooled to r.t. and the solid precipitate was filtered and washed (cold
i-PrOH). The combined solvent was evaporated and the crude resi-
due was subjected to column chromatography (silica gel, hexane–
EtOAc, 9:1) to give 4ai (0.25 g, 85%) as a pale yellow solid; mp 112
°C.
MS (ESI): m/z = 340 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO3: 340.1912; found:
IR (KBr): 2924, 2853, 1682, 1577, 1454, 1420, 1382, 1240, 1189,
1020, 898, 815, 775 cm–1.
340.1902.
1H NMR (300 MHz, CDCl3): d = 8.22 (d, J = 8.3 Hz, 1 H), 8.09 (d,
J = 8.3 Hz, 1 H), 8.01 (d, J = 7.5 Hz, 1 H), 6.74 (d, J = 7.5 Hz, 1 H),
5.01–5.08 (m, 1 H), 3.28 (dd, J = 9.0, 6.0 Hz, 1 H), 3.16 (t, J = 6.0
Hz, 2 H), 2.76 (dd, J = 7.5, 7.5 Hz, 1 H), 2.66 (t, J = 6.0 Hz, 2 H),
2.26 (s, 3 H), 2.17–2.23 (m, 2 H), 1.54 (d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 198.0, 163.2, 158.4, 157.8, 136.8,
135.1, 128.1, 127.0, 125.7, 122.0, 121.8, 80.0, 38.6, 35.6, 32.8,
29.6, 22.1, 14.0.
Methyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-meth-
ylnicotinate (3ad)
Yield: 85%; mp 82 °C.
IR (KBr): 2936, 2846, 1715, 1584, 1426, 1371, 1268, 1241, 1190,
1158, 1082, 1034, 903, 824 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.16 (d, J = 8.0 Hz, 1 H), 8.05 (d,
J = 8.0 Hz, 1 H), 8.01 (d, J = 8.2 Hz, 1 H), 6.74 (d, J = 8.2 Hz, 1 H),
5.02–5.07 (m, 1 H), 3.90 (s, 3 H), 3.28 (dd, J = 9.0, 6.0 Hz, 1 H),
2.86 (s, 3 H), 2.76 (dd, J = 7.3, 7.8 Hz, 1 H), 2.26 (s, 3 H), 1.54 (d,
J = 6.3 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.7, 159.4, 156.5, 138.7, 136.0,
128.6, 126.5, 122.0, 120.3, 118.5, 79.7, 51.8, 35.9, 22.4, 19.2, 14.8.
MS (ESI): m/z = 294 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO2: 294.1494; found:
294.1496.
Ethyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-methyl-
nicotinate (3aa)
Yield: 82%; mp 96 °C.
MS (ESI): m/z = 298 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO3: 298.1443; found:
IR (KBr): 2981, 1714, 1578, 1449, 1372, 1257, 1195, 1035, 863,
823, 724 cm–1.
298.1433.
1H NMR (300 MHz, CDCl3): d = 8.18 (d, J = 8.3 Hz, 1 H), 8.05 (d,
J = 8.1 Hz, 1 H), 8.01 (d, J = 8.3 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H),
5.00–5.09 (m, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 3.27 (dd, J = 8.8, 6.0
Hz, 1 H), 2.86 (s, 3 H), 2.75 (dd, J = 7.5, 7.7 Hz, 1 H), 2.26 (s, 3 H),
1.53 (d, J = 6.3 Hz, 3 H), 1.40 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.4, 159.2, 157.7, 156.3, 138.7,
136.1, 128.3, 126.6, 122.4, 121.9, 120.3, 118.5, 79.7, 60.6, 35.8,
25.3, 22.2, 19.1, 14.4.
Ethyl 2-(Chloromethyl)-6-(2,4-dimethyl-2,3-dihydrobenzo-
furan-7-yl)nicotinate (3ae)
Yield: 83%; mp 77 °C.
IR (KBr): 2976, 2854, 1720, 1585, 1492, 1461, 1418, 1366, 1192,
1108, 1028, 801, 738 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.25 (d, J = 8.1 Hz, 1 H), 8.18 (d,
J = 8.1 Hz, 1 H), 8.11 (d, J = 7.9 Hz, 1 H), 6.75 (d, J = 7.9 Hz, 1 H),
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3752
S. Kantevari et al.
PAPER
5.12 (s, 2 H), 5.02–5.09 (m, 1 H), 4.41 (q, J = 7.1, 6.9 Hz, 2 H), 3.28
(dd, J = 8.6, 6.4 Hz, 1 H), 2.76 (dd, J = 6.9, 8.6 Hz, 1 H), 2.27 (s, 3
H), 1.54 (d, J = 5.8 Hz, 3 H), 1.44 (t, J = 6.9 Hz, 3 H).
