Synthesis of enantiopure 4-amino-3-hydroxymethyl-tetrahydroquinolines via an intramolecular nitrone cycloaddition

Article abstract of DOI:10.1016/j.tetasy.2007.06.004

Enantiopure 4-amino-3-hydroxymethyl-1,2,3,4-tetrahydroquinolines are synthesized by using an intramolecular cycloaddition of chiral nitrones prepared from aldehydes 5 and (R)-α-(hydroxymethyl)benzylhydroxylamine. Reaction times of the nitrone cycloadditio

Full text of DOI:10.1016/j.tetasy.2007.06.004

Tetrahedron: Asymmetry 18 (2007) 1495–1501
Synthesis of enantiopure 4-amino-3-hydroxymethyl-
tetrahydroquinolines via an intramolecular nitrone cycloaddition
Gianluigi Broggini,* Francesco Colombo, Ivan De Marchi, Simona Galli,
Michela Martinelli and Gaetano Zecchi
`
Dipartimento di Scienze Chimiche e Ambientali, Universita dell’Insubria, via Valleggio 11, 22100 Como, Italy
Received 17 May 2007; accepted 6 June 2007
Available online 5 July 2007
Abstract—Enantiopure 4-amino-3-hydroxymethyl-1,2,3,4-tetrahydroquinolines are synthesized by using an intramolecular cycloaddition
of chiral nitrones prepared from aldehydes 5 and (R)-a-(hydroxymethyl)benzylhydroxylamine. Reaction times of the nitrone cycloaddi-
tion were optimized by activation under MW-assisted conditions. The absolute configuration of the products was determined by X-ray
analysis.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
aldehydes B. In turn, we envisaged the possibility of syn-
thesizing intermediates B starting from benzoic acids with
electron-donor substituents in order to introduce the for-
myl group under Vilsmeier conditions.
Nitrones are very useful tools for the construction of struc-
turally complex molecules, in particular nitrogen-contain-
ing biologically active compounds.1 One of the most
fruitful synthetic methodologies is represented by 1,3-di-
polar nitrone cycloadditions in an intramolecular sense,2
which allow direct access to fused- or bridged-ring struc-
tures, often with a high degree of diastereocontrol. The
isoxazolidine derived ring is then susceptible to reductive3
or oxidative4 transformations yielding polifunctionalized
products.
R'
+
N
_
CHO
O
R
R
N
N
PG
PG
B
A
Considerable effort has been devoted to intramolecular
cycloadditions of non-racemic chiral nitrones, above all
having a benzylic nature5 or sugar-derived structure.6
2. Results and discussion
Among the commercially available 4-substituted benzoic
acids, 3,4,5-trimethoxy, 3-methoxy-4-methyl, and 3,4-
methylenedioxy ones 1a–c were chosen as starting materi-
als for our purpose. As depicted in Scheme 1, compounds
1 were converted in the corresponding acyl azides 2, which
were subsequently refluxed in EtOH to afford carbamates 3
as the product of Curtius degradation. N-Allylation took
place in THF with NaH as base giving allylanilines 4,
which were submitted to a Vilsmeier formylation in
DMF and POCl3. The latter reaction gave rise to only
one isomer in all cases, the attack at the less encumbered
o-position being most effective.
1,2,3,4-Tetrahydroquinolines are an important class of
compounds among which there are antitumour,7 cardio-
vascular,8 immunosuppressant,9 NMDA antagonist,10
antiallergic,11 antibacterial,12 analgesic,13 and antipsy-
chotic14 agents.
Our synthetic protocol allows access to enantiopure func-
tionalized tetrahydroquinolines by means of the intra-
molecular cycloaddition of key intermediates of type A,
bearing a stereocentre at the R0-pendant, available from
*
(R)-a-(Hydroxymethyl)benzylhydroxylamine, whose syn-
Corresponding author. Tel.: +39 031 2386444; fax: +39 031 2386449;
e-mail: gianluigi.broggini@uninsubria.it
thesis has been reported in the literature,5d was chosen as
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.004

1496
G. Broggini et al. / Tetrahedron: Asymmetry 18 (2007) 1495–1501
R''
R''
Ph
OH
HO
H
R''
R'
R
R'
H
_
1) SOCl2, CHCl3
2) NaN3
H
C
+
EtOH
reflux
HOHN
Ph
R'
R
N
(R)-6
O
5
CO2H
CON3
R
_
+
MgSO4
Me3CetylN Br
N
1
2 (71-89%)
Δ
toluene,
CH2Cl2/H2O
CO2Et
(R)-7
R''
R''
OH
H
O
OH
H
O
R'
R'
NaH, THF
Br
Ph
R''
Ph
R''
N
N
NHCO2Et
N
R
R
R'
R'
R
CO2Et
4 (80-95%)
3 (87-91%)
+
N
N
R
EtO2C
CO2Et
R''
a: 45%
b: 74%
c: 72%
8
a: 37%
9
R'
CHO
b: 12%
c: 14%
POCl3, DMF
90°C
N
R
H2-Pd(OH)2
MeOH
H2-Pd(OH)2
MeOH
CO2Et
5 (41-74%)
NH2
NH2
R''
R''
R'
R'
OH
OH
a
b
c
: R = OMe; R' = OMe; R'' = OMe
: R = OMe; R' = Me; R'' = H
: R, R' = -OCH2O-; R'' = H
N
N
R
R
CO2Et
(+)-10
CO2Et
(-)-10
Scheme 1. Synthesis of substituted 2-(N-allyl-N-carbethoxy-amino)-benz-
aldehydes 5.
a: R = OMe; R' = OMe; R'' = OMe
b: R = OMe; R' = Me; R'' = H
c: R, R' = -OCH2O-; R'' = H
the chiral reaction partner of aldehydes 5 in order to gen-
erate the non-racemic nitrones (R)-7. The attempt to gener-
ate nitrones 7 failed when the reaction was carried out in
diethyl ether at room temperature. However, nitrones
(R)-7 were successfully prepared and immediately trans-
formed into cycloadducts in a one-pot reaction by refluxing
reactants 5 and (R)-6 in dry toluene for 24 h in the presence
of anhydrous MgSO4 (Scheme 2). The resulting crude mix-
tures contained two products, which were isolated in a pure
state by chromatography. Analytical and spectral data are
consistent with diastereoisomeric cycloadducts both having
a fused-ring skeleton. With the known R-configuration of
the a-stereocentre, the absolute configuration of the minor
product derived from nitrone 7b (i.e., 9b) was established to
be aR,3aS,9bS by X-ray diffractrometric analysis (see
Fig. 1). So, the same stereochemistry was reasonably
ascribed to the other minor cycloadducts 9a,c.
Scheme 2. Formation and ring opening of cycloadducts 8 and 9.
