Hydrogenation of ortho-nitrochalcones over Pd/C as a simple access to 2-substituted 1, 2, 3, 4-tetrahydroquinolines

Article abstract of DOI:10.1016/j.tet.2010.05.090

The preparation of some 2-substituted-1, 2, 3, 4-tetrahydroquinoline has been achieved by the one-pot reductive intramolecular cyclization of ortho-nitrochalcones with gaseous hydrogen in the presence of a Pd/C catalyst and the best selectivity was observed using CH₂Cl₂ as solvent. The method is operationally simple and versatile since ortho-nitrocalchones are easily accessible by Claisen-Schmidt condensation of 2-nitrobenzaldehydes and enolizable ketones. Selected examples on structurally different substrates have been considered and a novel tetrahydroquinoline and a benzo[h]tetrahydroquinoline were prepared and characterised.

Full text of DOI:10.1016/j.tet.2010.05.090

Tetrahedron 66 (2010) 5607e5611
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydrogenation of ortho-nitrochalcones over Pd/C as a simple access
to 2-substituted 1,2,3,4-tetrahydroquinolines
*
Angela Patti , Sonia Pedotti
Istituto di Chimica Biomolecolare del CNR, Via Paolo Gaifami, 18 95126 Catania, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The preparation of some 2-substituted-1,2,3,4-tetrahydroquinoline has been achieved by the one-pot
reductive intramolecular cyclization of ortho-nitrochalcones with gaseous hydrogen in the presence of
a Pd/C catalyst and the best selectivity was observed using CH2Cl2 as solvent. The method is operationally
simple and versatile since ortho-nitrocalchones are easily accessible by ClaiseneSchmidt condensation of
2-nitrobenzaldehydes and enolizable ketones. Selected examples on structurally different substrates
have been considered and a novel tetrahydroquinoline and a benzo[h]tetrahydroquinoline were prepared
and characterised.
Received 2 March 2010
Received in revised form 30 April 2010
Accepted 24 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
asymmetric induction in metal-promoted or organocatalytic
hydrogenations.14
Quinolines and the related tetrahydroquinolines derivatives
constitute a group of heterocycles largely occurring in plants and
microorganism1 whose main importance resides in their broad
range of biological activities. They have been reported as anti-
bacteric,2 fungicide3 or pesticide agents4 and their inhibiting or
antagonist properties towards specific enzymes or receptors in-
volved in human diseases make them promising compounds in
anticancer,5 antidepressive,6 antiinflammatory7 and antidiabetes8
therapies. Quinoline-based compounds, e.g., quinine or chloro-
quine, have been widely employed as effective and cheap antima-
larial drugs, but a continuous effort is directed toward the
development of related molecules in order to overcome chemo-
resistance problems.9
The 2-substituted 1,2,3,4-tetrahydroquinoline platform has
been recently used in the design of selective estrogen receptor
modulators10 and inhibitors of the cholesteryl ester transfer pro-
tein,11 whose activity can be potentially exploited for the treatment
of estrogen responsive cancer and osteoporosis or in the ther-
apeutical control of the blood level of cholesterol.
The synthesis of different functionalised THQs has been also
accomplished by multicomponent aza-DielseAlder reaction in the
presence of various Lewis acid catalysts15 or by intramolecular
cyclization of suitable designed amino-16 or nitro-17 aromatic
compounds. In this context, we developed a simple and versatile
method for the preparation of 2-substituted THQs starting from
ortho-nitrochalcones and the obtained results are here reported.
