Application of a cross-metathesis and intramolecular aza-diels-alder sequence to the synthesis of trans -2,3-disubstituted tetrahydroquinolines

Article abstract of DOI:10.1055/s-0031-1289790

The synthesis of 2,3-disubstituted tetrahydroquinolines has been achieved by first performing a cross-metathesis of different alkenes with readily available N-allyloxycarbonyl-2-chloromethylaniline. Among the catalysts tested, Hoveyda-Grubbs reagent appeared to be the most suitable, reaching the substituted analogues with complete E-stereocontrol and convenient yields. An intramolecular aza-Diels-Alder reaction was further carried out in the presence of potassium phosphate as promoter to deliver the corresponding 2,3-disubstituted tetrahydroquinolines. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289790

PAPER
▌2431
paper
Application of a Cross-Metathesis and Intramolecular Aza-Diels–Alder
Sequence to the Synthesis of trans-2,3-Disubstituted Tetrahydroquinolines
trans-2,3-Disubstituted Tetrahydroquinolines
Sophie Feuillastre, Vincent Pellet, Olivier Piva*
Université de Lyon - Université Lyon 1, Institut de Chimie et de Biochimie Moléculaire et Supramoléculaire (ICBMS) - UMR 5246 CNRS,
Equipe SURCOOF - Bat Raulin, 43, Bd du 11 novembre 1918, 69622 Villeurbanne cedex, France
Fax +33(0)472448136; E-mail: piva@univ-lyon1.fr
Received: 12.04.2012; Accepted after revision: 11.05.2012
however, this route does not meet the criteria of supplying
Abstract: The synthesis of 2,3-disubstituted tetrahydroquinolines
diversity in organic chemistry.8 Aza-Diels–Alder reac-
has been achieved by first performing a cross-metathesis of differ-
tions also seem a very attractive way to build the hetero-
ent alkenes with readily available N-allyloxycarbonyl-2-chloro-
methylaniline. Among the catalysts tested, Hoveyda–Grubbs
cycle moiety.9 As pericyclic reactions, high level of
reagent appeared to be the most suitable, reaching the substituted stereocontrol should also be expected. Furthermore, the
analogues with complete E-stereocontrol and convenient yields. An
intramolecular aza-Diels–Alder reaction was further carried out in
the presence of potassium phosphate as promoter to deliver the cor-
ies. Ferraccioli et al. reported the thermal decomposition
responding 2,3-disubstituted tetrahydroquinolines.
acyclic precursors could be prepared from readily avail-
able compounds as already pointed out in previous stud-
of benzoxazin-2-one to generate aza-orthoxylylene,
Key words: cross-metathesis, azaxylylenes, cycloadditions, Diels–
Alder reaction
which further reacted in either an inter- or intramolecular
manner with dienophiles.10 The latter strategy was consid-
ered for the total synthesis of 3 by Steinhagen and Corey11
and, more recently, by Bräse et al.12 The Bräse group stud-
The tetrahydroquinoline heterocycle is a very important
subunit that is found in a large number of biologically ac-
ied in detail the reaction of 4 under thermal conditions and
developed an efficient route to the tricyclic oxazolidinone
tive compounds with a large range of activities.1,2 Galipi-
nine (1; Figure 1), for example, has been isolated from
Galipea officinalis trunk bark and exhibits activity against
plasmodium falciparum, the protozoan parasite responsi-
ble of malaria;3 the synthetic compound 2, known as
SL 25.1131, is a reversible monoamine oxidase that is
structurally related to befloxatone and has shown real
therapeutic potential in the early phase of treatment
against Parkinson’s disease.4 Virantmycin (3), an antiviral
agent, also possesses a highly functionalized tetrahydro-
quinoline ring.5
6 (Scheme 1).13 Finally, it should be mentioned that a pho-