HRMS (ESI): m/z [M + Na]+ calcd for C17H16NO3FNa: 324.1011;
found: 324.1020.
2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-7,8-di-
hydroquinolin-5(6H)-one (4bi)
Yield: 79%; mp 124 °C.
13C NMR (75 MHz, CDCl3): d = 165.5, 157.8, 156.9, 156.6, 139.5,
128.4, 126.8, 122.5, 122.1, 117.8, 80.0, 61.3, 46.3, 35.7, 22.2, 19.1,
14.3.
IR (KBr): 2926, 1680, 1580, 1474, 1440, 1389, 1327, 1273, 1244,
1173, 1123, 1030, 839, 783 cm–1.
MS (ESI): m/z = 346 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C19H21NO3Cl: 346.1209;
1H NMR (300 MHz, CDCl3): d = 8.25 (d, J = 8.3 Hz, 1 H), 8.15 (d,
J = 8.3 Hz, 1 H), 7.84 (dd, J = 2.6, 7.9 Hz, 1 H), 6.90 (dd, J = 2.8,
4.3 Hz, 1 H), 5.00–5.09 (m, 1 H), 3.35 (dd, J = 8.8, 6.7 Hz, 1 H),
3.17 (t, J = 6.2 Hz, 2 H), 2.85 (dd, J = 7.7, 7.9 Hz, 1 H), 2.67 (t,
J = 6.9 Hz, 2 H), 2.22 (q, J = 6.4 Hz, 2 H), 1.54 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 197.0, 163.0, 159.1, 156.7, 154.1,
135.4, 129.6, 126.4, 122.1, 114.0, 113.7, 80.5, 38.6, 36.9, 32.9,
29.8, 22.1.
found: 346.1199.
Ethyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-propyl-
nicotinate (3af)
Yield: 64%.
IR (neat): 2965, 2930, 1718, 1583, 1455, 1374, 1259, 1194, 1153,
1027, 792 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.14 (d, J = 8.3 Hz, 1 H), 8.06 (d,
J = 7.9 Hz, 1 H), 7.99 (d, J = 8.3 Hz, 1 H), 6.74 (d, J = 7.9 Hz, 1 H),
4.98–5.07 (m, 1 H), 4.35 (q, J = 7.1 Hz, 2 H), 3.27 (dd, J = 8.8, 6.6
Hz, 1 H), 3.17 (t, J = 7.9 Hz, 2 H), 2.76 (dd, J = 6.4, 7.7 Hz, 1 H),
2.26 (s, 3 H), 1.76–1.88 (m, 2 H), 1.53 (d, J = 6.2 Hz, 3 H), 1.39 (t,
J = 7.1 Hz, 3 H), 1.03 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 162.4, 157.6, 156.1, 138.6,
136.0, 128.2, 126.6, 122.4, 121.8, 120.0, 118.5, 79.6, 60.6, 35.7,
31.8, 29.6, 22.8, 14.23, 14.21.
MS (ESI): m/z = 298 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H17NO2F: 298.1243;
found: 298.1244.
2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-7,7-dimethyl-7,8-
dihydroquinolin-5(6H)-one (4aj)
Yield: 82%; mp 105 °C.
IR (KBr): 2924, 1678, 1578, 1450, 1380, 1241, 1194, 1024, 905,
804, 765 cm–1.
MS (ESI): m/z = 340 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO3: 340.1912; found:
1H NMR (300 MHz, CDCl3): d = 8.20 (d, J = 8.3 Hz, 1 H), 8.10 (d,
J = 8.3 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H),
5.01–5.09 (m, 1 H), 3.28 (dd, J = 8.8, 6.2 Hz, 1 H), 3.05 (s, 2 H),
2.76 (dd, J = 7.3, 7.3 Hz, 1 H), 2.50 (s, 2 H), 2.27 (s, 3 H), 1.54 (d,
J = 6.2 Hz, 3 H), 1.14 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 198.1, 161.8, 158.8, 151.7, 136.8,
134.7, 128.2, 127.0, 124.7, 122.0, 121.7, 80.0, 52.1, 46.7, 35.7,
29.6, 28.3, 22.1, 19.0.