2. Results and discussion
In a recent paper Barros et al.18 have reported that ortho-nitro-
chalcones can be subjected to a reductive intramolecular coupling
to afford mixtures of quinolines and quinolines N-oxides using
ammonium formate as the hydrogen source and Pd/C as catalyst
and the reaction course was found to be substrate-dependent, so
that in some cases only the reduction of nitrogroup without further
cyclization occurred. However, the same strategy could be useful to
prepare THQs from ortho-nitrocalchones under one-pot hydroge-
nation conditions following the different routes depicted in
Scheme 1. In both cases when the reduction of the ethylenic bond
occurs as first reaction step (path A), or the hydrogenation of an
intermediate aminocalchone proceeds at higher reaction rate with
respect to its cyclization (path B1) a saturated aminoketone as 5a
could be formed as suitable substrate for the subsequent formation
of 3,4-dihydroquinoline, further hydrogenated to THQ. Since aro-
matic quinolines could be also produced (path B2) as final products
or as other reducible intermediates contributing to the formation of
THQ, the competitive hydrogenation/cyclization routes should lead
to different quinoline/THQ ratios. So, we decided to investigate the
Among the different methods available for the synthesis of
1,2,3,4-tetrahydroquinolines (THQs),12 the selective reduction of
nitrogen ring in quinoline derivatives13 has been applied and its
enantioselective version represents the method of choice for the
preparation of chiral THQs, thanks to the development of different
phosphorous-based catalysts displaying excellent levels of
* Corresponding author. Tel.: þ39 0957338328; fax: þ39 0957338310; e-mail
address: angela.patti@icb.cnr.it (A. Patti).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.090

5608
A. Patti, S. Pedotti / Tetrahedron 66 (2010) 5607e5611
path B2
N
R
O
3a
R =Ph
R
path B
path B1
NH2
O
O
4a R =Ph
R
R
NO2
NH2
N
H
R
1a
5a
R =Ph
R =Ph
2a
R =Ph
O
R
path A
NO2
Scheme 1. Possible cyclization under hydrogenation conditions.
hydrogenation reaction of 1a in search of the optimal conditions for
the selective formation of 2a.
With Pd/C catalyst (10% w/w) and gaseous H2 (1.2 atm) the sub-
strate was firstly converted in a mixture of different compounds
that converged after 12 h to tetrahydroquinoline 2a and quinoline
3a in 1:1 ratio (entry 1), as the result of a similar reaction rates for
both path B1 and path B2 shown in Scheme 1.
Using the same Pd/C catalyst and excess of ammonium formate
as hydrogen source, 3a was obtained as main product (entry 2) and
no quinoline N-oxide was detected in the reaction mixture, con-
trary to the reported data.18 The observed reaction outcome, that
could be related with a strongly favoured cyclization rather than
hydrogenation of 4a, seems to be substrate-specific since in the
same conditions the ethylenic bond of 1,3-diphenyl-2-propenone
was reduced in quantitative yield.
The synthesis of chalcones is usually accomplished by Clai-
seneSchmidt condensation of enolizable ketones and benzalde-
hydes in the presence of a base or a Lewis acid and solvent-free or
microwave-assisted modified methods have been also reported.19
Different procedures for the condensation of acetophenone and 2-
nitrobenzaldehyde were tested and it was found that the reaction
in the presence of 40% ZrCl4 at 40 ꢀC for 20 h afforded the best
result giving nitrochalcone 1a in 85% yield, easily obtained as
pure compound by crystallization. When the ZrCl4 percentage was
decreased as reported in the original procedure,19d significant
amount of the aldol product was isolated from the reaction
mixture.
In the presence of Pd(OH)2/C and H2 1a gave a complex mixture
of aromatic products, none of which was predominant, whereas Ni/
Raney catalyst induced good selectivity affording a 9:1 mixture of
2a and 3a (entry 4) in acceptable chemical yield.
Compound 1a was then subjected to hydrogenation in MeOH in
the presence of different metal catalysts and the composition of the
reaction mixtures was determined by 1H NMR analysis (Table 1).
Table 1
Hydrogenation of 1a in different systemsa
O
4
5
8
6
3
2'
5'
6
7
Catalyst
3
2
5
4
3'
4'
6'
+
Hydrogen donor
2'
5'
N
H
NO2
3'
4'
N
6'
1a
2a
3a
Entry
Catalyst
H2 source
Solvent
Time (h)
2a/3ab
2ac (%)
1
2
3
4
5
6
7
8
9
Pd/C
Pd/C
Pd(OH)2
Ni Raney
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
H2
HCOONH4
MeOH
MeOHd
MeOH
MeOH
12
3
50/50
8/92
de
45
6
H2
H2
H2
H2
H2
H2
H2
20
20
20
20
20
4
d
75
78
85
85
84
58
86
90/10
85/15
95/5
95/5
93/7
82/18
95/5
Toluene
THFf
EtOAc
CH2Cl2
CH2Cl2
g
4
2
h
10
Pd/C
H2
CH2Cl2
a
See Experimental section.
b
c
Determined by 1H NMR analysis of the reaction mixture.