tochemical activation based on a sigmatropic hydrogen
shift was recently reported by Kutateladze et al. from par-
ent benzaldehyde structures.14
X
N
N
NH
O
O
O
O
O
O
6
5
4
Scheme 1 Access to tetrahydroquinolines by aza-Diels–Alder reac-
tion
O
N
H
O
1
Cross-metathesis is a very useful process for the synthesis
of 1,2-disubstituted alkenes when performed with two ter-
minal olefins.15 Thanks to the discovery of powerful cata-
lysts such as Grubbs type II (GBII) and Hoveyda–Grubbs
(HG) catalysts (Figure 2), which tolerate numerous func-
tionalities, this reaction has been applied to the synthesis
of complex structures and natural products albeit far less
often than the related ring closure.16,17
O
Cl
HO2C
N
N
H
OMe
CF3
O
MeO
O
2
3
Figure 1 Naturally occurring tetrahydroquinolines
Control of the E/Z selectivity in cross-metathesis has re-
mained a problem until recently. In the presence of the
catalysts mentioned above, formation of the thermody-
namically preferred isomer – usually E – is observed. In-
terestingly, the recent design of efficient catalysts by
Hoveyda and colleagues and Grubbs and co-workers al-
lows formation of the Z-isomer.18,19 In connection with
our interest in metathesis processes and their direct appli-
cations in total synthesis,20 we have investigated a two-
To date, numerous methods have been reported to access
these heterocycles.6,7 Among them, selective reduction of
quinolines seems the most straightforward approach,
SYNTHESIS 2012, 44, 2431–2435
Advanced online publication: 20.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289790; Art ID: SS-2012-T0358-OP
© Georg Thieme Verlag Stuttgart · New York

2432
S. Feuillastre et al.
PAPER
In contrast, when the same reaction was conducted with
chloro-derivative 4b and catalyzed with HG16b the expect-
ed adducts were furnished in reasonable yields and reac-
tion times with complete E-selectivity in all cases (Table
1). Concerning the [4+2] cycloaddition step, previous
studies had revealed that use of cesium carbonate as the
base could promote the formation of the tricyclic tetrahy-
droquinoline 6 from 4b.12 In order to find a less expensive
and less hygroscopic reagent and also to decrease the re-
action time, we examined new conditions using the same
unsubstituted starting material; the results are reported in
Table 2.
N
N
Mes
Mes
N
N
Cl
Cl
Mes
Mes
Ph
Ru
Cl
Cl
Ru
O
PCy3
GBII
HG
Figure 2 Ruthenium-based catalysts used for this study
step approach to the synthesis of 2,3-disubstituted tetrahy-
droquinolines by a thermal [4+2] cycloaddition from re-
lated substituted carbamates. To readily prepare these
structures, it was anticipated that a cross-metathesis from
compounds 4a and 4b and various alkenes could allow the
expected functionalization of the olefinic moiety to be in-
troduced before the cycloaddition step (Scheme 2).
Table 2 Optimization of the Synthesis of 6 from 4b
Cl
N
NH
O
O
R
O
O
X
4b
6
R
R
+
Base
Equiv Solvent
Temp (°C) Time (d) Yield (%)
N
N
NH
O
O
Cs2CO3
Cs2CO3
guanidine
KF, Al2O3
K3PO4
3
3
3
3
3
5
5
CH2Cl2
DCE
23
80
3
16 h
3
70
86
0
O
O
O
O
7
4a (X = OH)
4b (X = Cl)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
23
Scheme 2 Strategy adopted for the synthesis of 2,3-tetrahydroquin-
a
23
3
–
olines
23
7
88
82
89
Compound 4a (X = OH), which was easily prepared from
commercially available o-amino benzyl alcohol and allyl
chloroformate,13 was first tested for cross-metatheses.
However, in the presence of GBII or HG catalyst, only low
conversion was observed even after a long reaction time.
K3PO4
23
3
K3PO4
110b
2 h
a Degradation of the starting material.
b Reaction performed under microwave activation.
