Inverse electron demand Diels-Alder reactions of heterodienes catalyzed by potassium hydrogen sulfate: Diastereoselective, one-pot synthesis of pyranobenzopyrans, furanobenzopyrans and tetrahydroquinolines derivatives

Article abstract of DOI:10.1055/s-2004-822332

Potassium hydrogen sulfate catalyzes the one-pot three components coupling of aldehydes, anilines, and electron rich dienophiles such as dihydropyran, dihydrofuran, ethyl vinylether, and cyclopentadiene. With o-hydroxybenzaldehyde, the reaction probably p

Full text of DOI:10.1055/s-2004-822332

PAPER
949
Inverse Electron Demand Diels–Alder Reactions of Heterodienes Catalyzed by
Potassium Hydrogen Sulfate: Diastereoselective, One-Pot Synthesis of Pyrano-
benzopyrans, Furanobenzopyrans and Tetrahydroquinolines Derivatives
Inverse
Electron
.emand
Die
S
ls–Alder Reac
e
tions of
H
e
n
terodienes
C
t
atalyze
h
dbyKHS
O
4il Kumar, Rajagopal Nagarajan, Paramasivan T. Perumal*
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai – 600 020, India
Fax +91(44)24911589; E-mail: ptperumal@hotmail.com
Received 3 November 2003; revised 10 February 2004
balfouridine21 and the phenanthridine skeleton22 is present
in lycorine, haemanthamine, and chelidonine alkaloids.
Abstract: Potassium hydrogen sulfate catalyzes the one-pot three
components coupling of aldehydes, anilines, and electron rich di-
enophiles such as dihydropyran, dihydrofuran, ethyl vinylether, and
cyclopentadiene. With o-hydroxybenzaldehyde, the reaction proba-
bly proceeds through the formation of o-quinonemethide intermedi-
ate, which subsequently undergoes cycloaddition with cyclic and
acyclic enol ethers leading to the formation of respective chro-
manes. However, in case of benzaldehydes with no o-hydroxy
group, the imine formed acts as the heterodiene and leads to the for-
mation of tetrahydroquinolines.
The classical Diels–Alder reaction, a [4+2] cycloaddition
of a diene and dienophile to generate a six membered car-
bocyclic system, in its modified form can be used to gen-
erate nitrogen or oxygen containing six-membered system
by the use of appropriate heterodiene or heterodienophile.
However, instead of starting with preformed diene the in
situ formation of diene is preferred. This one-pot proce-
dure is especially useful when the diene is unstable and is
difficult to purify either by distillation or chromatogra-
phy.23 Lewis acids such as lanthanide triflates, Yb(OTf)3,
Sc(OTf)3, BF3· OEt2, and GdCl3 were found to catalyze
this reaction. However most of these reactions suffer from
various disadvantages such as, more than stoichimetric
amount of Lewis acid is needed due to strong co-ordina-
tion of it with the heteroatoms, longer reaction time, high
cost and use of only aprotic solvents under anhydrous
conditions. Also these reactions cannot be performed in
one-pot because the amines and water that are present dur-
ing imine formation can decompose or deactivate these
Lewis acids. However to the best of our knowledge there
is no report of the use of KHSO4 as catalyst for this type
of reactions. The catalyst is inexpensive, mild, and does
not require the maintenance of anhydrous conditions.
Keywords: heterodienes, potassium hydrogen sulfate, pyranoben-
zopyrans, furanobenzopyrans, tetrahydroquinolines
Nitrogen and oxygen containing heterocycles are ubiqui-
tous in nature and display a wide variety of interesting bi-
ological properties. Among the numerous oxygen
heterocycles, chromenes (2H-1 benzopyrans), chromans
(3,4-dihydro-2H-1-benzopyrans) and their pyran, furan
fused analogs seems attractive targets for synthetic chem-
ists due to the useful biological properties that their natu-
rally occurring representatives1,2 display. For example, 4-
aminobenzopyran and its derivatives are found to act as
modulators of potassium channels and influence the activ-
ity of heart and blood pressure levels.3
Tetrahydroquinolines and their derivatives form a major
part of nitrogen containing heterocycles that occurs in na-
ture. Discohabdin C, a polycyclic system based on tet-
rahydroquinoline is a marine alkaloid.4–6 Dynemycin, a
natural antitumor antibiotic has a complex structure built
on a tetrahydroquinoline system.7,8 Some tetrahydroquin-
olines are potent inhibitors of (H+ and K+) adenosine
Treatment of salicylaldehyde, amine, and dihydropyran in
the presence of KHSO4 in methanol at room temperature
gave an inseparable mixture of linearly cis fused pyrano-
chromanes 3 and 4 with high diasteroselectivity in favor
of 3 (Scheme 1). The stereochemistry of the product 3 was
assigned based on the coupling constant values and NOE
studies. The cis fusion of the tetrahydropyran ring in com-
pound 3 was determined from the coupling constant of 2.5
Hz between H4 and H5. Along with a coupling constant
between H4 and H6 of 1.8 Hz and the presence of NOE be-
tween H6 and H5 and H5 and H4 proved that H6 is cis to H4.
From the coupling constant value and absence of NOE be-
tween H6 and H5 and H5 and H4 in compound 4 it is con-
cluded that H6 is trans to H4. Reactions were also
performed with substituted anilines and the results are
given in Table 1.
triphosphatase9 and angiotension I converting enzyme,10
11
they also are cardiovascular
and anticonvulsant
agents.12 Besides pharmaceutical applications they are
also useful as pesticides,13 antioxidants,14 and corrosion
inhibitors.15 Pyranotetrahydroquinolines are found in sev-
eral alkaloids such as flindersine, oricine, and veprisine.16
Derivatives of these alkaloids are found to have useful bi-
ological activities such as psychotropic,17 antiallergic,18
anti-inflammatory19 and estrogenic properties.20 The furo-
quinoline moiety is seen in the alkaloids skimmianine and
SYNTHESIS 2004, No. 6, pp 0949–0959
x
x
.
x
x
.2
0
0
4
Advanced online publication: 07.04.2004
DOI: 10.1055/s-2004-822332; Art ID: Z15903SS
© Georg Thieme Verlag Stuttgart · New York

950
R. S. Kumar et al.
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Table 1 Synthesis of Pyrano and Furobenzopyrans
Entry
Amine
Dienophile
Producta
Time (min)
50
Yieldb (%)
61
Product Ratioc
3:4
a
98:2d
3a,4a
b
50
50
97:3d
3b,4b
c
50
71
98:2d
3c,4c
d
30
60
77:23
3d,4d
e
30
50
77:23
3e,4e
f
30
80
75:25
3f,4f
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Inverse Electron Demand Diels–Alder Reactions of Heterodienes Catalyzed by KHSO4
951
Table 1 Synthesis of Pyrano and Furobenzopyrans (continued)
Entry
Amine
Dienophile
Producta
Time (min)
70
Yieldb (%)
45
Product Ratioc
3:4
g
42:58
3g,4g
h
60
50
40:60
3h,4h
i
60
50
39:61
3i,4i
a All the products were characterized by IR, NMR, and mass spectroscopy and elemental analysis.
b The yield is based on isolation by column chromatography.
c The product ratio is based on isolation by column chromatography.
d The product ratio is based on 1H NMR of product mixture.