340.1919.
Ethyl 6-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-2-
methylnicotinate (3ba)
Yield: 80%; mp 60 °C.
IR (KBr): 2924, 2853, 1728, 1584, 1467, 1430, 1264, 1210, 1177,
1083, 1032, 908, 816 cm–1.
MS (ESI): m/z = 322 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H24NO2: 322.1807; found:
1H NMR (500 MHz, CDCl3): d = 8.19 (d, J = 8.7 Hz, 1 H), 8.06 (d,
J = 8.7 Hz, 1 H), 7.88 (dd, J = 2.9, 7.7 Hz, 1 H), 6.86 (dd, J = 1.9,
4.8 Hz, 1 H), 5.01–5.06 (m, 1 H), 4.36 (q, J = 7.7 Hz, 2 H), 3.32 (dd,
J = 8.7, 6.7 Hz, 1 H), 2.86 (s, 3 H), 2.83 (dd, J = 7.7, 7.7 Hz, 1 H),
1.52 (d, J = 5.8 Hz, 3 H), 1.40 (t, J = 7.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.0, 159.3, 159.1, 155.9, 154.8,
138.8, 129.4, 129.2, 123.2, 120.5, 114.0, 113.5, 80.3, 60.7, 36.9,
25.3, 21.9, 14.4.
322.1818.
2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-7,7-dimeth-
yl-7,8-dihydroquinolin-5(6H)-one (4bj)
Yield: 76%; mp 101 °C.
IR (KBr): 2930, 1682, 1578, 1460, 1384, 1286, 1176, 1113, 1028,
847, 756 cm–1.
MS (ESI): m/z = 316 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C18H19NO3F: 316.1348;
1H NMR (500 MHz, CDCl3): d = 8.23 (d, J = 7.8 Hz, 1 H), 8.15 (d,
J = 7.8 Hz, 1 H), 7.85 (dd, J = 2.9, 6.8 Hz, 1 H), 6.90 (dd, J = 2.9,
3.9 Hz, 1 H), 5.02–5.09 (m, 1 H), 3.35 (dd, J = 6.8, 7.8 Hz, 1 H),
3.06 (s, 2 H), 2.86 (dd, J = 7.8, 7.8 Hz, 1 H), 2.52 (s, 2 H), 1.54 (d,
J = 6.8 Hz, 3 H), 1.14 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 196.8, 161.5, 159.2, 158.1, 157.0,
134.9, 125.5, 122.0, 114.3, 114.04, 114.01, 113.7, 80.5, 52.2, 46.8,
37.0, 33.0, 28.6, 28.5, 22.0.
found: 316.1344.
Methyl 6-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-2-
methylnicotinate (3bb)
Yield: 82%; mp 80 °C.
IR (KBr): 2924, 2853, 1728, 1584, 1467, 1430, 1264, 1210, 1177,
1083, 1032, 908, 816 cm–1.
MS (ESI): m/z = 326 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H21NO2F: 326.1556;
1H NMR (300 MHz, CDCl3): d = 8.18 (d, J = 8.3 Hz, 1 H), 8.06 (d,
J = 8.3 Hz, 1 H), 7.88 (dd, J = 3.0, 7.5 Hz, 1 H), 6.86 (dd, J = 2.2,
4.5 Hz, 1 H), 5.00–5.09 (m, 1 H), 3.90 (s, 3 H), 3.32 (dd, J = 9.0, 6.7
Hz, 1 H), 2.86 (s, 3 H), 2.83 (dd, J = 7.5, 7.5 Hz, 1 H), 1.52 (d,
J = 6.7 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 159.4, 159.0, 155.1, 154.0,
138.9, 129.8, 123.0, 120.5, 113.7, 113.6, 113.2, 80.5, 52.0, 36.8,
21.7, 14.0.
found: 326.1570.
2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-6,6-dimethyl-7,8-
dihydroquinolin-5(6H)-one (4ak)
Yield: 76%; mp 97 °C.
IR (KBr): 2922, 1675, 1582, 1381, 1238, 1191, 1025, 903, 781
cm–1.
1H NMR (500 MHz, CDCl3): d = 8.24 (d, J = 7.8 Hz, 1 H), 8.09 (d,
J = 7.8 Hz, 1 H), 7.99 (d, J = 8.7 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H),
MS (ESI): m/z = 302 [M + H]+.