Isolated yield refers to substrate.
Under reflux.
d
e
f
Compound 2a was not detected.
Freshly distilled.
Reaction at 40 ꢀC.
g
h
H2 (2.5 atm).

A. Patti, S. Pedotti / Tetrahedron 66 (2010) 5607e5611
5609
The difficulty of achieving selective hydrogenation of substrates
containing different reducible functions has been ascribed to the
high activity of the metal catalysts and the use of additives or se-
lected reaction solvents has been reported effective in suppressing
reactivity or controlling chemoselectivity.20 The hydrogenation of
1a on Pd/C was then carried out in different solvents. In toluene
a higher 2a/3a ratio with respect to MeOH was measured (entry 5).
More selective conversion of 1a into the target 2a was achieved in
AcOEt or freshly distilled THF after 20 h (entries 6 and 7); however,
CH2Cl2 proved to be the best solvent for the higher reaction rate and
comparable selectivity (entry 8). Changing the operational tem-
perature to 40 ꢀC, the reaction in CH2Cl2 proceeded with a sensible
decrease in the selectivity and some unidentified product other
than 2a and 3a was also present in the final reaction mixture (entry
9); on the contrary, applying a doubled H2 pressure high 2a/3a ratio
and concomitant twofold increase in the reaction rate were de-
termined (entry 10).
When the hydrogenation of 1a in CH2Cl2 at room temperature
was terminated after 2 h, a 1:1 ratio of 2a and aminochalcone 4a
was determined; the structure of 4a was unequivocally determined
after isolation on the basis of its NMR spectra, displaying the di-
agnostic doublets for two protons in a trans ethylenic system and
a carbonyl resonance, and its spontaneous cyclization in CH2Cl2
solution to quinoline 3a. Under the same reaction conditions 3a did
not react, so that the presence of 4a as intermediate compound and
the low amount of 3a in the final reaction mixture support the
preferential occurrence of path B1 (Scheme 1) for the hydrogena-
tion of 1a in CH2Cl2.
high level of selectivity but lower reaction rate (entry 4), probably
for the sterical hindrance of the naphtyl moiety in the cyclization
step.
Substitution on the nitrophenyl ring led to a marked decrease
in the reactivity and under the standard conditions 1e and 1f
gave a mixture containing uncyclised intermediates in addition to
both THQs and quinolines. However, upon doubling the amount
of the catalyst the reaction profiles were comparable with those
observed for the other nitrochalcones (entries 5 and 6). The hy-
drogenation/cyclization protocol could be also applied to the
synthesis of 2-alkyl-1,2,3,4-tetrahydroquinoline, as evidenced in
the case of 2g (entry 7), but the lack of selective methods for the
Claisen-Schmidt condensation of benzaldehydes and aliphatic
ketones could represent a limit in the availability of the starting
nitrocalchones.
The synthesis of benzo[h]tetrahydroquinoline 2h was then
attempted using the same approach starting from 1-nitro-2-
naphthylaldehyde and acetophenone (Scheme 2), but 50% Pd/C
catalyst was required in order to achieve complete conversion of
the reaction intermediates into 2h and the corresponding aromatic
derivative, isolated in 75% and 15% yield, respectively.