The regioselective and stereoselective outcome of the cyclo-
addition deserves some comments. Firstly, the regioselec-
tivity was total being operative only with the approach
which binds the nitrone carbon atom to the inner atom
of the ethylenic bond. Moreover, all products show a cis
relationship of the two new stereocentres as a consequence
of the intramolecular nature of the reaction, which feels the
effect of the strict geometric restraint between dipole and
dipolarophile. The induction exerted by the pre-existent
stereocentre gave rise to a good diastereoselectivity in the
case of nitrones (R)-7b and (R)-7c while, unaccountably,
no chiral induction was operative in the case of (R)-7a.
As depicted in Figure 2, the intramolecular hydrogen bond
Figure 1. ORTEP plot of 9b. Atomic displacement parameters at 20%
probability level. The CH2CH3 residue has been depicted by considering
an average ordered model (see Section 4).
of the hydroxyl group with the oxygen atom of the (Z)-nit-
rone determines a chair-like conformation. If the phenyl

G. Broggini et al. / Tetrahedron: Asymmetry 18 (2007) 1495–1501
1497
O
4.2. General procedure for the preparation of benzoyl azides
2a–c
O
_
_
+
+
O
O
H
N
H
N
CO2Et
R''
N
H
H
N
These compounds were prepared as described in the
literature.16
R'
R''
EtO2C
R
R
R'
C
D
4.2.1. 3-Methoxy-4-methyl-benzoyl azide 2b. Yield: 89%.
Mp 104–105 ꢁC (diisopropyl ether). IR (Nujol): 2139,
Figure 2. Proposed approach of the functional groups for the formation
of compounds 8 and 9.
1
1687 cmꢀ1. H NMR (400 MHz, CDCl3) d: 2.29 (3H, s),
3.90 (3H, s), 7.21 (1H, d, J = 7.7 Hz), 7.47 (1H, s), 7.56
(1H, d, J = 7.7 Hz); 13C NMR (100 MHz, CDCl3) d: 16.0
(q), 55.6 (t), 126.4 (d), 128.2 (d), 132.1 (d), 134.9 (s),
139.1 (s), 143.4 (s), 168.0 (s). MS: m/z 191 (M+). Anal.
Calcd for C9H9N3O2: C, 56.54; H, 4.74; N, 21.98. Found:
C, 56.35; H, 4.91; N, 22.12.
group reasonably occupies the equatorial position, the
allylic moiety preferably approaches from the upper face
(C) to avoid steric repulsions.
Since nitrone cycloadditions are ideal candidates for
acceleration by microwaves,15 a series of experiments were
carried out under microwave irradiation with the aim of
reducing the reaction time. When the mixture of alde-
hydes 5, hydroxylamine (R)-6 and MgSO4 in toluene
was irradiated at 100 ꢁC in a multimode oven equipped
with temperature control at 250 W for 70 min, the cyclo-
addition process occurred with similar yield and diaste-
reoselective ratio to those obtained by conventional
heating.
4.3. General procedure for the preparation of N-carbethoxy-
benzenamines 3a–c
A solution of 2a–c (11.7 mmol) in EtOH (20 ml) and tolu-
ene (30 ml) was heated at reflux for 24 h. The solvent was
removed under reduced pressure to directly give the
product.
4.3.1. N-Carbethoxy-3,4,5-trimethoxy-benzenamine 3a.
Yield: 88%. Mp 88–90 ꢁC (diisopropyl ether). IR (Nujol):
The last step of our work consisted of the hydrogenolytic
treatment of the cycloadducts with the aim of opening
the isoxazole ring and removing the benzylic chiral pen-
dant. Compounds 8a–c and 9a–c were submitted to hydro-
genation in methanol in the presence of Pd(OH)2 giving
both the enantiomers of the 4-amino-3-hydroxymethyl-
1,2,3,4-tetrahydroquinolines 10a–c. The enantiomeric pur-
ity of the final b-aminoalcohols was confirmed by taking
the NMR spectra of compound (+)-10c and of its racemate
in the presence of (R)-O-acetylmandelic acid.
1
1705 cmꢀ1. H NMR (400 MHz, CDCl3) d: 1.32 (3H, t,
J = 7.1 Hz), 3.82 (3H, s), 3.86 (6H, s), 4.23 (2H, q,
J = 7.1 Hz), 6.55 (1H, br s, missing after deuteriation),
6.69 (2H, s); 13C NMR (100 MHz, CDCl3) d: 14.8 (q),
56.2 (q), 56.5 (q), 61.1 (q), 61.2 (t), 96.7 (d), 133.8 (s),
135.0 (s), 153.6 (s), 154.4 (s). MS: m/z 255 (M+). Anal.
Calcd for C12H17NO5: C, 56.46; H, 6.71; N, 5.49. Found:
C, 56.25; H, 6.99; N, 5.43.
4.3.2. N-Carbethoxy-3-methoxy-4-methyl-benzenamine 3b.
Yield: 87%. Mp 68–70 ꢁC (diisopropyl ether). IR (Nujol):
3. Conclusion
1
1702 cmꢀ1. H NMR (400 MHz, CDCl3) d: 1.33 (3H, t,
In conclusion, intramolecular nitrone cycloadditions have
been demonstrated to be useful key reactions in the synthe-
sis of highly functionalized 1,2,3,4-tetrahydroquinolines
starting from simple 4-substituted benzoic acids.
J = 7.1 Hz), 2.17 (3H, s), 3.84 (3H, s), 4.23 (2H, q,
J = 7.1 Hz), 6.59 (1H, s), 6.68 (1H, d, J = 8.0 Hz), 7.03
(1H, d, J = 8.0 Hz), 7.18 (1H, br s, missing after deuteria-
tion); 13C NMR (100 MHz, CDCl3) d: 14.9 (q), 16.0 (q),
55.6 (t), 61.4 (t), 102.3 (d), 110.9 (d), 121.7 (s), 130.8 (d),
137.6 (s), 154.5 (s), 158.3 (s). MS: m/z 209 (M+). Anal.
Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found:
C, 63.01; H, 7.48; N, 6.48.
4. Experimental
4.1. General
Melting points were determined on a Buchi B-540 heating
¨
4.3.3. 5-Carbethoxyamino-benzo[1,3]dioxole 3c. Yield:
apparatus and are uncorrected. Optical rotations were
91%. Mp 79–81 ꢁC. IR (Nujol): 1704 cmꢀ1 1H NMR
.
1
measured on a Jasco P-1010 polarimeter. H NMR and
(400 MHz, CDCl3) d: 1.31 (3H, t, J = 7.1 Hz), 4.22 (2H,
q, J = 7.1 Hz), 5.95 (2H, s), 6.56 (1H, s), 6.69 (1H, d,
J = 8.3 Hz), 6.73 (1H, d, J = 8.3 Hz), 7.10 (1H, br s, miss-
ing after deuteriation); 13C NMR (100 MHz, CDCl3) d:
14.9 (q), 61.6 (t), 101.5 (t), 102.4 (d), 108.4 (d), 112.5 (d),
132.7 (s), 144.1 (s), 148.3 (s), 154.4 (s). MS: m/z 209
(M+). Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N,
6.70. Found: C, 57.18; H, 5.49; N, 6.92.
13C NMR spectra were obtained on an AVANCE Bruker
400. Chemical shifts are given in parts per million down-
field from SiMe4; 13C NMR spectra are 1H-decoupled
and the determination of the multiplicities was achieved
by the APT pulse sequence. IR spectra were recorded on
a Jasco FT/IR 5300 spectrophotometer. Mass spectra were
determined on a WG-70EQ instrument.