Table 1 Cross-Metathesis of 4b with Alkenes 8a–g
As previously reported, reactions promoted by cesium
carbonate delivered compound 6 in high yields. When the
reaction was performed in dichloromethane at room tem-
perature for three days in the presence of potassium tri-
phosphate, compound 6 was isolated with a similar
chemical yield. This value was slightly improved to 89%
under microwave activation, indeed the reaction time was
significantly reduced to only two hours. Classic thermal
activation and microwave-assisted reactions were applied
to compounds 7a–g (Table 3). The cycloaddition proceed-
ed efficiently with aryl derivatives (Table 3, entries 1–5).
In all cases, a single stereoisomer was isolated, for which
a trans relationship was assigned and confirmed by NOE
measurements. In comparison with previous attempts at
the synthesis of 6, microwave activation applied to 7c
gave lower yields.
Cl
Cl
R
8a–g
R
NH
NH
HG (5 + 2 mol%)
CH2Cl2, 40 °C, 16 h
O
O
O
O
4b
(E)-7a–g
8
R
Conv. (%)
7
Yield (%)a
8a
8b
8c
8d
8e
8f
Ph
65
74
7a
7b
7c
7d
7e
7f
37
32
63
49
62
80
71
p-F3CC6H4
m-F3CC6H4
n-Bu
100
77
n-Hex
84
In contrast, substrates 7d and 7e, possessing an alkyl moi-
ety, furnished the expected tetrahydroquinolines in very
low yields with formation of a large number of side prod-
ucts being observed by TLC analysis.
Ac
100
95
8g
p-MeC6H4CO
7g
a Isolated yield.
Synthesis 2012, 44, 2431–2435
© Georg Thieme Verlag Stuttgart · New York

PAPER
trans-2,3-Disubstituted Tetrahydroquinolines
2433
reaction. Best results were obtained by using Hoveyda–
Grubbs catalyst for the first step, whereas inexpensive and
non-hygroscopic potassium phosphate was used as base
for the generation of the azaxylylene intermediate.
Table 3 Intramolecular Thermal Cycloadditions of Esters 7a–g
Cl
R
K3PO4
(5 equiv)
R
N
NH
CH2Cl2, r.t.
O
O
All commercially available compounds were used without further
purification. Solvents were dried according to standard procedures.
Petroleum ether (PE) refers to a hydrocarbon mixture with a boiling
range of 40–60 °C. Column chromatography was performed with
silica gel (0.040–0.063 mm, ROTH). NMR spectra were recorded
at 293 K, using a 300 MHz spectrometer (Bruker, AMX 300); shifts
are referenced relative to deuterated solvent residual peaks. High-
resolution mass spectra (HRMS) were recorded in the positive
mode with a Bruker MicrOTOF-Q II XL spectrometer. Infrared
spectra were recorded with a Nicolet IS 100 spectrometer. Melting
points were recorded with a B-540 Büchi melting point apparatus.
O
O
7a–g
9a–g
Entry
7
R
Temp (°C) Time (d) 9 (%)a
1
2
3
4
5
6
7
8
9
7a
Ph
Ph
23
23
7
56
51b
45
66
54c
11
8
7a
7b
7c
7c
7d
7e
7f
3
p-F3CC6H4
m-F3CC6H4
m-F3CC6H4
n-Bu
23
7
23
7
Cross-Metathesis Reaction; General Procedure
100
23
2 h
7
To a solution of (2-chloromethylphenyl)carbamic acid allyl ester
(4b; 1 equiv) and the corresponding alkene derivative 8 in anhy-
drous CH2Cl2 (0.1 M) under an argon atmosphere, was added sec-
ond-generation Hoveyda–Grubbs catalyst (5 mol%). The reaction
mixture was stirred at reflux under an argon atmosphere for 3 h be-
fore adding further second-generation Hoveyda–Grubbs catalyst
(2 mol%) and the reaction mixture was stirred at reflux overnight.