Similarly when dihydrofuran was treated with salicylalde- 4-N-arylaminobenzopyrans 3g–i and 4g–i were obtained
hyde and amine in the presence of KHSO4 in methanol at as a separable mixture of diastereomers (Scheme 2). The
room temperature, a mixture of linearly cis fused fura- diastereomers were isolated by column chromatography
nobenzopyrans was obtained in good yield (Scheme 1). and the stereochemistry of the products was arrived at
1
The diastereoselectivity, however in this case was moder- from the H NMR spectroscopy based on the chemical
ate and the isomers were separated by column chromatog- shift and coupling constant values.
raphy. From the coupling constant value and a similar
One pot cycloaddition of 2,3-dihydropyran with imines
NOE study as was done for pyranochromanes, the cis fu-
generated in situ from aldehydes having no o-hydroxy
sion of the furan ring was proven.
group was performed in the presence of KHSO4
When the acyclic dienophile, ethylvinylether was used in (Scheme 4). A diastereomeric mixture of the correspond-
the above procedure the corresponding adducts 2-ethoxy- ing pyranoquinolines was obtained. The pyran ring is cis
Scheme 1
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952
R. S. Kumar et al.
PAPER
Scheme 2
Scheme 3
Scheme 4
fused and the stereochemistry of the products was estab- hydropyran or 2,3-dihydrofuran giving the pyrano or fura-
lished based on the coupling constant values. In isomer 5c no benzopyrans. However with aldehydes having no ortho
J(H4a-H5) is 4.5 Hz and is significantly smaller and typical hydroxy group, reaction takes alternative path in which
for a gauche conformation. This orientation is present in case the imine formed acts as a azadiene giving the pyrano
both conformers of the configuration having a cis orienta- and furoquinolines.
tion of the pyran ring and phenyl group. The J(H4a-H5)
value of 10.6 Hz in isomer 6c is appropriate and indicative
of anti reciprocal orientation of protons H5 and H4a. Simi-
larly with 2,3-dihydrofuran the corresponding furoquino-
lines were obtained as a mixture of diastereomers with cis
fused ring junction.
In summary, we have shown for the first time that the salt,
KHSO4 can catalyze the one-pot coupling of various alde-
hydes, amines, and dieneophiles (both cyclic and acyclic)
giving the cycloadducts. The catalyst is mild, inexpensive,
and easily available and also offers several advantages in-
cluding shorter reaction times, cleaner reactions as well as
Cyclopentaquinolines were synthesized by three compo- simple experimental and isolation procedures, which
nent coupling reaction of aldehyde, aniline with cyclopen- makes it useful and attractive for the synthesis of chro-
tadiene (Scheme 5, Table 2). Imines derived from manes and tetrahydroquinolines.
phenylglyoxal are generally unstable at higher tempera-
tures and are difficult to purify either by distillation or by
column chromatography so the one-pot coupling of phe-
nylglyoxal, aniline and cyclopentadiene was attempted
successfully (Table 2).
In the case of o-hydroxy benzaldehyde the reaction prob-
ably proceeds through the intermediate formation of o-
quinonemethides24 from the in situ generated imine 3j. A
plausible mechanism for the formation of o-quinoneme-
thide, 3k is given in Scheme 3. The o-quinonemethide
Scheme 5
formed acts as oxadiene and subsequently adds to 2,3-di-
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Inverse Electron Demand Diels–Alder Reactions of Heterodienes Catalyzed by KHSO4
953
Table 2 Synthesis of Tetrahydroquinolines
No
a
Amine
Aldehyde
Dienophile
Producta
Time (min) Yieldb (%) Product Ratioc
5: 6
45
60
38:62
b
40
57
35:65
c
60
60
64
52
65:35
26:73
d
e
60
40
35:65
f
75
75
44
40
–
–
g
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954
R. S. Kumar et al.
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Table 2 Synthesis of Tetrahydroquinolines (continued)
No
h
Amine
Aldehyde
Dienophile
Producta
Time (min) Yieldb (%) Product Ratioc
5: 6
75
42
–
i
75
41
–
j
75
60
52
42
–
–
k
HCHO(aq)
a All the products were characterized by IR, NMR, and mass spectroscopy and elemental analysis.
b The yield is based on isolation by column chromatography.
c The product ratio is applicable for pyrano and furoquinolines only. In the case of cyclopentaquinolines only one isomer was observed.
Phenyl(3,4,4a,10a-Tetrahydro-2H,5H-pyrano[2,3-b]chromen-
5-yl)amine (3a and 4a)
Yield: 0.80g (60%).
Mass spectra were recorded on Varian VG 70-70H mass spectro-
meter. Analytical TLC was performed on precoated sheets of silica
gel G of 0.25 mm thickness containing PF 254 indicator (Merck,
Darmstadt). Column chromatography was performed with silica gel
(60–120 mesh, S.d Fine, Boisar). IR spectra were recorded as solids
3a
IR (KBr): 3347 (NH), 3029, 1485 cm–1.
1
in KBr pellets on a Perkin-Elmer FTIR spectrometer. H NMR
1H NMR (300 MHz, CDCl3): d = 1.57–1.67 (m, 2 H, H3), 1.87–1.96
(m, 2 H, H2), 3.08-3.15 (m, 1 H, H4), 3.82–3.95 (m, 3 H, H1, in-
cluding NH), 4.98 (d, 1 H, H6, J = 4.9 Hz), 5.89 (d, 1 H, H5,
J = 5.4 Hz), 6.74, (d, 2 H, J = 7.8 Hz), 6.79 (t, 1 H, J = 7.6 Hz),
6.92–6.98 (m, 2 H), 7.19–7.27 (m, 2 H), 7.36 (d, 2 H, J = 7.8 Hz).
13C NMR (75 MHz, CDCl3, proton decoupled): d = 17.1, 24.2, 34.8,
50.9, 60.9, 96.4, 112.6, 113.2, 116.4, 118.1, 121.1, 126.7, 128.9,
129.5, 146.8, 153.1.
spectra were recorded on a Bruker spectrometer using TMS as in-
ternal standard. 13C NMR spectra were recorded on 300, 400, and
500 MHz spectrometer in CDCl3 and chemical shifts are given rel-
ative to the solvent peak. The enol ether used was brought from
Lancaster. The procedure does not require dry solvent or an inert at-
mosphere. All the products obtained were purified by column chro-
matography using silica gel (Merck, 100–200 mesh).
MS: m/z = 281 (M+).
Preparation of Pyrano and Furanobenzopyran; General Proce-
dure
Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C,
76.68; H, 6.94; N, 4.76.
A
mixture of o-hydroxybenzaldehyde (4 mmol), aniline
(4.8 mmol), dihydropyran or dihydrofuran (10 mmol) and KHSO4
(0.21g, 40 mol%) in MeOH (10 mL) was stirred at ambient temper-
ature for the appropriate time. After completion of the reaction, as
indicated by TLC monitoring, the excess MeOH was distilled off
and the reaction mixture was diluted with water (20 mL) and ex-
tracted with CH2Cl2 (2 × 30 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated in vacuum and the
resulting product was purified by column chromatography (EtOAc–
and petroleum ether, 1:9) to afford pure cis-fused pyrano and fura-
nochromanes obtained as mixture of 3a–c and 4a–c or pure 3d–f or
4d–f.