1498
G. Broggini et al. / Tetrahedron: Asymmetry 18 (2007) 1495–1501
4.4. General procedure for the preparation of N-allyl-N-
carbethoxy-benzenamines 4a–c
ture was warmed at 90 ꢁC for 48 h. The mixture was ad-
justed to pH 8 with NaHCO3, then vigorously stirred for
1 h and extracted with CH2Cl2 (2 · 250 ml). The organic
layer was dried over Na2SO4 and the solvent removed
under reduced pressure. The crude products were purified
through a silica gel column.
NaH (155 mg, 6.46 mmol) was added in an N2 atmosphere
to a solution of 3a–c (4.31 mmol) in dry THF (50 ml). Allyl
bromide (1.04 g, 8.62 mmol) was added at ꢀ3 ꢁC, and then
the mixture was refluxed for 24 h. After cooling at room
temperature, H2O was added. The mixture was extracted
with CH2Cl2 (2 · 60 ml), and the organic layer was dried
over Na2SO4. The solvent was removed under reduced
pressure and the crude products were purified through a sil-
ica gel column with light petroleum/AcOEt = 10/1 as
eluent.
4.5.1.
N-Allyl-N-carbethoxy-2-formyl-3,4,5-trimethoxy-
benzenamine 5a. Eluent: light petroleum/AcOEt = 3/1.
Yield: 74%. Mp 58–60 ꢁC (diisopropyl ether). IR (Nujol):
1715, 1663 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 1.09
.
(3H, br s), 3.89 (6H, s), 3.99 (3H, s), 4.03–4.20 (3H, over-
lapping), 4.43 (1H, br s), 5.08 (1H, dd, J = 1.4, 10.2 Hz),
5.12 (1H, dd, J = 1.4, 17.2 Hz), 5.90 (1H, tdd, J = 5.9,
10.2, 17.2 Hz), 6.51 (1H, s), 10.20 (1H, s); 13C NMR
(100 MHz, CDCl3) d: 14.8 (q), 53.8 (t), 56.5 (q), 61.2 (q),
61.9 (t), 62.7 (q), 109.2 (d), 117.9 (t), 119.9 (s), 134.2 (d),
138.7 (s), 141.3 (s), 155.5 (s) 157.6 (s), 158.3 (s), 188.3
(d). MS: m/z 323 (M+). Anal. Calcd for C16H21NO6:
C, 59.43; H, 6.55; N, 4.33. Found: C, 59.58; H, 6.30; N,
4.11.
4.4.1. N-Allyl-N-carbethoxy-3,4,5-trimethoxy-benzenamine
4a. Yield: 95%. Oil. IR (Nujol): 1703 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) d: 1.24 (3H, t, J = 7.0 Hz), 3.81 (6H,
s), 3.83 (3H, s), 4.17 (2H, q, J = 7.0 Hz), 4.21 (2H, d,
J = 5.8 Hz), 5.15 (1H, dd, J = 1.4, 17.2 Hz), 5.17 (1H,
dd, J = 1.4, 10.2 Hz), 5.93 (1H, tdd, J = 5.8, 10.2,
17.2 Hz), 6.46 (2H, s); 13C NMR (100 MHz, CDCl3) d:
14.9 (q), 53.8 (t), 56.4 (q), 56.5 (q), 61.1 (q), 62.0 (t),
104.7 (d), 104.8 (d), 117.3 (t), 134.5 (d), 136.8 (s), 138.4
(s), 153.3 (s), 153.4 (s), 155.8 (s). MS: m/z 295 (M+). Anal.
Calcd for C15H21NO5: C, 61.00; H, 7.17; N, 4.74. Found:
C, 60.79; H, 7.28; N, 4.96.
4.5.2. N-Allyl-N-carbethoxy-2-formyl-5-methoxy-4-methyl-
benzenamine 5b. Eluent: light petroleum/AcOEt = 5/1.
1
Yield: 48%. Oil. IR (Nujol): 1718, 1667 cmꢀ1. H NMR
(400 MHz, CDCl3) d: 1.12 (3H, t, J = 7.1 Hz), 2.24 (3H,
s), 3.89 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 4.24 (2H, d,
J = 5.9 Hz), 5.12 (1H, d, J = 16.1 Hz), 5.16 (1H, d,
J = 9.0 Hz), 5.95 (1H, tdd, J = 5.9, 9.0, 16.1 Hz), 6.64
(1H, s), 7.69 (1H, s), 9.93 (1H, s); 13C NMR (100 MHz,
CDCl3) d: 14.8 (q), 16.0 (q), 54.3 (t), 56.1 (q), 62.3 (t),
106.3 (d), 117.7 (t), 125.8 (s), 126.9 (s), 131.3 (d), 133.4
(d), 144.2 (s), 155.7 (s) 163.1 (s), 189.0 (d). MS: m/z 277
(M+). Anal. Calcd for C15H19NO4: C, 64.97; H, 6.91; N,
5.05. Found: C, 65.13; H, 6.66; N, 5.16.
4.4.2. N-Allyl-N-carbethoxy-3-methoxy-4-methyl-benzen-
amine 4b. Yield: 80%. Oil. IR (Nujol): 1707 cmꢀ1 1H
.
NMR (400 MHz, CDCl3) d: 1.25 (3H, t, J = 6.9 Hz), 2.21
(3H, s), 3.81 (3H, s), 4.19 (2H, q, J = 6.9 Hz), 4.26 (2H,
d, J = 5.8 Hz), 5.15 (1H, dd, J = 0.7, 10.0 Hz), 5.18 (1H,
dd, J = 0.7, 17.2 Hz), 5.95 (1H, tdd, J = 5.8, 10.0,
17.2 Hz), 6.72–6.74 (2H, overlapping), 7.08 (1H, d,
J = 8.2 Hz); 13C NMR (100 MHz, CDCl3) d: 14.9 (q),
16.1 (q), 55.6 (t), 55.4 (d), 61.8 (t), 109.4 (d), 117.1 (t),
118.6 (d), 125.0 (s), 130.6 (d), 134.6 (d), 141.5 (s), 155.7
(s), 158.0 (s). MS: m/z 249 (M+). Anal. Calcd for
C14H19NO3: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.42;
H, 7.94; N, 5.47.
4.5.3.
5-(N-Allyl-N-carbethoxy-amino)-6-formyl-benzo-
[1,3]dioxole 5c. Eluent: light petroleum/AcOEt = 1/1.