3. Conclusions
In summary, we have developed a simple route to the 2-
substituted-1,2,3,4-tetrahydroquinoline skeleton based on a one
pot hydrogenation/cyclization of 2-nitrochalcones in the presence
of Pd/C catalyst and gaseous hydrogen. The solvent was found to be
crucial on determining the reaction rate and selectivity and the best
results were observed in CH2Cl2, a quite unusual solvent for this
type of hydrogenation reaction. The advantages of the method re-
side in: (a) operationally simplicity, since the required hydrogen
pressure is compatible with normal glassware; (b) good atom
economy and atom efficiency;21 (c) versatility, due to the easy ac-
cess to a variety of the starting ortho-nitrochalcones by condensa-
tion of simple or substituted 2-nitrobenzaldehydes with enolizable
ketones.
The standard conditions (10% w/w Pd/C, CH2Cl2, 1.2 atm, rt)
developed for 1a were then applied to nitrochalcones 1beg, pre-
pared varying the ketone or the 2-nitrobenzaldehyde component in
the aldol condensation, and the corresponding THQs 2beg could be
obtained as predominant products (Table 2) in all the cases. Al-
though both substituted nitrocalchones 1b and 1c were reduced
with comparable reaction rate, the hydrogenation of 1c displayed
lower selectivity affording about 30% of the aromatic heterocycle
together with THQ 2c. Conversion of 1d into 2d proceeded with
Table 2
Synthesis of tetrahydroquinolines from nitrocalchones
H
O
Pd/C
O
10%(w/w)
O
NO2
R'
+
H2 (1.2 atm)
CH2Cl2
N
H
R'
H3C
R'
R
NO2
R
R
Entry
Substrate
R
R0
Time (h)
Producta (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
H
H
H
H
Ph
1.5
3
3
20
20b
15b
3
2a (88)
2b (87)
2c (65)
2d (82)
2e (77)
2f (82)
2g (90)
(4-OMe)Ph
(2-OMe)Ph
2-Naphthyl
Ph
Ph
CH3
4-NMe2
5-OMe
H
1g
a
Isolated yield; all the compound were characterised (1H and 13C NMR, ESI-MS) and their properties compared with literature data.
Pd/C (20% w/w) catalyst.
b
5
ZrCl4
Pd/C
CH3
13
12
6
50%(w/w)
(0.4 eqv.)
Ph
14
9
O
+
N
H
Ph
7
8
11
10
CHO
CH2Cl2
40 °C
H
2 (1.2 atm)
CH2Cl2
O
NO2
NO2
1h
2h
75% yield
69% yield
Scheme 2. Synthesis of 2-phenyl-benzo[h]-1,2,3,4-tetrahydroquinoline.

5610
A. Patti, S. Pedotti / Tetrahedron 66 (2010) 5607e5611
4. Experimental section
148.6 (C-2), 190.3 (CO). Anal. Calcd for C19H13NO3: C, 75.24; H, 4.32;
N, 4.62. Found: C, 75.12; H, 4.29; N, 4.59.
4.1. General methods
4.2.5. 1-Phenyl-3-(2-nitro-4-dimethylaminophenyl)-2-propen-1-
All the reagents were from Aldrich and used as received. Column
chromatography was performed on Si 60 (230e400 mesh) silica gel
using the specified eluants. 1H and 13C NMR spectra were registered
in CDCl3, unless otherwise specified, at 400.13 and 100.69 MHz,
respectively. 2D NMR spectra were performed using standard
one, 1e. Orange solid (207 mg, 70% yield), mp 155e156 ꢀC; IR (KBr)
1650, 1578, 1515, 1343, 1012 cmꢂ1 1H NMR:
; d 3.11 (s, 6H, NMe2),
6.89 (dd, 1H, J¼2.8 and 8.8, H-5), 7.17 (d, 1H, J¼2.8, H-3), 7.26 (d, 1H,
J¼15.6, CH]), 7.51 (t, 2H, J¼7.6, H-30 and H-50), 7.58 (t, 1H, J¼7.6, H-
40), 7.68 (d, 1H, J¼8.8, H-6), 7.80 (d, 2H, J¼7.6, H-20 and H-60), 8.04
Bruker microprograms. Chemical shifts (
d
) are given as parts per
(d, 1H, J¼15.6, CH]); 13C NMR:
d 40.0 (NMe2), 106.5 (C-3), 115.4 (C-
million relative to the residual solvent peak and coupling constants
(J) are in hertz. Assignment of the resonances, when possible, was
given following the chemical numeration showed in Table 1 or
Scheme 2. Melting points are uncorrected. Elemental analyses were
obtained from the Department of Pharmaceutical Sciences, Uni-
versity of Catania.