Synthesis 2010, No. 21, 3745–3754 © Thieme Stuttgart · New York

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Dihydrobenzofuran-Tethered Pyridines and Dihydroquinolin-5(6H)-ones
3753
5.01–5.06 (m, 1 H), 3.28 (dd, J = 9.7, 5.8 Hz, 1 H), 3.17 (t, J = 6.81
Hz, 2 H), 2.76 (dd, J = 7.8, 7.8 Hz, 1 H), 2.27 (s, 3 H), 2.04 (t,
J = 6.8 Hz, 2 H), 1.54 (d, J = 6.2 Hz, 3 H), 1.23 (s, 6 H).
2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-5H-inde-
no[1,2-b]pyridin-5-one (4bm)
Yield: 62%; mp146 °C.
13C NMR (75 MHz, CDCl3): d = 202.4, 162.0, 158.2, 157.7, 136.7,
136.0, 128.1, 127.0, 124.4, 122.0, 121.8, 118.4, 80.0, 41.3, 35.7,
35.4, 29.6, 29.1, 24.2, 22.1, 19.0.
MS (ESI): m/z = 322 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C21H24NO2: 322.1807; found:
IR (KBr): 2923, 2853, 1710, 1577, 1461, 1410, 1259, 1180, 1033,
911, 841, 763 cm–1.
1H NMR (500 MHz, CDCl3): d = 8.16 (d, J = 8.3 Hz, 1 H), 8.01 (dd,
J = 2.2, 8.30 Hz, 1 H), 7.94 (d, J = 7.5 Hz, 1 H), 7.89 (d, J = 7.5 Hz,
1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.42 (t,
J = 7.5 Hz, 1 H), 6.92 (dd, J = 2.2, 4.5 Hz, 1 H), 5.03–5.11 (m, 1 H),
3.37 (dd, J = 9.0, 6.7 Hz, 1 H), 2.88 (dd, J = 7.5, 7.5 Hz, 1 H), 1.57
(d, J = 6.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 188.7, 162.7, 159.2, 157.5, 142.0,
134.8, 131.7, 130.7, 123.9, 122.9, 121.1, 120.7, 114.3, 114.1, 113.9,
113.7, 80.6, 37.0, 22.1.
322.1819.
2-(5-Fluoro-2-methyl-2,3-dihydrobenzofuran-7-yl)-6,6-dimeth-
yl-7,8-dihydroquinolin-5(6H)-one (4bk)
Yield: 72%; mp 106 °C.
IR (KBr): 2928, 1679, 1471, 1442, 1386, 1353, 1324, 1238, 1182,
1103, 1031, 898, 791 cm–1.
MS (ESI): m/z = 332 [M + H]+.
1H NMR (500 MHz, CDCl3): d = 8.28 (d, J = 8.7 Hz, 1 H), 8.14 (d,
J = 8.7 Hz, 1 H), 7.83 (d, J = 10.7 Hz, 1 H), 6.90 (d, J = 5.8 Hz, 1
H), 5.02–5.09 (m, 1 H), 3.35 (dd, J = 6.8, 7.8 Hz, 1 H), 3.18 (t,
J = 5.8 Hz, 2 H), 2.86 (dd, J = 7.8, 7.8 Hz, 1 H), 2.05 (t, J = 5.8 Hz,
2 H), 1.54 (d, J = 6.8 Hz, 3 H), 1.24 (s, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C21H15NO2F: 332.1086;
found: 332.1082.
Ethyl 6-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-2-[(4-phe-
nylpiperazin-1-yl)methyl]nicotinate (5)
To a soln of 3ae (0.1 g, 0.29 mmol) in MeCN (3 mL), was added
pyridine (0.5 mL), DMAP (10 mg), and N-phenylpiperzine (50 mL,
0.3 mmol) at r.t. The mixture was stirred for 6 h, it was concentrated
under vacuum, and the residue was dissolved in EtOAc (10 mL),
washed with H2O (5 mL) and brine (5 mL), dried (anhyd Na2SO4),
and evaporated. Purification by column chromatography (silica gel)
yielded 6 (0.105 g, 77%) as a light brown solid; mp 158 °C.
13C NMR (75 MHz, CDCl3): d = 202.3, 162.1, 159.0, 156.7, 155.9,
136.2, 130.0, 125.1, 122.0, 114.0, 113.7, 113.4, 80.6, 41.4, 36.8,
35.3, 29.0, 24.1, 21.7.