1
Yield: 41%. Oil. IR (Nujol): 1714, 1662 cmꢀ1. H NMR
(400 MHz, CDCl3) d: 1.16 (3H, t, J = 7.1 Hz), 4.06–4.22
(4H, overlapping), 5.10 (1H, d, J = 17.4 Hz), 5.14 (1H, d,
J = 11.3 Hz), 5.95 (1H, tdd, J = 6.7, 11.3, 17.4 Hz), 6.06
(2H, s), 6.65 (1H, s), 7.29 (1H, s), 9.86 (1H, s); 13C NMR
(100 MHz, CDCl3) d: 14.8 (q), 54.4 (t), 62.4 (t), 101.5 (t),
103.0 (t), 106.8 (d), 107.1 (d), 117.6 (s), 119.5 (s), 128.0
(s), 132.9 (d), 147.8 (s), 157.3 (s), 188.4 (d). MS: m/z 277
(M+). Anal. Calcd for C14H15NO5: C, 60.65; H, 5.45; N,
5.05. Found: C, 60.87; H, 5.41; N, 4.82.
4.4.3. 5-(N-Allyl-N-carbethoxy-amino)-benzo[1,3]dioxole 4c.
Yield: 86%. Oil. IR (Nujol): 1703 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d: 1.23 (3H, t, J = 7.0 Hz), 4.16 (2H,
q, J = 7.0 Hz), 4.19 (2H, d, J = 5.9 Hz), 5.13 (1H, d,
J = 16.4 Hz), 5.15 (1H, d, J = 11.3 Hz), 5.95 (1H, ddd,
J = 5.9, 11.3, 16.4 Hz), 5.98 (2H, s), 6.65–6.71 (2H, over-
lapping), 6.76 (1H, d, J = 8.2 Hz); 13C NMR (100 MHz,
CDCl3) d: 14.5 (q), 53.7 (t), 61.8 (t), 101.7 (t), 108.1 (d),
108.8 (d), 117.3 (t), 120.5 (d), 134.2 (d), 136.4 (s), 146.3
(s), 148.0 (s), 155.7 (s). MS: m/z 249 (M+). Anal. Calcd
for C13H15NO4: C, 62.64; H, 6.07; N, 5.62. Found: C,
62.74; H, 5.79; N, 5.43.
4.6. General procedure for the reactions of 5a–c with (R)-6
Hydroxylamine (R)-6 (0.380 g, 2.48 mmol) and MgSO4
(2.60 g, 21.7 mmol) were added to a solution of 5a–c
(2.16 mmol) in toluene (70 ml). The mixture was warmed
at 100 ꢁC for 24 h and then, after cooling to room temper-
ature, filtered on Celite. The solvent was removed under
reduced pressure and the crude residue was purified
through a silica gel column.
4.5. General procedure for the preparation of 2-formyl-N-
allyl-N-carbethoxy-benzenamines 5a–c
A solution of POCl3 (6.3 g, 0.041 mol) in DMF (9.5 ml)
was stirred at 0 ꢁC for 1 h under N2. After the addition
of a solution of 4a–c (0.013 mol) in 2 ml CHCl3, the mix-
Entry a: Elution with AcOEt/light petroleum (6:4) gave 8a
(45%) and 9a (37%).

G. Broggini et al. / Tetrahedron: Asymmetry 18 (2007) 1495–1501
1499
4.6.1. (aR,3aR,9bR)-5-Carbethoxy-1-(1-phenyl-2-hydroxy-
ethyl)-7,8,9-trimethoxy-1,3a,4,9b-tetrahydro-3H-isoxazolo-
[4,3-c]quinoline 8a. IR (Nujol): 3478, 1701 cmꢀ1. Mp 49–
4.6.4. (aR,3aS,9bS)-5-Carbethoxy-1-(1-phenyl-2-hydroxy-
ethyl)-7-methoxy-8-methyl-1,3a,4,9b-tetrahydro-3H-isoxaz-
olo[4,3-c]quinoline 9b. IR (Nujol): 3472, 1700 cmꢀ1. Mp
23
23
1
51 ꢁC (diisopropyl ether). ½aꢁD ¼ ꢀ19:5 (c 0.7, CHCl3). H
NMR (400 MHz, CDCl3) d: 1.30 (3H, t, J = 7.1 Hz), 2.09
(1H, br s, missing after deuteriation), 2.89–2.95 (1H, m),
3.06 (1H, dd, J = 3.3, 13.4 Hz), 3.65 (1H, dd, J = 1.7,
8.5 Hz), 3.76 (1H, dd, J = 7.2, 8.2 Hz), 3.86 (3H, s), 3.92
(3H, s), 3.96 (3H, s), 4.01–4.08 (3H, overlapping), 4.19
(1H, dd, J = 7.1, 17.8 Hz), 4.30 (1H, dd, J = 7.1,
17.8 Hz), 4.32 (1H, dd, J = 7.8, 13.4 Hz), 4.51 (1H, d,
J = 9.3 Hz), 6.91 (1H, s), 7.33–7.38 (3H, overlapping),
7.52–7.55 (2H, overlapping); 13C NMR (100 MHz, CDCl3)
d: 14.9 (q), 44.3 (d), 46.4 (t), 56.3 (q), 57.4 (d), 61.3 (q), 61.5
(q), 62.5 (t), 64.5 (t), 68.6 (d), 69.6 (t), 104.9 (d), 115.8 (s)
128.3 (d), 128.4 (d), 130.5 (d), 136.8 (s), 137.1 (s), 139.5
(s), 152.5 (s), 153.1 (s), 156.9 (s). MS: m/z 458 (M+). Anal.
Calcd for C24H30N2O7: C, 62.87; H, 6.59; N, 6.11. Found:
C, 63.13; H, 6.30; N, 6.22.
172–174 ꢁC (diisopropyl ether). ½aꢁD ¼ ꢀ9:3 (c 0.8, CHCl3).
1H NMR (400 MHz, 50 ꢁC, CDCl3) d: 1.32 (3H, t,
J = 7.1 Hz), 2.25 (3H, s), 2.55 (1H, br s, missing after deu-
teriation), 2.88–2.92 (1H, m), 3.19 (1H, dd, J = 4.9,
13.5 Hz), 3.63 (1H, ddd, J = 4.7, 9.2, 9.9 Hz), 3.82 (1H,
d, J = 8.3 Hz), 3.85 (3H, s), 3.91 (1H, d, J = 8.7 Hz), 3.93
(1H, dd, J = 4.7, 9.3 Hz), 4.05 (1H, dd, J = 9.3, 9.9 Hz),
4.12 (1H, d, J = 8.3 Hz), 4.17 (1H, dd, J = 2.5, 13.5 Hz),
4.25 (1H, dq, J = 7.1, 10.7 Hz), 4.33 (1H, dq, J = 7.1,
10.7 Hz), 6.94 (1H, s), 7.06 (1H, s), 7.36–7.42 (3H, overlap-
ping), 7.46–7.49 (2H, overlapping); 13C NMR (100 MHz,
CDCl3) d: 15.0 (q), 16.4 (q), 45.8 (d), 46.9 (t), 55.8 (q),
60.6 (d), 62.4 (t), 64.1 (t), 67.3 (d), 70.1 (t), 107.7 (d),
120.2 (s), 124.0 (s) 128.5 (d), 128.7 (d), 130.8 (d), 131.8
(d), 136.0 (s), 139.9 (s), 155.5 (s), 157.7 (s). MS: m/z 412
(M+). Anal. Calcd for C23H28N2O5: C, 66.97; H, 6.84; N,
6.79. Found: C, 67.13; H, 6.55; N, 6.99.
4.6.2. (aR,3aS,9bS)-5-Carbethoxy-1-(1-phenyl-2-hydroxy-
ethyl)-7,8,9-trimethoxy-1,3a,4,9b-tetrahydro-3H-isoxazolo-
[4,3-c]quinoline 9a. IR (Nujol): 3489, 1702 cmꢀ1. Mp 46–
Entry c: Elution with AcOEt/light petroleum (1:2) gave 9c
(14%) and 8c (72%).