5), 116.2 (C-1), 122.2 (CH]), 128.5 (C-20,C-30, C-50 and C-60), 129.3
(C-6),132.5 (C-40), 138.0 (C-10), 139.8 (CH]),150.6 (C-2),151.2 (C-4),
190.5 (CO). Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45.
Found: C, 68.82; H, 5.40; N, 9.39.
4.2.6. 1-Phenyl-3-(2-nitro-5-methoxyphenyl)-2-propen-1-one,
Yellow solid (240 mg, 85% yield), mp 98e99 ꢀC; IR (KBr) 1656, 1592,
1504, 1332, 1285, 1077 cmꢂ1; 1H NMR:
3.95 (s, 3H, OMe), 7.00 (dd,
1f.
d
4.2. General procedure for the synthesis of nitrochalcones
1H, J¼2.4 and 8.8, H-4), 7.09 (d, 1H, J¼2.4, H-6), 7.22 (d, 1H, J¼15.6,
CH]), 7.51 (t, 2H, J¼7.6, H-30 and H-50), 7.60 (t, 1H, J¼7.6, H-40), 8.02
(d, 2H, J¼7.6, H-20 and H-60), 8.16 (d, 1H, J¼8.8, H-3), 8.20 (d, 1H,
4.2.1. Chalcones 1aef, 1h. To a mixture of 2-nitrobenzaldehyde
(150 mg, 1.0 mmol) and ketone (1.0 mmol) in dry CH2Cl2 (1 mL),
ZrCl4 (93 mg, 0.4 mmol) was added and the suspension maintained
at 40 ꢀC under stirring for 20e48 h, until TLC analysis showed
complete disappearance of the substrates. After addition of CH2Cl2
(2ꢁ30 mL) the mixture was extracted with water (30 mL) and the
organic layer washed with brine (30 mL). The CH2Cl2 extract was
dried over Na2SO4 and the taken to dryness. The crude solid was
washed with hexane and then crystallized from hexane/ethyl ace-
tate to give pure nitrochalcones in 70e85% yield.
J¼15.6, CH]); 13C NMR:
d 56.0 (OMe), 114.3 (C-6), 114.7 (C-4), 127.3
(CH]), 127.7 (C-3), 128.6 (C-30 and C-50), 128.8 (C-20 and C-60), 133.1
(C-40), 134.4 (C-1), 137.3 (C-10), 141.2 (C-2), 141.5 (CH]), 163.4 (C-5),
190.8 (CO). Anal. Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94.
Found: C, 67.75; H, 4.67; N, 4.99.
4.2.7. 1-Phenyl-3-(1-nitro-2-naphthyl)-2-propen-1-one, 1h. Brown
solid (210 mg, 69% yield), mp 198e199 ꢀC; IR (KBr) 1655,1582,1514,
1343, 1012 cmꢂ1; 1H NMR (CD3COCD3):
d
7.60 (t, 2H, J¼7.6, H-30 and
H-50), 7.70 (t, 1H, J¼7.6, H-40), 7.77e7.80 (m, 4H), 8.16 (d, 1H, J¼7.6),
4.2.2. Chalcone 1g. To a solution of 2-nitrobenzaldehyde (150 mg,
1.0 mmol) in acetone (3 mL), Cs2CO3 (325 mg, 1.0 mmol) was added
and the suspension stirred overnight at 40 ꢀC. The mixture was
then concentrated and partitioned between water (30 mL) and
CH2Cl2 (2ꢁ30 mL). The organic extract was dried over Na2SO4 and
taken to dryness to give a residue that was purified on Si gel column
(n-hexane/AcOEt/CH2Cl2 3:1:1) to afford 1g (88 mg, 46% yield) and
the corresponding aldol in 1:1 ratio.