4a
1H NMR: d = 4.62 (d, 1 H, H6, J = 2.3 Hz), 5.65 (d, 1 H, H5,
J = 5.4 Hz).
13C NMR: d = 21.7, 24.3, 36.6, 53.3, 61.7, 94.6, 112.6, 117.0, 117.8,
118.0, 121.2, 121.8, 129.5, 130.4, 146.2, 153.0.
(4-Methylphenyl)3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-
b]chromen-5-ylamine (3b and 4b)
Yield: 0.60g, (50%).
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3b
Inverse Electron Demand Diels–Alder Reactions of Heterodienes Catalyzed by KHSO4
955
Phenyl(2, 3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-
IR (KBr): 3360 (NH), 3022, 1485 cm–1.
yl)amine (4d)
Yield: 0.15 g (23%); colorless solid; mp 90–92 °C.
IR (KBr): 3363 (NH), 3022, 1454 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.18–1.62 (m, 4 H, H2, H2¢, H3,
H3¢), 2.18 (s, 3 H, CH3), 2.38–2.44 (m, 1 H, H4), 3.62 (br s over-
lapped, NH, 1 H), 3.62–3.69 (m, 1 H, H1), 3.89–3.96 (m, 1 H, H1¢),
4.88 (d, 1 H, H6, J = 1.8 Hz), 5.47 (d, 1 H, H5, J = 2.5 Hz), 6.45 (d,
1 H, J = 8.3 Hz), 6.55 (d, 2 H, J = 8.3 Hz), 6.81–6.94 (m, 1 H), 6.95
(d, 2 H, J = 7.8 Hz), 7.11–7.17 (m, 1 H), 7.36 (d, 1 H, J = 7.8 Hz).
13C NMR (100 MHz, CDCl3, proton decoupled): d = 17.0, 20.4,
24.1, 34.7, 51.1, 60.9, 96.3, 112.7, 113.3, 116.2, 120.7, 126.7,
127.0, 128.9, 130.0, 144.5, 153.0.
1H NMR (300 MHz, CDCl3): d = 1.23–1.70 (m, 1 H, H2), 2.12–2.19
(m, 1 H, H2¢), 2.89–2.96 (m, 1 H, H3), 3.90 (br s, 1 H, NH over-
lapped), 3.91–3.98 (m, 1 H, H1), 4.01–4.08 (m, 1 H, H¢1), 4.51 (br
s, 1 H, H5,), 5.66 (d, 1 H, H4, J = 4.7 Hz), 6.63 (d, 2 H, J = 8.0 Hz),
6.76 (t, 1 H, J = 7.3 Hz), 6.91–6.95 (m, 2 H), 7.16–7.24 (m, 4 H).
13C NMR (75 MHz, CDCl3, proton decoupled): d = 26.9, 43.3, 50.5,
67.8, 99.9, 113.0, 117.6, 118.1, 121.6, 121.7, 124.2, 129.5, 129.8,
146.3, 152.5.
MS: m/z = 295 (M+).
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74. Found: C,
77.41; H, 7.32; N, 4.53.
MS: m/z 267 (M+).
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C,
76.69; H, 6.15; N, 5.19.
4b
1H NMR: d = 4.17 (d, 1 H, H6, J = 2.4 Hz), 5.37 (d, 1 H, H5,
J = 2.5 Hz).
(4-Methylphenyl)2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
4-ylamine (3e)
Yield: 0.5 g (77%); colorless solid; mp 80–82 °C.
IR (KBr) 3386 (NH), 2976, 1482 cm–1.
13C NMR: d = 16.8, 21.7, 24.3, 36.6, 53.4, 61.7, 94.6, 116.9, 121.1,
121.2, 122.0, 127.2, 129.3, 129.9, 130.3, 144.1, 152.9.
1H NMR (500 MHz, CDCl3): d = 1.56–1.64 (m, 1 H, H2), 1.87–1.94
(m, 1 H, H2¢), 2.27 (s, 3 H, CH3), 3.08–3.14 (m, 1 H, H3), 3.70 (br
s, 1 H, NH), 3.84 (q, 1 H, H1, J = 8.6 Hz), 3.92 (dt, 1 H, H1¢ J = 4,
8.9 Hz), 4.95 (d, 1 H, H5, J = 4.6 Hz), 5.88 (d, 1 H, H4, J = 5.7 Hz),
6.67 (d, 2 H, J = 8.5 Hz), 6.91–6.99 (m, 2 H), 7.04 (d, 2 H,
J = 8.0 Hz), 7.20–7.29 (m, 1 H), 7.38 (d, 1 H, J = 7.4 Hz).
(4-Bromophenyl)3,4,4a,10a-tetrahydro-2H,5H-pyrano[2,3-
b]chromen-5-ylamine (3c and 4c)
Yield: 1.00 g (71%).
3c
IR (KBr): 3398 (NH), 3037, 1494 cm–1.
13C NMR (125 MHz, CDCl3, proton decoupled): d = 20.5, 24.0,
43.3, 49.1, 68.1, 102.4, 113.7, 117.2, 122.9, 124.8, 126.3, 127.7,
128.8, 130.1, 144.7, 153.0.
1H NMR (300 MHz, CDCl3): d = 1.28–1.69 (m, 4 H, H2, H3), 2.42–
2.46 (m, 1 H, H4), 3.71–3.85 (m, 1 H, H1), 3.94–4.03 (m, 1 H, H1¢),
3.83 (br s, 1 H, NH), 4.93 (d, 1 H, H6, J = 4.5 Hz), 5.52 (d, 1 H, H5,
J = 2.3 Hz), 6.45 (d, 1 H, J = 8.7 Hz), 6.57 (d, 2 H, J = 8.7 Hz),
6.89 (t, 1 H, J = 6.3 Hz), 7.21–7.33 (m, 2 H), 7.26 (d, 2 H,
J = 6.5 Hz).
13C NMR (75 MHz, CDCl3, proton decoupled): d = 17.1, 19.7, 24.1,
34.7, 51.1, 60.93, 96.2, 109.5, 114.8, 116.5, 121.3, 126.6, 129.1,
132.2, 145.6, 152.3.
MS: m/z = 281 (M+).
Anal. calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98; Found: C,
76.64; H, 6.53; N, 4.76.
(4-Methylphenyl)2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
4-ylamine (4e)
MS: m/z = 360 (M+).
Yield: 0.15 g (23%); colorless solid; mp 108–110 °C.
IR (KBr): 3384 (NH), 3022, 2948, 1486 cm–1.
Anal. Calcd for C18H18BrNO2: C, 60.01; H, 5.04; N, 3.89. Found: C,
60.18; H, 5.24; N, 3.72.