23
1
48 ꢁC (diisopropyl ether). ½aꢁD ¼ ꢀ63:5 (c 1.0, CHCl3). H
NMR (400 MHz, CDCl3) d: 1.34 (3H, t, J = 7.1 Hz), 3.01
(1H, br s, missing after deuteriation), 3.06 (1H, dd, J =
2.2, 13.3 Hz), 3.23–2.26 (1H, m), 3.44 (3H, s), 3.74 (3H,
s), 3.76–3.82 (4H, overlapping), 3.99 (1H, dd, J = 5.4,
8.4 Hz), 4.04 (1H, dd, J = 3.2, 6.7 Hz), 4.09–4.14 (1H,
m), 4.23 (1H, dd, J = 7.1, 10.6 Hz), 4.34 (1H, dd, J = 7.1,
10.6 Hz), 4.41–4.49 (3H, overlapping), 6.84 (1H, s), 7.28–
7.33 (3H, overlapping), 7.37–7.40 (2H, overlapping); 13C
NMR (100 MHz, CDCl3) d: 14.9 (q), 43.4 (d), 46.7 (t),
56.3 (q), 60.0 (d), 60.4 (q), 61.1 (q), 62.5 (t), 67.2 (t), 69.4
(d), 69.6 (t), 103.9 (d), 115.7 (s), 128.1 (d), 128.5 (d),
129.4 (d), 136.7 (s), 138.3 (s), 139.0 (s), 152.5 (s), 152.9
(s), 155.7 (s). MS: m/z 458 (M+). Anal. Calcd for
C24H30N2O7: C, 62.87; H, 6.59; N, 6.11. Found: C, 62.79;
H, 5.91; N, 6.38.
4.6.5. (aR,3aR,10bR)-5-Carbethoxy-1-(1-phenyl-2-hydroxy-
ethyl)-1,3a,4,10b-tetrahydro-3H,8H-[1,3]dioxolo[4,5-g]isox-
azolo[4,3-c]quinoline 8c. IR (Nujol): 3492, 1705 cmꢀ1. Mp
23
198–200 ꢁC. ½aꢁD ¼ ꢀ7:9 (c 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3) d: 1.31 (3H, t, J = 7.0 Hz), 2.95 (1H,
br s, missing after deuteriation), 3.34–3.39 (1H, m), 3.48
(1H, dd, J = 3.6, 13.4 Hz), 3.78 (1H, d, J = 6.7, Hz), 3.95
(1H, dd, J = 4.8, 8.5 Hz), 4.03 (1H, dd, J = 3.5, 6.7 Hz),
4.13–4.17 (2H, overlapping), 4.25 (2H, q, J = 7.0 Hz),
4.49 (1H, dd, J = 8.3, 8.5 Hz), 4.56 (1H, dd, J = 8.3,
8.5 Hz), 5.89 (2H, s), 6.42 (1H, s), 6.94 (1H, s), 7.35–7.43
(5H, overlapping); 13C NMR (100 MHz, CDCl3) d: 14.9
(q), 42.7 (d), 46.4 (t), 62.5 (t), 64.1 (d), 67.9 (t), 69.5 (d),
69.7 (t), 101.5 (t), 105.3 (d), 108.7 (d), 123.0 (s) 128.9 (d),
129.0 (d), 129.4 (d), 133.9 (s), 138.7 (s), 145.0 (s) 146.9
(s), 155.1 (s). MS: m/z 412 (M+). Anal. Calcd for
C22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C, 64.30;
H, 5.61; N, 6.55.
Entry b: Elution with AcOEt/light petroleum (1:1) gave 9b
(12%) and 8b (74%).
4.6.3. (aR,3aR,9bR)-5-Carbethoxy-1-(1-phenyl-2-hydroxy-
ethyl)-7-methoxy-8-methyl-1,3a,4,9b-tetrahydro-3H-isoxaz-
4.6.6. (aR,3aS,10bS)-5-Carbethoxy-1-(1-phenyl-2-hydroxy-
ethyl)-1,3a,4,10b-tetrahydro-3H,8H-[1,3]dioxolo[4,5-g]isox-
olo[4,3-c]quinoline 8b. IR (Nujol): 3481, 1701 cmꢀ1. Mp
azolo[4,3-c]quinoline 9c. IR (Nujol): 3475, 1705 cmꢀ1. Mp
23
23
56–58 ꢁC (diisopropyl ether). ½aꢁD ¼ ꢀ11:1 (c 0.9, CHCl3).
136–138 ꢁC (diisopropyl ether). ½aꢁD ¼ ꢀ7:4 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3) d: 1.33 (3H, t, J = 7.1 Hz),
2.07 (3H, s), 3.04 (1H, br s, missing after deuteriation),
3.31–3.38 (1H, m), 3.43 (1H, dd, J = 3.5, 13.4 Hz), 3.77–
3.80 (4H, overlapping), 3.98 (1H, dd, J = 4.9, 8.5 Hz),
4.05 (1H, dd, J = 3.2, 6.9 Hz), 4.14–4.18 (2H, overlapping),
4.23–4.30 (3H, overlapping), 4.48 (1H, dd, J = 8.4, 8.5 Hz),
6.67 (1H, s), 7.02 (1H, s), 7.36–7.45 (5H, overlapping);
13C NMR (100 MHz, CDCl3) d: 14.9 (q), 16.2 (q), 42.5
(d), 46.1 (t), 55.8 (q), 62.4 (t), 63.6 (d), 68.0 (t), 69.5 (t),
69.7 (d), 106.0 (d), 120.9 (s), 123.8 (s) 128.9 (d), 129.1 (d),
129.3 (d), 131.6 (d), 138.3 (s), 138.8 (s) 155.1 (s), 156.9
(s). MS: m/z 412 (M+). Anal. Calcd for C23H28N2O5:
C, 66.97; H, 6.84; N, 6.79. Found: C, 67.25; H, 7.14; N,
6.57.