8.18e8.22 (m, 3H), 8.26 (d, 1H, J¼8.8, H-3), 8.33 (d, 1H, J¼8.8, H-4);
13C NMR (CD3COCD3):
d 121.7, 123.0, 124.0, 127.4, 128.43, 128.6,
128.8, 129.5, 131.1, 133.4, 134.5, 134.8, 137.5 (C-10), 148.8 (C-1), 188.3
(CO). Anal. Calcd for C19H13NO3: C, 75.24; H, 4.32; N, 4.62. Found: C,
75.32; H, 4.29; N, 4.57.
4.3. General procedure for the hydrogenation reactions
The above procedures afforded exclusively trans-chalcones, that
were mainly characterised by NMR spectroscopy, and known
compounds were identified by comparison of their properties with
those reported in the literature.18
4.3.1. With gaseous H2. To a solution of 1a (30 mg, 0.12 mmol) in
the appropriate solvent (3 mL), the required catalyst (3 mg) was
added. After the flask was evacuated and filled with H2 the mixture
was maintained under stirring at room temperature until TLC
analysis showed complete disappearance of 1a. The suspension was
then filtered through a short plug of Celite and the solution evap-
orated to give a residue that was analysed by 1H NMR in order to
determine 2a/3a ratio and then purified on Si gel column.
4.2.3. 1-(2-Methoxyphenyl)-3-(2-nitrophenyl)-2-propen-1-one, 1c.
Pale yellow solid (240 mg, 85% yield), mp 105e106 ꢀC; IR (KBr)
1646, 1588, 1507, 1340, 1010 cmꢂ1 1H NMR:
; d 3.92 (s, 3H, OMe),
7.01 (d, 1H, J¼8.4, H-30), 7.05 (t, 1H, J¼7.6, H-50), 7.24 (d, 1H, J¼16.0,
CH]), 7.50 (t, 1H, J¼8.4, H-40), 7.54 (t, 1H, J¼7.6, H-4), 7.66 (m, 2H,
H-5 and H-60), 7.70 (d, 1H, J¼7.6, H-6), 7.96 (d, 1H, J¼16.0, CH]),
4.3.2. With NH4COOH. In a sealed tube, to a solution of 1a (50 mg,
0.20 mmol) in MeOH (5 mL), solid NH4COOH (126 mg, 2.0 mmol)
and Pd/C (5 mg) were added and the suspension was stirred at
65 ꢀC for 3 h. The reaction mixture was then filtered through a short
plug of Celite and the solution evaporated. The residue was ana-
lysed by 1H NMR and then purified by column chromatography.
8.03 (d, 1H, J¼7.6, H-3); 13C NMR:
d
55.7 (OMe), 111.5 (C-30), 120.8
(C-50), 124.8 (C-3), 128.3 (C-10), 129.2 (C-6), 130.0 (C-4), 130.5 (C-5),
131.3 (C-1), 131.6 (CH]), 133.3 (C-40 and C-60), 138.2 (CH]), 148.6
(C-2),158.2 (C-20),192.5 (CO). Anal. Calcd for C16H13NO4: C, 67.84; H,
4.63; N, 4.94. Found: C, 67.79; H, 4.59; N, 4.90.
4.4. General procedure for the synthesis of 2-substituted
1,2,3,4-tetrahydroquinolines
4.2.4. 1-(2-Naphthyl)-3-(2-nitrophenyl)-2-propen-1-one,
Brown solid (250 mg, 82% yield), mp 118e119 ꢀC; IR (KBr) 1659,
1d22
.