The solvent was removed in vacuo and the residue was purified by
silica gel flash chromatography (PE–EtOAc, 9:1) to afford the de-
sired compound 7.
n-Hex
23
7
Ac
23
7
71
62
7g
p-MeC6H4CO
23
7
a Isolated yield.
b Reaction performed with Cs2CO3 as base.
c Reaction performed under microwave activation.
Cinnamyl (E)-(2-Chloromethylphenyl)carbamate (7a)
Yield: 157 mg [37%; isolated from 4b (305 mg)]; white solid; mp
70–74 °C.
We assumed that under continuous heating and basic con-
ditions, these substrates underwent a hydrogen atom ab-
straction leading, after allylic rearrangement and β-
elimination, to cleavage of the carbamate moiety (Scheme
3). Interestingly, compounds (E)-7f and (E)-7g, bearing
an electron-withdrawing group, were smoothly converted
into the tricyclic ketones 9f and 9g, respectively, in high
yields.
IR (neat): 3286, 3025, 1689, 1590, 1530, 1458, 1297, 1246,
966 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.86 (s, 1 H), 7.43–7.24 (m, 7 H),
7.11 (dd, J = 7.5 Hz, 1 H), 6.99 (s, 1 H), 6.72 (d, J = 15.4 Hz, 1 H),
6.36 (dt, J = 6.6, 15.4 Hz, 1 H), 4.85 (dd, J = 1.3, 6.6 Hz, 2 H), 4.63
(s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 160.7, 136.8, 136.3, 134.6, 132.7,
130.3, 130.2, 128.8, 128.3, 126.8, 124.6, 123.4, 66.3, 44.2.
HRMS (ESI): m/z [M + Na+] calcd for C17H16ClNNaO2: 324.0762;
found: 324.0766.
Cl
Cl
Cl
p-Trifluoromethylcinnamyl (E)-(2-Chloromethylphenyl)carba-
mate (7b)
R
Yield: 104 mg [32%; isolated from 4b (200 mg)]; beige solid; mp
102–104 °C.
IR (neat): 3273, 2923, 1697, 1533, 1330, 1249, 1127, 1067 cm–1.
N
N
H
O
N
O
O
O
O
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 7.6 Hz, 1 H), 7.59 (d,
J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.44–7.35 (m, 1 H), 7.30
(dd, J = 1.4, 7.6 Hz, 1 H), 7.12 (t, J = 7.6 Hz, 1 H), 7.00 (br s, 1 H),
6.74 (d, J = 16.0 Hz, 1 H), 6.45 (dt, J = 6.2, 16.0 Hz, 1 H), 4.87 (dd,
J = 1.3, 6.2 Hz, 2 H), 4.63 (s, 2 H).
O
R
R
H
7d–e
Cl
Cl
13C NMR (75 MHz, CDCl3): δ = 153.7, 137.1, 136.7, 132.7, 130.3,
130.2, 129.9, 129.2, 125.5, 124.8, 124.7, 123.3, 122.4, 65.7, 44.1.
19F NMR (282 MHz, CDCl3): δ = –63.2.
+
CO2
NH
NH2
HRMS (ESI): m/z [M + Na+] calcd for C18H15ClF3NNaO2:
392.0636; found: 392.0624.
R
O
O
m-Trifluoromethylcinnamyl (E)-(2-Chloromethylphenyl)car-
Scheme 3 Competitive allylic rearrangement and β-elimination
bamate (7c)
Yield: 107 mg [63%; isolated from 4b (105 mg)]; beige solid; mp
83–84 °C.