1H NMR (400 MHz, CDCl3) d: 1.32 (3H, t, J = 7.1 Hz),
2.49 (1H, br s, missing after deuteriation), 2.90–2.94 (1H,
m), 3.13 (1H, dd, J = 5.1, 13.5 Hz), 3.63 (1H, dd, J = 4.7,
10.5 Hz), 3.82 (1H, d, J = 8.0 Hz), 3.87 (1H, d,
J = 8.9 Hz), 3.92 (1H, dd, J = 4.7, 9.9 Hz), 4.06 (1H, dd,
J = 9.9, 10.5 Hz), 4.14 (1H, dd, J = 8.4, 8.9 Hz), 4.16
(1H, dd, J = 2.2, 13.5 Hz), 4.25 (1H, dq, J = 7.1,
10.0 Hz), 4.29 (1H, dq, J = 7.1, 10.0 Hz), 5.99 (2H, s),
6.68 (1H, s), 6.99 (1H, s), 7.35–7.41 (3H, overlapping),
7.45–7.48 (2H, overlapping); 13C NMR (100 MHz, CDCl3)
d: 15.0 (q), 46.2 (d), 47.3 (t), 61.4 (d), 62.5 (t), 64.0 (t), 67.3
(d), 70.2 (t), 101.9 (t), 107.3 (d), 109.4 (d), 122.1 (s) 128.6
(d), 128.7 (d), 130.7 (d), 135.6 (s), 135.7 (s), 145.4 (s)
147.8 (s), 155.6 (s). MS: m/z 412 (M+). Anal. Calcd for

1500
G. Broggini et al. / Tetrahedron: Asymmetry 18 (2007) 1495–1501
C22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C, 63.99;
H, 6.16; N, 6.49.
m/z 294 (M+). Anal. Calcd for C15H22N2O4: C, 61.21; H,
7.53; N, 9.52. Found: C, 61.25; H, 7.38; N, 9.81.
4.8.4. (3S,4S)-4-Amino-1-carbethoxy-3-hydroxymethyl-7-
methoxy-6-methyl-1,2,3,4-tetrahydroquinoline 10b. Yield:
71%. ½aꢁD ¼ ꢀ29:9 (c 0.5, CHCl3).
4.7. General procedure for the reactions of 5a–c with (R)-6
under microwave irradiation
23
A suspension of hydroxylamine (R)-6 (0.30 g, 1.98 mmol),
MgSO4 (2.08 g, 17.4 mmol) and 5a–c (1.73 mmol) in tolu-
ene (70 ml) was heated in a microwave oven (250 W) at
100 ꢁC for 70 min. The mixture was filtered on Celite and
the solvent was removed under reduced pressure after
which the crude residue was purified through a silica gel
column (eluent given before) to give compounds 8a–c and
9a–c.
4.8.5. (7R,8R)-8-Amino-5-carbethoxy-7-hydroxymethyl-5,6,
7,8-tetrahydro-[1,3]dioxolo[4,3-c]quinoline 10c. IR (Nujol):
23
3377, 3296, 1703 cmꢀ1. Yield: 78%. Oil. ½aꢁD ¼ þ25:9 (c 0.6,
CHCl3). 1H NMR (400 MHz, CDCl3) d: 1.31 (3H, t,
J = 7.1 Hz), 2.03–2.08 (1H, m), 3.25 (3H, br s, missing after
deuteriation), 3.64 (1H, dd, J = 11.1, 12.6 Hz), 3.77 (1H,
dd, J = 5.4, 11.3 Hz), 3.93 (1H, dd, J = 5.4, 11.3 Hz),
3.96–4.01 (2H, overlapping), 4.25 (2H, q, J = 7.1 Hz),
5.93 (2H, s), 6.67 (1H, s), 7.34 (1H, s); 13C NMR
(100 MHz, CDCl3) d: 14.9 (q), 39.9 (d), 42.9 (t), 51.4 (d),
62.4 (t), 62.6 (t), 101.7 (t), 105.5 (d), 107.6 (d), 124.3 (s),
131.6 (s), 144.2 (s), 147.6 (s), 155.2 (s). MS: m/z 294
(M+). Anal. Calcd for C14H18N2O5: C, 57.14; H, 6.16; N,
9.52. Found: C, 56.92; H, 6.34; N, 9.62.
4.8. General procedure for the hydrogenation of compounds
8a–c and 9a–c
A suspension of 20% Pd(OH)2/C (120 mg, 0.17 mmol) and
isoxazolidine derived compound 8a–c or 9a–c (0.33 mmol)
in MeOH (12 ml) was stirred under H2 for 24 h. The mix-
ture was filtered through a Celite path and the solvent
was removed under reduced pressure after which the crude
residue was purified through a silica gel column to give
enantiopure 1,3-aminoalcohol 10a–c.
4.8.6. (7S,8S)-8-Amino-5-carbethoxy-7-hydroxymethyl-5,6,
7,8-tetrahydro-[1,3]dioxolo[4,3-c]quinoline 10c. IR (Nu-
23
jol): 3377, 3296, 1703 cmꢀ1. Yield: 74%. Oil. ½aꢁD
¼
ꢀ25:1 (c 0.5, CHCl3).
4.8.1. (3R,4R)-4-Amino-1-carbethoxy-3-hydroxymethyl-5,6,
7-trimethoxy-1,2,3,4-tetrahydroquinoline 10a. IR (Nujol):
4.8.7. X-ray crystallography for 9b. Monoclinic, space
˚
group C2, a = 35.22(3), b = 5.008(6), c = 12.10(1) A, b =
23
3371, 3298, 1753 cmꢀ1. Yield: 81%. Oil. ½aꢁD ¼ þ23:3 (c
3
˚
96.59(8)ꢁ, V = 2121(4) A , Z = 4, F(000) = 880, q =
1
1.292 g cmꢀ3, l(Mo Ka) = 0.091 mmꢀ1. The R, wR figures
of merit reached final values of 0.078, 0.181 for the 1981
observed reflections, and 0.157, 0.226 for all of the unique
reflections, 269 parameters and 7 restraints. Goodness of
fit, highest peak and deepest holeꢀr3eached final values of
1.3, CHCl3). H NMR (400 MHz, CDCl3) d: 1.28 (3H, t,
J = 7.0 Hz), 1.94–1.98 (1H, m), 3.12 (3H, br s, missing after
deuteriation), 3.57 (1H, dd, J = 12.7, 13.1 Hz), 3.81–3.89
(7H, overlapping), 3.97 (3H, s), 4.08 (1H, dd, J = 3.1,
10.7 Hz), 4.18 (1H, dd, J = 2.9, 13.1 Hz), 4.26 (2H, q,
J = 7.0 Hz), 4.32 (1H, d, J = 4.0 Hz), 7.44 (1H, s); 13C
NMR (100 MHz, CDCl3) d: 14.9 (q), 39.2 (d), 42.6 (t),
46.7 (d), 56.3 (d), 61.2 (q), 61.7 (q), 62.5 (t), 64.1 (t),
103.0 (d), 118.7 (s), 133.1 (s), 138.2 (s), 150.7 (s), 152.9
(s), 155.1 (s). MS: m/z 340 (M+). Anal. Calcd for
C16H24N2O6: C, 56.46; H, 7.11; N, 8.23. Found: C, 56.31;
H, 7.28; N, 7.97.
ꢀ3
˚
˚
1.014, 0.252 e A and ꢀ0.198 e A
.