MS (ESI): m/z = 326 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H21NO2F: 326.1556;
found: 326.1566.
IR (KBr): 2928, 1723, 1585, 1504, 1451, 1379, 1270, 1219, 911,
771 cm–1.
2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-6,7,8,9-tetra-
hydro-5H-cyclohepta[b]pyridin-5-one (4al)
Yield: 58%; mp 79 °C.
1H NMR (300 MHz, CDCl3): d = 8.09 (d, J = 8.1 Hz, 1 H), 8.03 (d,
J = 8.1 Hz, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.16 (q, J = 7.3 Hz, 2 H),
6.82 (d, J = 9.6 Hz, 2 H), 6.75 (t, J = 8.4 Hz, 2 H), 4.98–5.07 (m, 1
H), 4.32 (q, J = 6.9 Hz, 2 H), 4.05 (s, 2 H), 3.24 (dd, J = 8.6, 6.4 Hz,
1 H), 3.11 (t, J = 4.9 Hz, 4 H), 2.73 (dd, J = 7.3, 7.9 Hz, 1 H), 2.67
(t, J = 5.2 Hz, 4 H), 2.24 (s, 3 H), 1.51 (d, J = 6.2 Hz, 3 H), 1.37 (t,
J = 7.1 Hz, 3 H).
IR (KBr): 2924, 2853, 1673, 1579, 1455, 1379, 1271, 1194, 906,
818 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.00–8.08 (m, 3 H), 6.73 (d,
J = 8.3 Hz, 1 H), 4.97–5.10 (m, 1 H), 3.21–3.31 (m, 3 H), 2.71–2.81
(m, 3 H), 2.26 (s, 3 H), 1.88–2.02 (m, 4 H), 1.53 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.9, 157.6, 156.2, 155.5, 151.0,
138.1, 136.1, 128.9, 128.3, 126.5, 124.5, 122.0, 121.5, 119.7, 118.2,
116.1, 79.7, 62.1, 60.9, 52.9, 48.6, 35.7, 22.2, 19.0, 14.3.
MS (ESI): m/z = 472 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C29H34O3N3: 472.2600; found:
13C NMR (75 MHz, CDCl3): d = 197.4, 166.7, 157.0, 156.1, 137.2,
131.1, 128.3, 122.0, 121.3, 79.8, 40.9, 36.1, 35.8, 31.9, 22.2, 21.4,
14.2.
MS (ESI): m/z = 308 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H22NO2: 308.1650; found:
472.2611.
308.1660.
2-(2,4-Dimethyl-2,3-dihydrobenzofuran-7-yl)-5H-indeno[1,2-
b]pyridin-5-one (4am)
Yield: 68%; mp 107 °C.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are copies of 1H, 13C NMR and mass (HRMS) spectra of all the new
compounds.
IR (KBr): 2921, 2851, 1706, 1574, 1406, 1346, 1251, 1194, 1098,
1024, 910, 806 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.18 (d, J = 8.1 Hz, 1 H), 8.10 (d,
J = 7.9 Hz, 1 H), 7.93 (d, J = 7.3 Hz, 1 H), 7.87 (d, J = 8.1 Hz, 1 H),
7.69 (d, J = 7.3 Hz, 1 H), 7.56 (t, J = 7.3 Hz, 1 H), 7.40 (t, J = 7.3
Hz, 1 H), 6.78 (d, J = 8.1 Hz, 1 H), 5.02–5.11 (m, 1 H), 3.30 (dd,
J = 9.0, 6.2 Hz, 1 H), 2.78 (dd, J = 7.3, 7.9 Hz, 1 H), 2.29 (s, 3 H),
1.57 (d, J = 6.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 186.9, 161.8, 159.0, 157.7, 134.6,
131.6, 130.5, 130.2, 128.7, 123.8, 122.6, 122.1, 121.0, 79.9, 35.9,
22.4, 16.7.
Acknowledgment
Authors are thankful to Dr. J. S. Yadav, Director and Dr. V. V. N.
Reddy, Head, Organic Chemistry Division-II, IICT, Hyderabad for
continuous support, encouragement and financial assistance
through MLP project. D.A. (JRF) is thankful to CSIR for financial
assistance.
MS (ESI): m/z = 328 [M + H]+.
HRMS (ESI): m/z [M + H]+ calcd for C22H18NO2: 328.1337; found:
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