1H NMR (500 MHz, CDCl3): d = 1.65–1.73 (m, 1 H, H2), 2.13–2.10
(m, 1 H, H2¢), 2.27 (s, 3 H, CH3), 2.91–2.96 (m, 1 H, H3), 3.79 (br
s, 1 H, NH), 3.96 (q, 1 H, H1, J = 8.0 Hz), 4.07 (dt, 1 H, H1¢, J = 4,
8.6 Hz), 4.50 (d, 1 H, H5, J = 2.2 Hz), 5.68 (d, 1 H, H4, J = 5.1 Hz),
6.59 (d, 2 H, J = 8.0 Hz), 6.91–6.98 (m, 2 H), 7.04 (d, 2 H,
J = 8.0 Hz), 7.24–7.26 (m, 2 H).
4c
1H NMR: d = 3.99 (br s, 1 H, H6), 5.45 (br s, 1 H, H5).
13C NMR: d = 19.7, 21.8, 25.4, 30.7, 36.5, 53.2, 62.9, 94.5, 109.1,
114.2, 117.1, 121.3, 123.4, 129.6, 145.2, 152.1.
13C NMR (125 MHz, CDCl3, proton decoupled): d = 20.5, 27.0,
43.3, 50.8, 67.9, 100.0, 113.3, 117.6, 121.7, 121.9, 127.4, 129.8,
129.9, 130.1, 144.1, 152.5.
Phenyl(2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-4-
yl)amine (3d)
Yield: 0.5 g (77%); colorless solid; mp 110–112 °C.
IR (KBr): 3366 (NH), 3024, 1481 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.49–1.68 (m, 1 H, H2), 1.75–1.95
(m, 1 H, H2¢), 3.05–3.15 (m, 1 H, H3), 3.77–3.95 (m, 3 H, H1, in-
cluding NH), 4.96 (br s, 1 H, H5), 5.88 (br s, 1 H, H4), 6.70–7.20
(m, 8 H), 7.34 (d, 1 H, J = 6.4 Hz).
MS: m/z = 281 (M+).
Anal. Calcd for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found: C,
76.75; H, 6.46; N, 4.89.
(4-Bromophenyl)2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
4-ylamine (3f)
13C NMR (75 MHz, CDCl3, proton decoupled): d = 23.9, 43.3, 48.8,
68.0, 102.4, 113.4, 117.2, 118.4, 121.9, 124.6, 126.2, 128.8, 129.6,
147.0, 152.9.
Yield: 0.76g, (75%); colorless solid; mp 107–109 °C.
IR (KBr): 3383 (NH), 3038, 1493 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.54–1.83 (m, 1 H, H2), 1.90–
1.94 (m, 1 H, H2¢), 3.08–3.14 (m, 1 H, H3), 3.84–3.96 (m, 3 H, H1,
including NH), 4.93 (br s, 1 H, H5), 5.90 (d, 1 H, H4, J = 5.4 Hz),
6.63 (d, 2 H, J = 8.8 Hz), 6.94–7.00 (m, 2 H), 7.22–7.27 (m, 2 H),
7.31 (d, 2 H, J = 8.8 Hz).
MS: m/z = 267 (M+).
Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C,
76.62; H, 6.23; N, 5.36.
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R. S. Kumar et al.
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13C NMR (100 MHz, CDCl3, proton decoupled): d = 24.2, 43.5,
49.2, 68.2, 102.5, 110.0, 115.2, 117.6, 122.2, 124.4, 126.3, 129.2,
132.5, 146.3, 153.2.
13C NMR (100 MHz, CDCl3, proton decoupled): d = 15.1, 33.4,
45.1, 64.2, 97.5, 113.0, 117.0, 117.7, 121.1, 124.9, 127.6, 128.8,
129.5, 147.2, 152.2.
MS: m/z = 346 (M+).
MS: m/z = 269 (M+).
Anal. Calcd for C17H16BrNO2: C, 58.98; H, 4.66; N, 4.05. Found: C,
58.67; H, 4.43; N, 4.25.
Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C,
75.92; H, 7.09; N, 5.32.
(4-Bromophenyl)2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromen-
4-ylamine(4f)
(2-Ethoxy-3,4-dihydro-2H-chromen-4-yl)(4-methylphenyl)am-
ine (3h)
Yield: 0.26g, (25%); colourless solid; mp 124–126 °C.
Yield: 0.344 g (60%); colorless liquid.
IR (KBr): 3392 (NH), 3042, 1493 cm–1.
IR (neat): 3385 (NH), 3045, 1492 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.53–1.63 (m, 1 H, H2), 2.06–2.08
(m, 1 H, H2¢), 2.74–2.84 (m, 1 H, H3), 3.86–3.96 (m, 3 H, H1, in-
cluding NH), 4.39 (br s, 1 H, H5), 5.57 (d, 1 H, H4, J = 4.9 Hz),
6.44 (d, 2 H, J = 8.8 Hz), 6.84–7.16 (m, 4 H), 7.20 (d, 2 H,
J = 8.8 Hz).
13C NMR (100 MHz, CDCl3, proton decoupled): d = 27.2, 43.4,
50.8, 67.9, 100.1, 109.8, 114.8, 117.9, 121.6, 122.0, 129.9, 130.2,
132.4, 145.6, 152.7.
1H NMR (400 MHz, CDCl3): d = 1.15 (t, 3 H, J = 6.5 Hz), 2.15–
2.23 (m, 1 H), 2.26 (s, 3 H, CH3), 2.37–2.41 (m, 1 H), 3.53–3.58 (m,
1 H), 3.81–3.89 (m, 1 H), 4.32 (br s, 1 H, NH), 4.69 (br s, 1 H), 5.37
(t, 1 H, J = 2.8 Hz), 6.72 (d, 2 H, J = 8.4 Hz), 6.70–6.78 (m, 2 H),
7.08 (d, 2 H, J = 8.5 Hz), 7.25-7.29 (m, 1 H), 7.43 (d, 1 H,
J = 7.9 Hz).
13C NMR (100 MHz, CDCl3, proton decoupled): d = 15.4, 20.2,
31.4, 45.3, 64.3, 97.3, 114.3, 117.5, 118.9, 121.5, 124.1, 128.9,
129.4, 130.1, 147.5, 151.2.
MS: m/z = 346 (M+).
MS: m/z 283 (M+).
Anal. Calcd for C17H16BrNO2: C, 58.98; H, 4.66; N, 4.05. Found: C,
58.56; H, 4.57; N, 4.43.
Anal. Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C,
76.52; H, 7.23; N, 4.73.
Preparation of 2-Ethoxy-4-N-aryl Amino Benzopyran; General
Procedure
(2-Ethoxy-3,4-dihydro-2H-chromen-4-yl)(4-methylphenyl)am-
ine (4h)
Yield: 0.236 g (40%); colorless liquid.
IR (neat): 3392 (NH), 3042, 1495 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.23 (t, 3 H, J = 6.7 Hz), 1.98 (m,
1 H), 2.21 (s, 3 H, CH3), 2.35 (dt, 1 H, J = 6.5, 12.5 Hz), 3.64 (dq,
1 H, J = 6.6, 9.4 Hz), 3.79 (br s, 1 H, NH), 3.95 (dq, 1 H, J = 6.7,
9.4 Hz), 4.92 (dd, 1 H, J = 5.6, 9.4 Hz), 5.26 (dd, 1 H, J = 2.4,
9.4 Hz), 6.62 (d, 2 H, J = 8.5 Hz), 6.72–6.79 (m, 2 H), 7.09 (d, 2 H,
J = 8.5 Hz), 7.24–7.27 (m, 1 H), 7.45 (d, 1 H, J = 7.8 Hz).
