Convergent synthesis of dihydroquinolones from o-aminoarylboronates

Article abstract of DOI:10.1016/j.tet.2009.06.103

An efficient and convergent one-step synthesis of substituted dihydroquinolin-2-ones from α,β-unsaturated esters and aminoaryl pinacolboronates under rhodium catalysis is reported. The reaction is easily applicable in parallel synthesis format and provide

Full text of DOI:10.1016/j.tet.2009.06.103

Tetrahedron 65 (2009) 9002–9007
Contents lists available at ScienceDirect
Tetrahedron
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Convergent synthesis of dihydroquinolones from o-aminoarylboronates
,
a
,
a
Joachim Horn a, Ho Yin Li a, Stephen P. Marsden a , Adam Nelson , Rachel J. Shearer ,
*
*
Amanda J. Campbell b, David House b, Gordon G. Weingarten b
a School of Chemistry, University of Leeds, Leeds LS2 9JT, UK
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2009
Received in revised form 8 June 2009
Accepted 26 June 2009
Available online 2 July 2009
An efficient and convergent one-step synthesis of substituted dihydroquinolin-2-ones from
a,b-un-
saturated esters and aminoaryl pinacolboronates under rhodium catalysis is reported. The reaction is
easily applicable in parallel synthesis format and provides convenient access to this pharmaceutically-
relevant motif.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
also embedded within alkaloids of the Melodinus family, exempli-
fied by meloscine 4,4 as well as the structurally unique insecticidal
The dihydroquinolin-2-one (dihydroquinolone) structure is
found in a large number of interesting natural and man-made
compounds. Simple 5-, 6- and 7-alkoxydihydroquinolones re-
microbial metabolites yaequinolone J1 (5) and J2.5
Methods for the synthesis of dihydroquinolin-2-ones are
therefore of significant interest. Alongside classical Friedlander/
Friedel–Crafts cyclisation approaches,6 more recent methods in-
clude oxidative cyclisation of 2-(3-hydroxypropyl)anilines,7 radical
reactions (6-exo cyclisations of aryl radicals8 and cyclisation by
spectively form the core of the commercial drugs carteolol 1 (a b-
adrenergic blocker used in the treatment of glaucoma),1 cilostazol 2
(a PDE3 phosphodiesterase inhibitor used in the treatment of pe-
ripheral vascular disease)2 and aripiprazole 3 (an anti-psychotic
used in the treatment of schizophrenia) (Fig. 1).3 The structure is
addition of radicals to the aromatic ring9), 6
p-photocyclisations of
acrylanilides,10 and palladium-catalysed cyclocarbonylation of 2-
alkenylanilines.11 We recently reported12 a novel, regiospecific
rhodium-catalysed synthesis of quinolines from enones and ortho-
aminophenylboronates.13 In this process, the rhodium catalyst
mediates a 1,4-addition of the boronic acid to the enone, with the
resulting keto-aniline undergoing self-condensation to generate
a labile 3,4-dihydroquinoline which is aerobically oxidised to the
quinoline on addition of palladium on charcoal. The reaction offers
a mild and regiocomplentary route from enones to substituted
quinolines compared with the classical Skraup–Doebner–von
Miller reaction,14 wherein the product is one of formal aza-Michael
addition of an aniline nucleophile to the enone, followed by
intramolecular Friedel–Crafts alkylation. We therefore considered
whether we might be able to exploit similar Michael addition/
condensation chemistry to directly access dihydroquinolones by
N
N
N
N
tBuHN
O
OH
N
O
O
N
H
O
N
H
O
N
H
O
3
2
1
N
N
Cl
Cl
O
HO
H
O
OMe
O
addition of the aminoarylboronates to a,b-unsaturated esters. We
report herein the successful attainment of this goal.
N
H
N
H
5
4
2. Results and discussion
Figure 1. Pharmaceuticals and natural products containing the dihydroquinolin-2-one
structure.
Our initial work focused on the condensation of commercially
available 2-aminophenylboronic acid 6 with a,b-unsaturated esters 7
of varying substitution patterns and electronic properties. Under the
initiallychosen conditions (3 mol % [Rh(cod)Cl]2 and 12 mol % KOH in
aqueous dioxane at reflux), we were pleased to find that the
* Corresponding authors.
E-mail addresses: s.p.marsden@leeds.ac.uk (S.P. Marsden), a.s.nelson@leeds.ac.uk
(A. Nelson).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.103