In conclusion, we have reported the synthesis of 3-substi-
tuted oxazolidinotetrahydroquinolines by merging a
cross-metathesis and an intramolecular aza-Diels–Alder
IR (neat): 3282, 1694, 1591, 1532, 1458, 1336, 1299, 1251, 1165,
1120, 967 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2431–2435

2434
S. Feuillastre et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 7.9 Hz, 1 H), 7.45–
7.59 (m, 4 H), 7.39 (dd, J = 7.5, 7.9 Hz, 1 H), 7.30 (d, J = 7.5 Hz,
1 H), 7.09 (dd, J = 7.5, 7.5 Hz, 1 H), 6.99 (br s, 1 H), 6.74 (d, J =
15.8 Hz, 1 H), 6.43 (dt, J = 6.4, 15.8 Hz, 1 H), 4.87 (d, J = 6.4 Hz,
2 H), 4.63 (s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 153.7, 137.1, 136.7, 132.7, 130.3,
130.2, 129.9, 129.2, 125.5, 124.8, 124.7, 123.3, 122.4, 65.7, 44.1.
13C NMR (75 MHz, CDCl3): δ = 189.6, 153.3, 144.2, 140.8, 136.5,
134.9, 130.31, 130.25, 129.5, 128.9, 126.2, 125.0, 123.3, 64.4, 44.1,
21.8.
HRMS (ESI): m/z [M + Na+] calcd for C19H18ClNNaO3: 366.0867;
found: 366.0868.
Diels–Alder Reaction; General Procedure
To a solution of ester 7 (1 equiv) in anhydrous CH2Cl2 (0.1 M) was
added tripotassium phosphate (5 equiv). The reaction mixture was
stirred at r.t. under a nitrogen atmosphere for 7 d. After the excess
of K3PO4 was filtered off over Celite, the solvent was removed in
vacuo and the residue was purified by silica gel flash chromatogra-
phy (PE–EtOAc, 8:2) to afford the desired tetrahydroquinoline de-
rivatives 9.
19F NMR (282 MHz, CDCl3): δ = –63.2.
HRMS (ESI): m/z [M + Na+] calcd for C18H15ClF3NNaO2:
392.0636; found: 392.0624.
2-Heptenyl (E)-(2-Chloromethylphenyl)carbamate (7d)
Yield: 182 mg [49%; isolated from 4b (298 mg)]; white foam.
IR (neat): 2928, 1736, 1591, 1524, 1455, 1214 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.84 (d, J = 7.6 Hz, 1 H), 7.36 (dd,
J = 7.6, 7.6 Hz, 1 H), 7.27 (d, J = 7.6 Hz, 1 H), 7.10 (dd, J = 7.6,
7.6 Hz, 1 H), 6.92 (s, 1 H), 5.83 (dt, J = 6.6, 15.5 Hz, 1 H), 5.64 (dt,
J = 6.8, 15.5 Hz, 1 H), 4.62 (d, J = 6.6 Hz, 2 H), 4.61 (s, 2 H), 2.07
(dt, J = 6.8, 6.8 Hz, 2 H), 1.27–1.39 (m, 4 H), 0.90 (t, J = 7.1 Hz,
3 H).
13C NMR (75 MHz, CDCl3): δ = 153.8, 137.2, 136.9, 130.2, 130.1,
124.5, 123.9, 66.5, 44.1, 32.1, 31.1, 22.3, 14.0.
HRMS (ESI): m/z [M + Na+] calcd for C15H20ClNNaO2: 304.1075;
found: 304.1069.
4-Phenyl-3,3a,4,5-tetrahydrooxazolo[3,4-a]quinolin-1-one (9a)
Yield: 63 mg [56%; isolated from 7a (133 mg)]; white solid; mp
138–139 °C.
IR (neat): 2922, 1753, 1493, 1396, 1218, 1136, 756 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.22 (d, J = 8.3 Hz, 1 H), 7.14–
7.35 (m, 6 H), 7.09 (d, J = 7.3 Hz, 1 H), 7.00 (dd, J = 7.3, 7.3 Hz,
1 H), 4.21 (m, 2 H), 3.92 (t, J = 7.7 Hz, 1 H), 3.03 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 154.4, 140.5, 134.6, 129.4, 129.1,
128.1, 127.6, 127.5, 125.2, 123.7, 118.4, 66.3, 58.4, 43.7, 35.9.