Ethyl vinyl ether (10 mmol) was added slowly at 0 °C to a mixture
of o-hydroxybenzaldehyde (4 mmol), aniline (4.8 mmol), and
KHSO4 (0.21g, 40 mol%). The resulting reaction mixture was
stirred at ambient temperature for an appropriate time. After com-
pletion of the reaction, as indicated by TLC, the reaction mixture
was quenched with water (20 mL) and extracted with CH2Cl2
(2 × 20 mL). The combined extracts were dried over anhyd Na2SO4,
filtered, concentrated in vacuo and purified by column chromatog-
raphy on silica gel (Merck, 100–200 mesh; EtOAc–hexane, 5:95) to
afford pure cis-fused acetal 3g–i and 4g–i.
13C NMR (100 MHz, CDCl3, proton decoupled): d = 15.7, 20.5,
31.8, 45.6, 64.1, 97.2, 114.6, 117.9, 118.4, 121.2, 124.4, 128.3,
129.7, 130.4, 147.6, 151.4.
2-(Ethoxy-3, 4-dihydro-2H-chromen-4-yl)phenylamine (3g)
Yield: 0.29g (58%); colorless liquid.
IR (neat): 3390 (NH), 3048, 1498 cm–1.
MS: m/z = 283 (M+).
1H NMR (400 MHz, CDCl3): d = 1.19 (t, 3 H, J = 6.84 Hz), 2.1–
2.19 (m, 1 H), 2.34–2.38 (m, 1 H), 3.51–3.59 (m, 1 H), 3.84–3.91
(m, 1 H), 4.57 (br s, 1 H, NH), 4.67 (br s, 1 H), 5.35 (t, 1 H,
J = 2.9 Hz), 6.71–6.76 (m, 3 H), 6.89 (d, 1 H, J = 8.3 Hz), 6.94 (t,
1 H, J = 8.0 Hz), 7.18–7.24 (m, 3 H), 7.37 (d, 1 H, J = 7.8 Hz).
Anal. Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C,
76.46; H, 7.58; N, 4.82.
(2-Ethoxy-3,4-dihydro-2H-chromen-4-yl)(4-bromophenyl)am-
ine (3i)
13C NMR (100 MHz, CDCl3, proton decoupled): d = 15.2, 31.5,
45.5, 64.2, 97.2, 114.2, 117.4, 117.9, 121.3, 124.1, 128.9, 129.3,
130.1, 147.4, 151.1.
Yield: 0.380g (58%); colorless solid; mp 119–121 °C.
IR (KBr): 3394 (NH), 3026, 1491 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.17 (t, 3 H, J = 6.5 Hz), 1.93 (m,
1 H), 2.36–2.43 (m, 1 H), 3.52–3.56 (m, 1 H), 3.82–3.87 (m, 1 H),
4.30 (br s, 1 H, NH), 4.73 (br s, 1 H), 5.58 (t, 1 H, J = 2.9 Hz), 6.64
(d, 2 H, J = 8.9 Hz), 6.93–7.01 (m, 2 H), 7.21–7.29 (m, 2 H), 7.32
(d, 2 H, J = 8.9 Hz).
MS: m/z = 269 (M+).
Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C,
75.63; H, 7.26; N, 5.03.
13C NMR (100 MHz, CDCl3, proton decoupled): d = 15.4, 32.5,
45.7, 64.5, 97.2, 114.4, 117.7, 117.9, 122.3, 124.5, 126.3, 129.4,
132.5, 146.4, 153.4.
(2-Ethoxy-3,4-dihydro-2H-chromen-4-yl)phenylamine (4g)
Yield: 0.21g, (42%); colorless liquid.
IR (neat): 3395 (NH), 3050, 1494 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.22 (t, 3 H, J = 6.8 Hz), 1.97 (m,
1 H), 2.36 (dt, 1 H, J = 6.7, 12.8 Hz), 3.65 (dq, 1 H, J = 6.8,
9.2 Hz), 3.78 (br s, 1 H, NH), 3.94 (dq, 1 H, J = 6.8, 9.2 Hz), 4.91
(dd, 1 H, J = 5.4, 9.3 Hz), 5.28 (dd, 1 H, J = 2.4, 9.3 Hz), 6.70–6.76
(m, 3 H), 6.87 (d, 1 H, J = 8.3 Hz), 6.92 (t, 1 H, J = 7.4 Hz), 7.18–
7.25 (m, 3 H), 7.42 (d, 1 H, J = 7.8 Hz).
MS: m/z = 348 (M+).
Anal. Calcd for C17H18BrNO2: C, 58.63; H, 5.21; N, 4.02. Found: C,
58.24; H, 5.10; N, 4.24.
(2-Ethoxy-3, 4-dihydro-2H-chromen-4-yl)(4-bromophenyl)am-
ine (4i)
Yield: 0.270g (42%); colorless solid; mp 109–111 °C.
Synthesis 2004, No. 6, 949–959 © Thieme Stuttgart · New York

PAPER
Inverse Electron Demand Diels–Alder Reactions of Heterodienes Catalyzed by KHSO4
957
IR (KBr): 3390 (NH), 3040, 1493 cm–1.
3.69 (m, 3 H), 2.76–2.71 (m, 1 H), 2.19–2.10 (m, 1 H), 1.53–1.46
(m, 1 H).
1H NMR (400 MHz, CDCl3): d = 1.24 (t, 3 H, J = 6.8 Hz), 1.92 (m,
1 H), 2.34 (dt, 1 H, J = 6.8, 12.3 Hz), 3.63 (dq, 1 H, J = 6.8,
9.3 Hz), 3.76 (br s, 1 H, NH), 3.92 (dq, 1 H, J = 6.8, 9.3 Hz), 4.91
(dd, 1 H, J = 5.5, 9.4 Hz), 5.29 (dd, 1 H, J = 2.5, 9.4 Hz), 6.45 (d, 2
H, J = 8.9 Hz), 6.85-7.19 (m, 4 H), 7.21 (d, 2 H, J = 8.9 Hz).
13C NMR (100 MHz, CDCl3, proton decoupled): d = 15.3, 33.6,
45.2, 64.3, 97.9, 113.6, 117.2, 117.4, 121.7, 122.3, 129.8, 130.4,
132.6. 145.7, 152.5.
13C (75MHz, CDCl3): d = 144.7, 140.7, 133.3, 130.2, 128.9, 128.5,
127.9, 122.7, 119.5, 115.1, 75.8, 66.8, 57.0, 45.7, 24.6.
MS: m/z = 287 (M+ + 2), 285 (M+).
Anal. Calcd for C17H16ClNO: C, 71.48; H, 5.60; N, 4.90; Found: C,
71.40; H, 5.57; N, 5.10.