A
needle colourless crystal of approximate 0.02 ·
0.02 · 0.16 mm dimensions was mounted on top of a gonio-
meter head. The data were collected on a Enraf Nonius
CAD-4 automated diffractometer using graphite-mono-
˚
chromated Mo Ka radiation (k = 0.71073 A). The unit cell
was determined on the basis of the setting angles of 25 ran-
domly distributed reflections in the 8.0ꢁ < h < 11.5ꢁ range.
A total of 3945 unique and 1981 observed [I > 2r(I)] reflec-
tions, in the 3.0ꢁ < h < 25.3ꢁ range, were collected
by applying the x-scan mode [Dx = 1.2 + (0.35tanh)].
The data were corrected for Lorenz polarization. No
absorption corrections were applied. The structure was
solved by direct methods and refined by full-matrix least-
squares on F2. All the ordered non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were made riding
their parent atoms with an isotropic temperature factor 1.2
times that of their parent atoms. A –CH2CH3 moiety, af-
fected by disorder, was modelled by superimposing two,
geometrically identical, C–C vectors, restraining the C–C
4.8.2. (3S,4S)-4-Amino-1-carbethoxy-3-hydroxymethyl-5,6,
7-trimethoxy-1,2,3,4-tetrahydroquinoline 10a. Yield: 79%.
½aꢁD ¼ ꢀ22:9 (c 1.1, CHCl3)
23
4.8.3. (3R,4R)-4-Amino-1-carbethoxy-3-hydroxymethyl-
7-methoxy-6-methyl-1,2,3,4-tetrahydroquinoline 10b. IR
23
(Nujol): 3371, 3293, 1707 cmꢀ1. Yield: 74%. Oil. ½aꢁD
¼
þ29:3 (c 0.6, CHCl3). 1H NMR (400 MHz, CDCl3) d:
1.35 (3H, t, J = 7.1 Hz), 2.04–2.09 (1H, m), 2.17 (3H, s),
3.40 (3H, br s, missing after deuteriation), 3.65 (1H, dd,
J = 12.2, 13.1 Hz), 3.78 (1H, dd, J = 5.7, 11.5 Hz), 3.82
(3H, s), 3.95 (1H, dd, J = 3.1, 11.5 Hz), 4.04 (1H, dd,
J = 4.9, 13.1 Hz), 4.07 (1H, d, J = 4.7 Hz), 4.26 (2H, q,
J = 7.1 Hz), 6.97 (1H, s) 7.52 (1H, s); 13C NMR
(100 MHz, CDCl3) d: 14.9 (q), 15.9 (q), 39.7 (d), 42.8 (t),
50.6 (d), 55.8 (q), 62.4 (t), 63.1 (t), 105.6 (d), 122.6 (s),
123.8 (s), 130.0 (d), 136.8 (s), 155.1 (s), 157.3 (s). MS:
˚
and O–C distances to 1.54 and 1.48 A, respectively, and
assigning to each C atom a s.o.f. of 0.5. No hydrogen
atoms were introduced on the carbon atoms of the disor-
dered part and on the –OH groups. CCDC Number
646199.

G. Broggini et al. / Tetrahedron: Asymmetry 18 (2007) 1495–1501
1501
Passarella, D.; Terraneo, A.; Zecchi, G. J. Org. Chem. 1998,
63, 9279–9284; (g) Wovkulich, P. M.; Uskokovic, M. R.
Tetrahedron 1985, 41, 3455–3462.
Acknowledgements
We are grateful to MIUR for financial support and to the
Centro Interuniversitario di Ricerca sulle Reazioni Perici-
cliche e Sintesi di Sistemi Etero e Carbociclici.
6. (a) Osborn, H. M. I.; Gemmell, N.; Harwood, L. M. J. Chem.
Soc., Perkin Trans. 1 2002, 2419–2438; (b) Shing, T. K. M.;
Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett. 2007, 9, 207–
´ ´
´
209; (c) Padar, P.; Bokros, A.; Paragi, G.; Forgo, P.; Kele, Z.;
´
Howarth, N. M.; Kovacs, L. J. Org. Chem. 2006, 71, 8669–
8672; (d) Moutel, S.; Shipman, M.; Martin, O. R.; Ikeda, K.;
Asano, N. Tetrahedron: Asymmetry 2005, 16, 487–491; (e)
Sahabuddin, Sk.; Roy, A.; Drew, M. G. B.; Roy, B. G.;
Achari, B.; Mandal, S. B. J. Org. Chem. 2006, 71, 5980–5992;
(f) Shing, T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. J.
Org. Chem. 2006, 71, 3253–3263; (g) Sharma, G. V. M.;
Begum, A.; Reddy, K. R.; Sankar, A. R.; Kunwar, A. C.
Tetrahedron: Asymmetry 2003, 14, 3899–3905; (h) Bhatta-
charjee, A.; Datta, S.; Chattopadhyay, P.; Ghoshal, N.;
Kundu, A. P.; Pal, A.; Mukhopadhyay, R.; Chowdhury, S.;
Bhattacharjya, A.; Patra, A. Tetrahedron 2003, 59, 4623–
4639.
References
1. Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Synthesis; VCH: New York, 1988.
2. (a) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1–
173; (b) Chiacchio, U.; Rescifina, A.; Romeo, G. In Targets in
Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.; SCI:
Rome, 1997; Vol. I, pp 225–276; (c) Frederickson, M.
Tetrahedron 1997, 53, 403–425; (d) Beccalli, E. M.; Broggini,
G.; Contini, A.; De Marchi, I.; Zecchi, G.; Zoni, C.
Tetrahedron: Asymmetry 2004, 15, 3181–3187; (e) Padwa,
A.; Pearson, W. H. Synthetic Applications of 1,3-Dipolar
Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Wiley: New York, 2003, Chapter 1; (f) Jeong, J. H.;
Weinreb, S. M. Org. Lett. 2006, 8, 2309–2312; (g) Grave-
stock, M. B.; Knight, D. W.; Lovell, J. S.; Thornton, S. R. J.
Chem. Soc., Perkin Trans. 1 1999, 3143–3155; (h) Werner, K.
M.; De los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org.
Chem. 1999, 64, 4865–4873; (i) Romeo, R.; Iannazzo, D.;
Piperno, A.; Chiacchio, M. A.; Corsaro, A.; Rescifina, A.
Eur. J. Org. Chem. 2005, 2368–2373; (j) Alcaide, B.; Saez, E.
Eur. J. Org. Chem. 2005, 1680–1693; (k) Aggarwal, V. K.;
Roseblade, S.; Alexander, R. Org. Biomol. Chem. 2003, 1,
684–691; (l) Cordero, F. M.; Pisaneschi, F.; Gensini, M.;
Goti, A.; Brandi, A. Eur. J. Org. Chem. 2002, 1941–1951; (m)
Davison, E. C.; Fox, M. E.; Holmes, A. B.; Roughley, S. D.;
Smith, C. J.; Williams, G. M.; Davies, J. E.; Raithby, P. R.;
Adams, J. P.; Forbes, I. T.; Press, N. J.; Thompson, M. J. J.