HRMS (ESI): m/z [M + H+] calcd for C17H16NO2: 266.1176; found:
266.1164.
2-Nonenyl (E)-(2-Chloromethylphenyl)carbamate (7e)
Yield: 279 mg [62%; isolated from 4b (327 mg)]; white foam.
IR (neat): 3296, 2927, 2855, 1728, 1591, 1526, 1456, 1214 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.85 (d, J = 7.5 Hz, 1 H), 7.37 (dd,
J = 7.5, 7.5 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1 H), 7.09 (dd, J = 7.5,
7.5 Hz, 1 H), 6.92 (s, 1 H), 5.83 (dt, J = 6.6, 15.2 Hz, 1 H), 5.64 (dt,
J = 6.4, 15.2 Hz, 1 H), 4.62 (d, J = 6.6 Hz, 2 H), 4.61 (s, 2 H), 2.10
(m, 2 H), 1.29–1.40 (m, 8 H), 0.89 (t, J = 6.8 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 153.8, 137.2, 137.1, 130.2, 130.1,
124.5, 123.9, 66.5, 44.1, 32.4, 31.8, 28.9, 22.7, 14.2.
HRMS (ESI): m/z [M + Na+] calcd for C17H24ClNNaO2: 332.1388;
found: 332.1387.
4-(p-Trifluoromethyl)phenyl-3,3a,4,5-tetrahydrooxazolo [3,4-
a]quinolin-1-one (9b)
Yield: 42 mg [45%; isolated from 7b (102 mg)]; white solid; mp
211–213 °C.
IR (neat): 2923, 1755, 1494, 1398, 1325, 1125, 1067 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.29 (d, J = 8.3 Hz, 1 H), 7.48 (d,
J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.32 (dd, J = 7.5, 8.3 Hz,
1 H), 7.16 (d, J = 7.5 Hz, 1 H), 7.08 (dd, J = 7.5, 7.5 Hz, 1 H), 4.32
(m, 2 H), 3.97 (t, J = 7.5 Hz, 1 H), 3.15 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 154.4, 140.5, 134.6, 129.9, 129.1,
128.1, 127.8, 126.5, 124.6, 123.9, 118.6, 66.0, 58.2, 43.7, 35.9.
19F NMR (282 MHz, CDCl3): δ = –63.1.
4-Oxopent-2-enyl (E)-(2-Chloromethylphenyl)carbamate (7f)
Yield: 330 mg [80%; isolated from 4b (347 mg)]; brown foam.
HRMS (ESI): m/z [M + H+] calcd for C18H15F3NO2: 334.1049;
found: 334.1047.
IR (neat): 3356, 1708, 1670, 1592, 1526, 1456, 1298, 1232, 979
cm–1.
4-(m-Trifluoromethyl)phenyl-3,3a,4,5-tetrahydrooxazolo[3,4-
a]quinolin-1-one (9c)
Yield: 57 mg [66%; isolated from 7c (95 mg)]; beige solid; mp 181–
182 °C.