4-(4-Chlorophenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quino-
line (6b)
MS: m/z = 348 (M+).
Yield: 0.250g (65%); colorless solid; mp 98–100 °C.
IR (KBr): 3392, 1481 cm–1.
Anal. Calcd for C17H18BrNO2: C, 58.63; H, 5.21; N, 4.02. Found: C,
58.81; H, 5.07; N, 4.14.
1H NMR (300 MHz, CDCl3): d = 7.40–7.33 (m, 5 H), 7.12 (t, 1 H,
J = 7.2 Hz), 6.80 (td, 1 H, J = 7.4, 1.0 Hz), 6.63 (d, 1 H, J = 8.2 Hz),
4.58 (d, 1 H, J = 5.1 Hz), 4.10 (br s, 1 H), 4.04–3.70 (m, 3 H), 2.43–
2.37 (m, 1 H), 2.04–1.97 (m, 1 H), 1.69–1.62 (m, 1 H).
13C (75 MHz, CDCl3): d = 145.2, 140.3, 133.9, 131.3, 129.6, 129.1,
128.9, 120.7, 118.7, 114.8, 76.1, 65.2, 57.2, 43.5, 28.8.
Synthesis of Tetrahydroquinolines; General Procedure
KHSO4 (0.256g, 40 mol%) was added to a mixture of aldehyde (4.7
mmol), aromatic amine (5.1 mmol), and dienophile [cyclopentadi-
ene (11.7 mmol) or 3,4-dihydropyran (11.7 mmol) dihydrofuran
(11.7 mmol)] in MeOH (10 mL) and stirred at room temperature for
the appropriate time. To the reaction mixture water was added
(25 mL), the product was extracted with CH2Cl2 (3 × 10 mL), the
combined organic phase was washed with brine, dried over anhyd
Na2SO4, filtered, and the solvent evaporated. The residue was puri-
fied by column chromatography ( petroleum ether–EtOAc) to af-
ford the cycloadducts.
MS: m/z = 287 (M+ + 2), 285 (M+).
Anal. Calcd for C17H16ClNO: C, 71.48; H, 5.60; N, 4.90. Found: C,
71.42; H, 5.56; N, 5.09.
5-Phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline
(5c)
4-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (5a)
Yield: 0.510g (60%); colorless solid; mp115–117°C (Lit.25 117–
118 °C).
IR (KBr): 3345, 1484 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.47–7.25 (m, 6 H), 7.10 (td, 1 H,
J = 8.0, 1.1 Hz), 6.80 (t, 1 H, J = 7.4 Hz), 6.60 (d, 1 H, J = 8.0 Hz),
5.28 (d, 1 H, J = 7.4 Hz), 4.60 (d, 1 H, J = 2.8 Hz), 3.76 (m, 3 H,),
2.78 (m, 1 H), 2.21 (m, 1 H), 1.52 (m, 1 H).
13C (75 MHz, CDCl3): d = 145.0, 142.2, 130.2, 128.7, 128.4, 127.7,
126.6, 122.7,119.2, 115.0, 76.0, 66.9, 57.6, 45.8, 24.7.
MS: m/z = 251 (M+).
Yield: 0.515 g (65%); colorless solid; mp 129–131 °C (Lit.25
132 °C).
IR (KBr): 3378, 3316, 2936, 1605, 1485, 1071 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.41–7.24 (m, 6 H), 7.13–7.06 (m,
1 H), 6.83–6.76 (m, 1 H), 6.62 (d, 1 H, J = 7.6 Hz), 5.34 (d, 1 H,
J = 4.5 Hz), 4.68 (s, 1 H), 3.89 (br s, 1 H, NH), 3.61 (d, 1 H,
J = 11.2 Hz), 3.44–3.26 (m, 1 H), 2.17–1.99 (m, 1 H), 1.75–1.31
(m, 4 H).
13C NMR (75 MHz, CDCl3): d = 145.2, 141.1, 128.3, 128.0, 127.6,
127.5, 126.8, 119.8, 118.3, 114.4, 72.8, 60.6, 59.3, 38.9, 25.4, 18.0.
MS: m/z = 265 (M+).
Anal. Calcd for C17H17NO: C, 81.28; H, 6.77; N, 5.58. Found: C,
80.90; H, 6.68; N, 5.30.
Anal. calcd for C18H19NO: C, 81.48; H, 7.22; N, 5.28. Found: C,
81.07; H, 7.25; N, 5.30.
4-Phenyl-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quinoline (6a)
Yield: 0.340g (40%); viscous oil.
IR (KBr): 3324, 1483 cm–1.
5-Phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline
(6c)
Yield: 0.275 g (35%); viscous oil.
1H NMR (300 MHz, CDCl3): d = 7.45–7.25 (m, 6 H), 7.12 (td, 1 H,
J = 7.4, 1.1 Hz), 6.80 (t, 1 H, J = 7.4 Hz), 6.62 (d, 1 H, J = 8.0 Hz),
4.60 (d, 1 H, J = 5.1 Hz), 4.15 (br s, 1 H), 4.05–4.01(m, 1 H), 3.86–
3.78 (m, 2 H), 2.50–2.43 (m, 1 H), 2.06–1.97 (m, 1 H), 1.74–1.69
(m, 1 H).
13C (75 MHz, CDCl3): d = 145.5, 141.7, 131.3, 129.0, 128.7, 128.3,
128.2, 120.1, 118.4, 114.8, 76.3, 65.3, 57.8, 43.4, 28.9.
IR (KBr): 3374, 2928, 1610, 1489, 1077 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.34 (m, 5 H), 7.26 (d, 1 H,
J = 7.0 Hz), 7.13–7.03 (m, 1 H), 6.75–6.59 (m, 1 H), 6.54 (d, 1 H,
J = 7.8 Hz), 4.74 (d, 1 H, J = 10.6 Hz), 4.41 (br s, 1 H, NH), 4.10–
4.02 (m, 2 H), 3.78–3.69 (m, 1 H), 2.08–2.02 (m, 1 H), 1.89–1.31
(m, 4 H).
13C NMR (75 MHz, CDCl3): d = 144.1, 141.7, 130.2, 128.7, 128.0,
127.2, 127.1, 120.0, 116.8, 113.5, 73.9, 68.0, 54.1, 38.2, 23.5, 21.4.
MS: m/z = 251 (M+).
MS: m/z = 265 (M+).
Anal. Calcd for C17H17NO: C, 81.28; H, 6.77; N, 5.58. Found: C,
80.92; H, 6.66; N, 5.31.
Anal. Calcd for C18H19NO: C, 81.48; H, 7.22; N, 5.28. Found: C,
81.09; H, 7.24; N, 5.25.
4-(4-Chlorophenyl)-2,3,3a,4,5,9b-hexahydrofuro[3,2-c]quino-
line (5b)
Yield: 0.450g (65%); colorless solid; mp 129–130 °C.
IR (KBr): 3321, 1486 cm–1.
9-Methoxy-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinoline (5d)
Yield: 0.740 g (73%); mp146–147 °C (Lit.25 144–146 °C).