1595, 1504, 1332, 1170 cmꢂ1; 1H NMR:
d
7.46 (d, 1H, J¼15.6, CH]),
The required 2-nitrochalcone (50 mg) was dissolved in CH2Cl2
(5 mL) in a 100 ml flask equipped with a Teflon stopcock and Pd/C
catalyst (10% Pd on activated carbon, 5 mg) was added. After the flask
was evacuated and then refilled with H2 (1.2 atm), the reaction
mixture was stirred at room temperature. At the end of the reaction,
the suspension was filtered through a short plug of Celite and the
solution evaporated. The residue was purified by column chroma-
tography (Si gel, n-hexane/Et2O 95:5 or n-hexane/CH2Cl2/AcOEt
7.60 (m, 2H, H-70 and H-4), 7.63 (m,1H, H-60), 7.71 (t,1H, J¼7.6, H-5),
7.80 (d,1H, J¼7.6, H-6), 7.91 (d,1H, J¼7.9, H-50), 7.95 (d,1H, J¼8.6, H-
40), 8.01 (d, 1H, J¼7.9, H-80), 8.09 (br d, 2H, H-3 and H-30), 8.20 (d,
1H, J¼15.6, CH]), 8.57 (s, 1H, H-10); 13C NMR:
d
124.5 (C-30), 125.0
(C-3), 126.9 (C-70), 127.5 (CH]), 127.8 (C-50), 128.6 (C-60), 128.7 (C-
40), 129.3 (C-6), 129.6 (C-80), 130.3 (C-4), 130.6 (C-10), 131.4 (C-1),
132.5 (C-90), 133.5 (C-5), 134.7 (C-20), 135.6 (C-100), 140.1 (CH]),

A. Patti, S. Pedotti / Tetrahedron 66 (2010) 5607e5611
5611
Cortes, D. Bioorg. Med. Chem. 2009, 17, 4968e4980; (c) Scott, J. D.; Miller, M. W.;
Li, S. W.; Lin, S.-I.; Vaccaro, H. A.; Hong, L.; Mullins, D. E.; Guzzi, M.; Weinstein,
J.; Hodgson, R. A.; Varty, G. B.; Stamford, A. W.; Chan, T.-Y.; McKittrick, B. A.;
Greenlee, W. J.; Priestley, T.; Parker, E. M. Bioorg. Med. Chem. Lett. 2009, 19,
6018e6022.
8:1:1) to afford pure tetrahydroquinolines as clear oils. Known
compounds 2aed,14b,c 2f23 and 2g14d were identified by comparison
of their properties with those reported in the literature.
7. (a) Di Fabio, R.; Alvaro, G.; Bertani, B.; Donati, D.; Pizzi, M.; Gentile, G.; Pen-
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Brindisi, M.; Savini, L.; Novellino, E.; Nacci, V.; Fattorusso, E.; Parapini, S.;
Basilico, N.; Taramelli, D.; Yardley, V.; Croft, S.; Borriello, M.; Gemma, S. J. Med.
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4.4.1. 2-Phenyl-7-dimethylamino-1,2,3,4-tetrahydroquinoline
Yield 77% (33 mg); IR (liquid film) 3370, 2972, 1612, 1470,
1246 cmꢂ1; 1H NMR:
1.99 (m, 1H, H-3a), 2.10 (m, 1H, H-3b), 2.67
2e.
d
(dt, 1H, J¼4.8, 4.8 and 15.6, H-4a), 2.86 (ddd, 1H, J¼5.2, 10.4 and
15.6, H-4b), 2.90 (s, 6H, NMe2), 4.03 (br s, 1H, NH), 4.42 (dd, 1H,
J¼3.2 and 9.2, H-2), 5.98 (d, 1H, J¼2.4, H-8), 6.19 (dd, 1H, J¼2.4 and
8.4, H-6), 6.90 (d, 1H, J¼8.4, H-5), 7.29 (t, 1H, J¼7.2, H-40), 7.36 (t, 2H,
J¼7.2, H-30 and H-50), 7.41 (d, 2H, J¼7.2, H-20 and H-60); 13C NMR:
d
25.5 (C-4), 31.6 (C-3), 41.0 (NMe2), 56.4 (C-2), 98.6 (C-8), 103.5 (C-
6), 110.3 (C-10), 126.6 (C-20 and C-60), 127.3 (C-40), 128.5 (C-30 and C-
50), 129.7 (C-5), 145.0 (C-10), 145.2 (C-9) 150.4 (C-7). Anal. Calcd for
C17H20N2: C, 80.91; H, 7.99; N, 11.10. Found: C, 80.82; H, 8.01; N,
11.15.