1H NMR (300 MHz, CDCl3): δ = 7.82 (d, J = 7.9 Hz, 1 H), 7.38 (td,
J = 1.5, 7.9 Hz, 1 H), 7.30 (dd, J = 1.5, 7.6 Hz, 1 H), 7.12 (td, J =
7.6, 1 H), 7.07 (s, 1 H), 6.82 (dt, J = 4.7, 16.1 Hz, 1 H), 6.31 (d, J =
16.1 Hz, 1 H), 4.88 (dd, J = 1.9, 4.7 Hz, 2 H), 4.63 (s, 2 H), 2.30 (s,
3 H).
IR (neat): 2924, 2846, 1737, 1495, 1399, 1333, 1219, 1122,
1073 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.29 (d, J = 7.5 Hz, 1 H), 7.62 (d,
J = 7.9 Hz, 1 H), 7.55 (dd, J = 7.5, 7.9 Hz, 1 H), 7.48 (s, 1 H), 7.43
(d, J = 7.5 Hz, 2 H), 7.16 (d, J = 7.5 Hz, 1 H), 7.08 (dd, J = 7.5,
7.5 Hz, 1 H), 4.34 (m, 2 H), 3.97 (t, J = 7.5 Hz, 1 H), 3.12 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ = 197.9, 153.8, 140.2, 131.1, 130.3,
130.2, 63.8, 44.0, 27.5.
HRMS (ESI): m/z [M + Na+] calcd for C13H14ClNNaO3: 290.0554;
found: 290.0561.
13C NMR (75 MHz, CDCl3): δ = 154.4, 140.5, 134.5, 131.1, 130.0,
129.1, 127.7, 124.6, 124.3, 123.9, 118.5, 66.0, 58.1, 43.6, 35.9.
19F NMR (282 MHz, CDCl3): δ = –63.1.
HRMS (ESI): m/z [M + H+] calcd for C18H15F3NO2: 334.1049;
found: 334.1056.
4-Oxo-4-toluylbut-2-enyl (E)-(2-Chloromethylphenyl)carba-
mate (7g)
Yield: 217 mg [71%; isolated from 4b (200 mg)]; beige solid; mp
116–117 °C.
IR (neat): 3263, 1692, 1668, 1530, 1295, 1251, 1088, 960 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 8.2 Hz, 2 H), 7.85 (s,
1 H), 7.46–7.38 (m, 1 H), 7.34 (dd, J = 7.8, 1.4 Hz, 1 H), 7.32–7.28
(m, 3 H), 7.20–7.13 (m, 2 H), 7.07 (dt, J = 4.2, 15.5 Hz, 1 H), 4.99
(dd, J = 4.2, 1.2 Hz, 2 H), 4.67 (s, 2 H), 2.44 (s, 3 H).
4-Butyl-3,3a,4,5-tetrahydrooxazolo[3,4-a]quinolin-1-one (9d)
Yield: 18 mg [11%; isolated from 7d (188 mg)]; yellow oil.
IR (neat): 2956, 2927, 1745, 1493, 1459, 1401, 1224, 1135, 969
cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 8.0 Hz, 1 H), 7.22 (d,
J = 8.0 Hz, 1 H), 7.13 (d, J = 7.5 Hz, 1 H), 7.04 (td, J = 1.1, 7.5 Hz,
Synthesis 2012, 44, 2431–2435
© Georg Thieme Verlag Stuttgart · New York

PAPER
trans-2,3-Disubstituted Tetrahydroquinolines
References
2435
1 H), 4.50 (t, J = 8.0 Hz, 1 H), 4.39–4.27 (m, 1 H), 4.26 (dd, J = 6.3,
8.0 Hz, 1 H), 3.01 (dd, J = 5.0, 16.8 Hz, 1 H), 2.86 (dd, J = 2.1,
16.8 Hz, 1 H), 1.95 (ddd, J = 2.1, 5.0, 10.2 Hz, 1 H), 1.51–1.01 (m,
6 H), 0.87 (t, J = 7.0 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 155.1, 135.0, 130.1, 127.2, 123.94,
123.85, 118.9, 64.2, 57.6, 33.2, 31.6, 29.9, 24.2, 22.9, 14.2.
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HRMS (ESI): m/z [M + Na+] calcd for C15H19NNaO2: 268.1308;
found: 268.1309.
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Marc, C.; Lolivier, J.; Gardes, A.; Perron, C.; Le Kim, A.;
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4-Hexyl-3,3a,4,5-tetrahydrooxazolo[3,4-a]quinolin-1-one (9e)
Yield: 19 mg [8%; isolated from 7e (269 mg)]; yellow oil.