1H NMR (300 MHz, CDCl3): d = 7.42–7.32 (m, 5 H), 7.09 (t, 1 H,
J = 8.5 Hz), 6.82 (t, 1 H, J = 7.4 Hz), 6.60 (d, 1 H, J = 8.0 Hz), 5.26
(d, 1 H, J = 8.0 Hz), 4.67 (d, 1 H, J = 2.9 Hz), 4.01(m, 1 H), 3.82–
IR (KBr): 3295, 2942, 1502, 1262, 1065 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.40–7.29 (m, 5 H), 7.03 (s, 1 H),
6.73 (d, 1 H, J = 8.2 Hz), 6.57 (d, 1 H, J = 8.2 Hz), 5.31 (d, 1 H,
Synthesis 2004, No. 6, 949–959 © Thieme Stuttgart · New York

958
R. S. Kumar et al.
PAPER
J = 5.4 Hz), 4.61 (s, 1 H), 3.73 (s, 3 H), 3.67 (br s, 1 H, NH), 3.61–
3.36 (m, 2 H), 2.15 (m, 1 H), 1.54–1.26 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 152.8, 141.3, 139.1, 128.3, 127.4,
126.8, 121.1, 115.7, 115.0, 111.8, 72.9, 60.8, 59.5, 55.8, 39.1, 25.3,
17.9.
13C NMR (75 MHz, CDCl3): d =145.6, 142.8, 134.0, 130.3, 129.0,
128.4, 127.2, 126.4, 126.3, 126.0, 119.1, 115.9, 58.0, 46.4, 46.0,
31.5.
MS: m/z = 247 (M+).
Anal. Calcd for C18H17N: C, 87.41; H, 6.93; N, 5.66. Found: C,
86.88; H, 6.95; N, 5.68.
MS: m/z = 295 (M+).
Anal. Calcd for C19H21NO2: C, 77.26; H, 7.17; N, 4.74; Found: C,
77.65; H, 7.20; N, 4.77.
4-(4-Chlorophenyl)-3a,4,5,9b-tetrahydro-3H-cyclopen-
ta[c]quinoline (5g)
Yield: 0.398g (40%); colorless solid; mp 141–142 °C.
IR (KBr): 3363, 1478 cm–1.
9-Methoxy-5-phenyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinoline (6d)
Yield: 0.280 g (27%); viscous liquid.
IR (neat): 3361, 2938, 1504, 1255, 1032 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.43–7.27 (m, 5 H), 6.82 (s, 1 H),
6.75 (d, 1 H, J = 9.1 Hz), 6.49 (d, 1 H, J = 8.5 Hz), 4.62 (d, 1 H,
J = 10.5 Hz), 4.38 (s, 1 H), 4.10 (m, 1 H), 3.75 (m, 5 H), 2.10 (m, 1
H), 1.84–1.30 (m, 4 H).
1H NMR (300 MHz, CDCl3): d = 7.40 (m, 4 H), 7.36–6.98 (m, 2 H),
6.80–6.75 (m, 1 H), 6.65 (d, 1 H, J = 7.7 Hz), 5.87–5.85 (m, 1 H),
5.66 (s, 1 H), 4.62 (d, 1 H, J = 3.0 Hz), 4.13 (d, 1 H, J = 8.5 Hz),
3.69 (br s, 1 H, NH), 3.03–2.93 (m, 1 H), 2.65–2.56 (m, 1 H), 1.85–
1.76 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 145.2, 141.3, 133.9, 132.8, 130.2,
128.9, 127.9, 126.3, 125.9, 119.4, 115.9, 57.4, 46.2, 45.9, 31.3.
13C NMR (75 MHz, CDCl3): d = 151.9, 142.2, 138.7, 128.1, 127.7,
121.3, 116.7, 115.5, 114.7, 74.5, 68.3, 55.7, 55.1, 38.8, 24.0, 21.9.
MS: m/z = 281 (M+), 283 (M + 2).
MS: m/z = 295 (M+).
Anal. Calcd for C18H16ClN: C, 76.72; H, 5.72; N, 4.97. Found: C,
76.56; H, 5.53; N, 4.91.
5-(4-Chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinoline (5e)
Yield: 0.300 g (64%); colorless solid; mp 168–169 °C.
4-Phenyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-
carboxylic acid (5h)
Yield: 0.580g (42%); colorless solid; mp 206–207 °C.
IR (KBr): 3349, 1608, 1491 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.80 (d, 1 H, J = 8.0 Hz), 7.38 (m,
5 H), 6.64 (m, 2 H), 5.81 (m, 1 H), 5.65 (m, 1 H), 4.75 (d, 1 H,
J = 2.7 Hz), 4.48 (s, 1 H), 4.13 (d, 1 H, J = 8.4 Hz), 3.02 (m, 1 H),
2.58 (m, 1 H), 1.82 (m, 1 H).
IR (KBr): 3379, 2928, 1492, 1261 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.26 (m, 5 H), 7.21 (s, 1 H),
6.76–6.62 (m, 1 H), 6.54 (d, 1 H, J = 8.1 Hz), 5.23 (d, 1 H,
J = 5.4 Hz), 4.84 (s, 1 H), 3.91 (br s, 1 H, NH), 3.71 (d, 1 H,
J = 11.3 Hz), 3.64–3.43 (m, 1 H), 1.98–1.81 (m, 1 H), 1.79–1.54
(m, 4 H).
13C NMR (75 MHz, CDCl3) 144.1, 140.6, 133.0, 130.4, 129.1,
128.8, 128.5, 120.6, 117.4, 113.9, 74.5, 68.6, 53.9, 38.8, 24.0, 21.9.
MS: m/z = 299 (M+); 301 (M + 2).
13C NMR (75 MHz, CDCl3): d =173.3, 150.2, 142.1, 135.5, 134.9,
130.6, 130.0, 128.6, 128.2, 127.1, 127.0, 126.8, 126.1, 116.2, 111.8,
56.4, 45.8, 45.3, 31.7.
MS: m/z = 291(M+).
Anal. Calcd for C18H18ClNO: C, 72.11; H, 6.05; N, 4.67. Found: C,
72.38; H, 5.98; N, 4.65.
Anal. Calcd for C19H17NO2: C, 78.33; H, 5.88; N, 4.81. Found: C,
77.99; H, 5.86; N, 4.82.
5-(4-Chlorophenyl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-
c]quinoline (6e)
Yield: 0.170 g (35%); colorless solid; mp 139–140°C.
6,7-Dimethyl-4-phenyl-3a,4,5,9b-tetrahydro-3H-cyclopen-
ta[c]quinoline (5i)
Yield: 0.530 g (41%); colorless solid; mp 114–115 °C.