4.4.2. 2-Phenyl-benzo[h]-1,2,3,4-tetrahydroquinoline 2h. Yield 75%
10. Wallace, O. B.; Lauwers, K. S.; Jones, S. A.; Dodge, J. A. Bioorg. Med. Chem. Lett.
(32 mg); IR (liquid film) 3365, 2995, 2864, 1483, 1244 cmꢂ1 1H
;
2003, 13, 1907e1910.
11. Rano, T.; Sieber-McMaster, E.; Pelton, P. D.; Yang, M.; Demarest, K. T.; Kuo, G.-H.
Bioorg. Med. Chem. Lett. 2009, 19, 2456e2460.
NMR:
d
2.15 (m,1H, H-3a), 2.25 (m,1H, H-3b), 2.88 (dt,1H, J¼4.8, 4.8
and 16.4, H-4a), 3.12 (ddd, 1H, J¼5.6, 10.0 and 16.4, H-4b), 4.61 (dd,
1H, J¼3.2 and 9.2, H-2), 4.68 (br s, 1H, NH), 7.19 (d, 1H, J¼8.4, H-5),
7.24 (d, 1H, J¼8.4, H-6), 7.34 (t, 1H, J¼7.2, H-40) 7.39e7.43 (m, 4H, H-
30, H-50, H-8 and H-9), 7.48 (d, 2H, J¼7.2, H-20 and H-60), 7.73 (m, 1H,
12. Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031e15070 and
references therein.
13. (a) Fache, F. Synlett 2004, 2827e2829; (b) Fujita, K.; Kitatsuji, C.; Furukawa, S.;
Yamaguchi, R. Tetrahedron Lett. 2004, 45, 3215e3217; (c) Lu, S. M.; Han, X.-W.;
Zhou, Y.-G. J. Organomet. Chem. 2007, 692, 3065e3069.
14. (a) Lu, S.-M.; Wang, Y.-Q.; Han, X.-W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006,
45, 2260e2263; (b) Rueping, M.; Antonchick, A. P.; Theissman, T. Angew. Chem.,
Int. Ed. 2006, 45, 3683e3686; (c) Tadaoka, H.; Cartigny, D.; Nagano, T.; Gosavi,
T.; Ayad, T.; Genet, J.-P.; Ohshima, T.; Ratovelomanana-Vidal, V.; Mashima, K.
Chem.dEur. J. 2009, 15, 9990e9994; (d) Wang, C.; Li, C.; Wu, X.; Pettman, A.;
Xiao, J. Angew. Chem., Int. Ed. 2009, 48, 6524e6528.
15. (a) Ishitani, H.; Kobayashi, S. Tetrahedron Lett. 1996, 37, 3357e3360; (b)
Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1996, 118, 8977e8978; (c) Zhang,
J.; Li, C.-J. J. Org. Chem. 2002, 67, 3969e3971; (d) Spanedda, M. V.; Hoang, V. D.;
Crousse, B.; Bonnet-Delpon, D.; Bégué, J.-P. Tetrahedron Lett. 2003, 44, 217e219;
(e) Savitha, G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589e3593; (f) Xing, X.;
Wu, J.; Dai, W.-M. Tetrahedron 2006, 62, 11200e11206.
16. (a) Fuijita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett. 2002, 4, 2691e2694; (b)
Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007, 72, 6577e6579; (c) Rano, T.
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H-7), 7.79 (m, 1H, H-10); 13C NMR:
d 26.8 (C-4), 30.7 (C-3), 56.5 (C-
2), 115.1, 117.0 (C-5), 119.4 (C-7), 122.7 (C-13), 124.8, 125.0, 126.6 (C-
20 and C-60), 127.5, 128.3 (C-10), 128.6 (C-30 and C-50), 133.1 (C-11),
138.9 (C-12), 144.8 (C-10). Anal. Calcd for C19H17N: C, 87.99; H, 6.61;
N, 5.40. Found: C, 87.86; H, 6.57; N, 5.44.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2010.05.090.
References and notes
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