IR (neat): 2927, 1746, 1493, 1401, 1224, 1136, 963 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 8.2 Hz, 1 H), 7.27–
7.20 (m, 1 H), 7.12 (d, J = 7.5 Hz, 1 H), 7.04 (td, J = 1.1, 7.5 Hz,
1 H), 4.50 (t, J = 8.0 Hz, 1 H), 4.36–4.29 (m, 1 H), 4.26 (dd, J = 6.4,
8.0 Hz, 1 H), 3.01 (dd, J = 5.1, 16.9 Hz, 1 H), 2.85 (dd, J = 1.7,
16.9 Hz, 1 H), 1.95 (ddd, J = 1.7, 5.1, 10.2 Hz, 1 H), 1.52–0.97 (m,
10 H), 0.86 (t, J = 6.9 Hz, 3 H).
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13C NMR (75 MHz, CDCl3): δ = 155.1, 135.0, 130.1, 127.2, 123.94,
123.86, 118.9, 64.2, 57.6, 33.2, 31.9, 31.7, 29.5, 27.6, 24.5, 22.7,
14.2.
HRMS (ESI): m/z [M + H+] calcd for C17H24NO2: 274.1802; found:
274.1805.
4-Acetyl-3,3a,4,5-tetrahydrooxazolo[3,4-a]quinolin-1-one (9f)
Yield: 122 mg [71%; isolated from 7f (198 mg)]; white solid; mp
161–162 °C.
IR (neat): 2910, 1747, 1708, 1583, 1499, 1460, 1398, 1318, 1254,
973 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.26 (d, J = 8.0 Hz, 1 H), 7.27 (t,
J = 8.0 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 7.12–7.00 (m, 1 H), 4.78
(t, J = 8.8 Hz, 1 H), 4.24 (q, J = 8.5 Hz, 1 H), 3.99 (t, J = 8.8 Hz,
1 H), 3.21–3.38 (m, 1 H), 2.98–2.85 (m, 2 H), 2.32 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 207.7, 154.4, 134.5, 129.1, 127.9,
123.8, 123.1, 118.5, 67.2, 54.7, 50.7, 30.5, 28.7.
HRMS (ESI): m/z [M + Na+] calcd for C13H13NNaO3: 254.0788;
found: 254.0783.
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4-(p-Toluyl)carbonyl-3,3a,4,5-tetrahydrooxazolo[3,4-a]quino-
lin-1-one (9g)
Yield: 119 mg [62%; isolated from 7g (214 mg)]; white solid; mp
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228–229 °C.
IR (neat): 2920, 1747, 1667, 1605, 1494, 1403, 1309, 1227, 1142,
972 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.27 (d, J = 7.9 Hz, 1 H), 7.88 (d,
J = 8.2 Hz, 2 H), 7.37–7.27 (m, 3 H), 7.12–7.01 (m, 2 H), 4.82–4.68
(m, 1 H), 4.54 (dt, J = 8.0, 10.0 Hz, 1 H), 4.01 (dd, J = 8.0, 9.0 Hz,
1 H), 3.80 (ddd, J = 5.0, 10.1, 12.8 Hz, 1 H), 3.26 (dd, J = 5.0,
16.7 Hz, 1 H), 3.01 (dd, J = 12.8, 16.7 Hz, 1 H), 2.45 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 199.5, 154.5, 145.6, 134.6, 132.9,
130.0, 129.0, 128.8, 127.9, 123.81, 123.76, 118.7, 66.9, 55.5, 45.5,
32.8, 21.9.
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1993.
HRMS (ESI): m/z [M + Na+] calcd for C19H17NNaO3: 330.1101;
found: 330.1096.
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Acknowledgment
Funding for this project was provided by a grant to S.F. from le
Région Rhône-Alpes (Program Cible 2011–2014). Support from
the Université de Lyon and CNRS are also warmly acknowledged.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2431–2435