Chem. Soc., Perkin Trans. 1 2002, 1494–1514.
3. (a) Nath, M.; Mukhopadhyay, R.; Bhattacharjya, A. Org.
Lett. 2006, 9, 317–320; (b) Revuelta, J.; Cicchi, S.; Brandi, A.
J. Org. Chem. 2005, 70, 5636–5642; (c) Basso, D.; Broggini,
G.; Passarella, D.; Pilati, T.; Terraneo, A.; Zecchi, G.
Tetrahedron 2002, 58, 4445–4450; (d) Casuscelli, F.; Chiac-
chio, U.; Di Bella, M. R.; Rescifina, A.; Romeo, G.; Romeo,
R.; Uccella, N. Tetrahedron 1995, 51, 8605–8612; (e) Funk, R.
L.; Bolton, G. L. J. Org. Chem. 1984, 49, 5021–5022; (f)
Liautard, V.; Christina, A. E.; Desvergnes, V.; Martin, O. R.
J. Org. Chem. 2006, 71, 7337–7345; (g) Tufariello, J.;
Dyszlewski, A. D. J. Chem. Soc., Chem. Commun. 1987,
1138–1140; (h) Alvarez de Cienfuegos, L.; Langlois, N.
7. (a) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2007, 72, 574–
582; (b) Schiemann, K.; Bruge, D.; Buchstaller, H.-P.; Emde,
U.; Finsinger, D.; Amendt, C.; Zenke, F. Ger. Offen. 61214,
2006; Chem. Abstr. 2007, 146, 62604; (c) Li, C.-J.; Zhang, J.
U.S. Patent Appl. Publ. 149069, 2003; Chem. Abstr. 2003,
139, 164711; (d) Searcey, M.; Patterson, L. H. PCT Int. Appl.
67937, 2002; Chem. Abstr. 2002, 137, 216884.
8. (a) Eda, M.; Takemoto, H.; Hihara, M.; Sakashita, H.;
Okada, T.; Eiraku, M.; Fukaya, T.; Nakamura, N.; Matsuno,
S. Jpn. Kokai Tokkyo Koho JP 06 09564, 1994; Chem. Abstr.
1994, 121, 83082; (b) Privitera, P. J.; Blickenstaff, T.; Gaffney,
T. E.; Mohammed, S. J. Pharmacol. Exp. Ther. 1971, 176,
655–661.
9. Kono, Y.; Kojima, E.; Saito, K.; Kudo, S.; Sekoe, Y. Jpn.
Kokai Tokkyo Koho JP 06 56788, 1994; Chem. Abstr. 1994,
121, 157536.
10. Carling, R. W.; Leeson, P. D.; Moore, K. W.; Smith, J. D.;
Moyes, C. R.; Mawer, I. M.; Thomas, S.; Chan, T.; Baker,
R.; Foster, A. C.; Grimwood, S.; Kemp, J. A.; Marshall, G.
R.; Tricklebank, M. D.; Saywell, K. L. J. Med. Chem. 1993,
36, 3397–3408.
11. Kennewell, P. D.; Clements-Jewery, S.; Westwood, R. Brit.
U.K. Patent Appl. GB 2192000, 1987; Chem. Abstr. 1988,
109, 54675.
12. Gerster, J. F.; Rohlfing, S. R.; Pecore, S.; Winandy, R. M.;
Stern, R. M.; Landmesser, J. E.; Olsen, R. A.; Gleason, W. B.
J. Med. Chem. 1987, 30, 839–843.
13. Vecchietti, V.; Clarke, G. D.; Colle, R.; Giardina, G.;
Petrone, G.; Sbacchi, M. J. Med. Chem. 1991, 34, 2624–2633.
14. Singer, J. M.; Barr, B. M.; Coughenour, L. L.; Gregory, T.
F.; Walters, M. A. Bioorg. Med. Chem. Lett. 2005, 15, 4560–
4563.
15. (a) Zanobini, A.; Brandi, A.; de Meijere, A. Eur. J. Org.
Chem. 2006, 1251–1255; (b) Enderlin, G.; Taillefumier, C.;
Didierjean, C.; Chapleur, I. Tetrahedron: Asymmetry 2005,
16, 2459–2474; (c) Raunak, R.; Kumar, V.; Mukherjee, S.;
Poonam, P.; Prasad, A. K.; Olsen, K. E.; Schaeffer, S. J. C.;
Sharma, S. K.; Watterson, A. C.; Errington, W.; Parmar, V.
S. Tetrahedron 2005, 61, 5687–5697; (d) Dugovic, B.; Fisera,
L.; Hametner, C.; Pronayova, N. ARKIVOC 2003, 162–169;
(e) Cheng, Q.; Zhang, W.; Tagami, Y.; Oritani, T. J. Chem.
Soc., Perkin Trans. 2001, 452–456; (f) Ondrus, V.; Orsag, M.;
Fisera, L.; Pronayova, N. Tetrahedron 1999, 55, 10425–
10436; (g) Loupy, A.; Petit, A.; Bonnet-Delpon, D. J.
Fluorine Chem. 1995, 75, 215–216; (h) Diaz-Ortiz, A.; Diez-
Barra, E.; de la Hoz, A.; Prieto, P.; Moreno, A.; Langa, F.;
Prange, T.; Neuman, A. J. Org. Chem. 1995, 60, 4160–4166.
16. Pfister, J.; Wymann, W. Synthesis 1983, 38–40.
´
Tetrahedron: Asymmetry 2006, 17, 1863–1866; (i) Alibes, R.;
Blanco, P.; Casas, P.; Montserrat, C.; de March, P.; Figue-
redo, M.; Font, J.; Sanfeliu, E.; Alvarez-Larena J. Org.
Chem. 2005, 70, 3157–3167.
4. (a) Broggini, G.; De Marchi, I.; Martinelli, M.; Zecchi, G. In
Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D.,
Eds.; SCI: Rome, 2005; Vol. 9, pp 211–229; (b) Wang, P.-F.;
Gao, P.; Xu, P.-F. Synlett 2006, 1095–1099.
5. (a) Broggini, G.; Chiesa, K.; De Marchi, I.; Martinelli, M.;
Pilati, T.; Zecchi, G. Tetrahedron 2005, 61, 3525–3531; (b)
Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. A. J. Org.
Chem. 2003, 68, 8739–8741; (c) Zhao, Q.; Han, F.; Romero,
D. L. J. Org. Chem. 2002, 67, 8669–8672; (d) Tamura, O.;
Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima, R.;
Kikuchi, M.; Miyawaki, T.; Mita, N.; Yamashita, M.;
Ishibashi, H.; Sakamoto, M. J. Org. Chem. 2000, 65, 8544–
8551; (e) Beccalli, E. M.; Broggini, G.; La Rosa, C.;
Passarella, D.; Pilati, T.; Terraneo, A.; Zecchi, G. J. Org.
Chem. 2000, 65, 8924–8932; (f) Arnone, A.; Broggini, G.;