IR (KBr): 3384, 1469 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.62–7.40 (m, 5 H), 6.97 (d, 1 H,
J = 7.5 Hz), 6.71 (d, 1 H, J = 7.5 Hz), 5.98 (m, 1 H), 5.79 (s, 1 H),
4.65 (d, 1 H, J = 2.7 Hz), 4.42 (d, 1 H, J = 8.1 Hz), 3.80 (br s, 1 H,
NH), 3.33–3.25 (m, 1 H), 2.96–2.87 (m, 1 H), 2.48 (s, 3 H), 2.26 (s,
3 H), 2.04–1.96 (m, 1 H).
IR (KBr): 3345, 2931, 1492, 1265 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.06 (m, 6 H), 6.73–6.68 (m,
1 H), 6.53 (d, 1 H, J = 8.0 Hz), 4.70 (d, 1 H, J = 10.8 Hz), 4.37 (d,
1 H, J = 2.5 Hz), 4.11–4.06 (m, 1 H), 4.02 (br s, 1 H, NH), 3.75–
3.67 (m, 1 H), 2.05–2.00 (m, 1 H), 1.83–1.60 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 144.5, 140.8, 133.5, 130.9, 129.4,
129.1, 128.8, 120.6, 117.7, 114.2, 74.3, 68.6, 54.2, 38.9, 24.0, 22.0.
13C NMR (75 MHz, CDCl3): d = 144.8, 142.9, 134.2, 130.6, 128.4,
127.6, 126.4, 124.4, 120.5, 119.7, 58.5, 46.1, 45.6, 32.0, 19.5, 17.0.
MS: m/z = 299 (M+); 301 (M + 2).
Anal. Calcd for C18H18ClNO: C, 72.11; H, 6.05; N, 4.67. Found: C,
72.01; H, 5.98; N, 4.75.
MS: m/z = 275.
Anal. Calcd for C20H21N: C, 87.23; H, 7.69; N, 5.09. Found: C,
87.36; H, 7.01; N, 4.99.
4-Phenyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline (5f)
Yield: 0.510g (44%); colorless solid; mp 120–121 °C (Lit.26
120 °C).
4-Benzoyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline (5j)
Yield: 0.480 g (50%); colorless solid; mp 157–158 °C.
IR (KBr): 3384, 1681 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.93–7.85 (m, 2 H), 7.60–7.47 (m,
3 H), 7.06–6.98 (m, 2 H), 6.76–6.67 (m, 2 H), 5.73 (t, 1 H), 5.56 (s,
1 H), 5.05 (d, 1 H, J = 3.1 Hz), 4.42 (br s, 1 H), 4.21 (d, 1 H,
J = 8.9 Hz), 3.37–3.27 (m, 1 H), 2.47–2.38 (m, 1 H), 1.94–1.86 (m,
1 H).
IR (KBr): 3353, 1478 cm-–1
.
1H NMR (300 MHz, CDCl3): d = 7.50 (m, 5 H), 7.06 (m, 2 H), 6.78
(m, 1 H), 6.64 (d, 1 H, J = 7.9 Hz), 5.90 (m, 1 H), 5.71 (m, 1 H),
4.67 (d, 1 H, J = 2.9 Hz), 4.15 (d, 1 H, J = 8.6 Hz), 3.78 (br s, 1 H),
3.05 (m, 1 H), 2.71 (m, 1 H), 1.85 (m, 1 H).
Synthesis 2004, No. 6, 949–959 © Thieme Stuttgart · New York

PAPER
Inverse Electron Demand Diels–Alder Reactions of Heterodienes Catalyzed by KHSO4
959
13C NMR (75 MHz, CDCl3): d = 199.1, 143.9, 135.5, 133.9, 133.2,
129.5, 128.7, 128.0, 126.5, 125.8, 118.9, 115.8, 59.7, 46.9, 42.5,
31.4.
(4) Perry, N. B.; Blunt, J. W.; McCombs, J. D.; Munro, M. H. G.
J.Org.Chem. 1986, 51, 5476.
(5) Perry, N. B.; Blunt, J. W.; Munro, M. H. G. Tetrahedron
1988, 44, 1727.
(6) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Sakai, R. J. Org.
Chem. 1988, 53, 4127.
(7) Konishi, M.; Zercher, C. K.; Bechkam, S.; Haubold, E.-M. J.
Am. Chem. Soc. 1990, 112, 3715.
(8) Wender, P. A.; Zercher, C. K.; Bechkam, S.; Haubold, E.-M.
J. Org. Chem. 1993, 58, 5867.
(9) Uchida, M.; Chihiro, M.; Morita, S.; Kanbe, T.; Yamashita,
H.; Yamasakai, K.; Yabuuchi, Y.; Nakagawa, K. Chem.
Pharm. Bull. 1989, 37, 2109.
MS: m/z = 275 (M+).
Anal. Calcd for C19H17NO: C, 82.88; H, 6.22; N, 5.08. Found: C,
83.69; H, 6.19; N, 5.16.
10-Nitro-3a,4,5,11b-tetrahydro-3H-benzo[h]cyclopenta[c]quin-
oline (5k)
Yield: 0.300 g (42%); brown solid; mp 198.7–199 °C.
IR (KBr): 3398, 1495 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.99 (d, 1 H, J = 8.8 Hz), 8.41 (s,
1 H), 7.72–7.60 (m, 2 H), 7.49–7.44 (m, 1 H), 5.90 (m, 1 H), 5.74–
5.72 (m, 1 H), 5.54 (br s, 1 H, NH), 3.99 (s, 1 H), 3.43–3.37 (m, 1
H), 3.06 (t, 1 H), 2.77–2.73 (m, 2 H), 2.20–2.15 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 147.5, 135.5, 130.1, 129.1, 126.3,
121.9, 119.8, 115.6, 46.2, 43.5, 37.0, 34.7.
(10) Miller, K. E.; Huang, C.-T.; Portlock, D. E.; Wright, G. C.
Life Sci. 1987, 40, 63.
(11) Atwal, K. Eur. Pat. EP 488,616, 1992.
(12) Carling, R. W.; Leeson, P. D.; Mosely, A. M.; Smith, J. D.;
Saywell, K.; Tricklebank, M. D.; Kemp, J. A.; Marshal, G.
R.; Foster, A. C.; Grimwood, S. Bioorg. Med. Chem. Lett.
1993, 3, 65.
(13) Tsushima, K.; Osumi, T.; Matsuo, N.; Itaya, N. Agricult.
Biol. Chem. 1989, 53, 2529.
(14) Evans, S. Eur. Pat. EP 497,735, 1992.
(15) Shikhaliev, Kh. S.; Shmyreva, Zh. V.; Gurova, E. M.
Izv.Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol. 1989, 32,
85.
MS: m/z = 266 (M+).
Anal. Calcd for C16H14N2O2: C, 72.17; H, 5.30; N, 10.52. Found: C,
71.32; H, 5.49; N, 9.88.
Acknowledgment
(16) Ramesh, M.; Mohan, P. A.; Shanmugam, P. Tetrahedron
1984, 40, 4041.
We thank the Council of Scientific and Industrial Research, New
Delhi, INDIA for financial support.
(17) Nesterova, I. N.; Alekseeva, L. M.; Andreeva, L. M.;
Andreeva, N. I.; Golovira, S. M.; Granic, V. G. Khim.-Farm.
Zh. 1995, 29, 31; Chem. Abstr. 1996, 128, 117128.
(18) Yamada, N.; Kadowaki, S.; Takahashi, K.; Umezu, K.
Biochem. Pharmacol. 1992, 44, 1211.
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Synthesis 2004, No. 6, 949–959 © Thieme Stuttgart · New York