J. Horn et al. / Tetrahedron 65 (2009) 9002–9007
9003
Table 1
Table 2
Comparison of boronic acids and pinacolboronate esters in addition to
saturated esters
a
,
b
-un-
Optimisation of the formation of 4-phenyldihydroquinolin-2-one 8ea
Entry
Base
Solvent
Yield, %
R1
1
2
3
4
5
6
7
8
12% KOH
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
Dioxane/H2O
THF/iPrOH
46
65
64
43
67
66
47
64
0
3% [Rh(cod)Cl]2,
R2
B(OR)2
NH2
200% KOH
400% KOH
12% KOHb
200% KOHb
400% KOHb
400% LiOH
200% Ba(OH)2
100% Et3N
200% K2CO3
200% KOH
200% KOH
200% KOH
200% KOH
200% KOH
12% KOH
CO2Me
R2
R1
+
dioxane/H2O,
reflux, 2 h
N
H
O
6 R = H
7
8
9 R = CMe2-
Entry
Boronate
Enoate
R1
R2
Product
Yield, %
9
1
2
3
4
5
6
7
8
6
6
6
6
6
6
9
9
9
9
9
9
9
9
9
7a
7b
7c
7d
7e
7f
7a
7b
7c
7d
7e
7g
7f
H
H
H
Me
H
Me
H
H
H
Me
H
Me
H
8a
8b
8c
8d
8e
8f
8a
8b
8c
8d
8e
8g
8f
86
56
47
0
0
0
69
45
48
0
46
32
10
11c
12d
13
14
15
0
Dioxane/H2O
Dioxane/H2O
Dioxane/iPrOH
2-Butanol
27
32
57
39
18
Me
Me
Ph
CO2Me
H
Toluene/H2O
a
Basic reaction conditions: 1 equiv of methyl cinnamate 7e, 2 equiv of 2-ami-
nophenyl pinacolboronate 9, 3% [Rh(cod)Cl]2, indicated base, solvent, reflux, 2 h.
H
9
Me
Me
Ph
b
Reaction also contains 200% KF.
10
11
12
13
14a
15
c
Reaction carried out at 70 ꢀC.
d
Reaction on iso-propyl cinnamate.
4-MeOC6H4
CO2Me
CO2Me
H
H
H
H
NHAc
7
7f
8f
8h
40 (10)b
71
7h
With this preliminary substrate scoping exercise complete, we
next sought to identify optimised conditions for the reaction using
methyl cinnamate 7e as the model substrate. Specifically, we focused
on the choice of reaction solvent and the nature and stoichiometry of
the base additive, and the results are shown in Table 2. We had been
employing a 12 mol % loading of potassium hydroxide to ensure for-
mation of the active catalyst [Rh(cod)OH],15 but wished to investigate
the effect of adding stoichiometric basic or nucleophilic additives for
boronateactivation.Increasingthequantityofhydroxideto200 mol %
(i.e.,1 equiv to the boronate reagent 9) lead to a significant increase in
yield to 65% (entries 1 and 2); increasing this to 400 mol % gave no
further improvement (entry 3). Fluoride is also commonly used to
activate boronates towards transmetalation, including in conjugate
addition reactions,16 but the addition of potassium fluoride had no
beneficial effect on either reaction (entries 4–6). Substitution of other
metal hydroxide salts for KOH was not successful (entries 7 and 8). In
some of the reactions using the higher base loadings, we were able to
observe cinnamic acid as a by-product in the NMR spectrum of the
crude reaction mixture. While this clearly arises by hydrolysis of the
ester, we were concerned as to whether this event occurred com-
petitively with Michael addition/cyclisation, or was simply occurring
slowly once all of the boronate 9 had been consumed (either by the
desired Michael addition or protodeboronation)din the former case,
the species liberated in the reaction would be the potassium cinna-
mate salt, which would likely be too poorly electrophilic to act as
a competent Michael acceptor and hence would compromise the
overall reaction yield. In an attempt to probe this, we investigated the
use of weaker inorganic or organic bases, but these gave no reaction
(entries 9 and 10). Decreasing the reaction temperature from reflux to
70 ꢀC gave a lower yield of addition (entry 11), while the use of the
bulkier iso-propyl cinnamate ester also gave a poor 32% yield of 8e
(entry 12). In this latter case, no cinnamic acid was observable in the
NMRspectrumof thecrudereactionmixture,withonlyunreactediso-
propyl cinnamate being present. This suggests that the incomplete
conversion of the enoates to dihydroquinolin-2-ones is due to the
competition between protodeboronation and Michael addition of
the boronate, rather than hydrolytic consumption of the electrophile
itself. Finally, the use of alternative solvent systems was investigated,
though no improvements on the aqueous dioxane regime were found
(entries 13–15).
a
Using 10% [Rh(cod)Cl]2, 200% KOH.
Yield of methyl (2-oxo-2,3-dihydro-1H-indol-3-yl)acetate by-product.
b
condensation proceeded smoothly with methyl acrylate 7a to gen-
erate the desired dihydroquinolone 8a in good yield (Table 1, entry 1).
The presumed intermediate 3-(2-aminophenyl)propionate ester was
not observed, suggesting that cyclisation to the lactam proceeds
rapidly following the initial 1,4-addition. The reaction was also suc-
cessful using both methyl crotonate and methyl methacrylate;
dihydroquinolones 8b and 8c were formed in moderate yield (entries
2 and 3), demonstrating that substituents at the a- and b-positions,
although detrimental to the reaction, were tolerated. Attempted re-
actions with the more hindered/less electrophilic methyl tiglate 7d,
the conjugated methyl cinnamate 7e, and the electron-deficient di-
methyl fumarate 7f, however, all met with failure (entries 4–6). In all
cases, the product of protodeboronation of the boronic acid (aniline)
was observed as the sole product of the reaction. We therefore ex-
amined the use of commercial 2-aminophenyl pinacolboronate 9 in
place of 6. In our previous work,12 9 was shown to be a competent
nucleophile in addition to enones, though less reactive than 6 (higher
catalyst loadings were required to effect addition on comparable
timescales). However, the slower rate of conjugate addition need not
be detrimental to the overall reaction efficiency provided that pro-
todeboronation is also slowed significantly with this reagent. In the
event, we were pleased to find that 9 proved to be an effective nu-
cleophilic aryl donor across a much wider range of electrophiles.
Reactionwithmethyl acrylate gave a slightlyloweryieldof8a, but the
yields for addition/cyclisation with crotonate and methacrylate to
give 8b and 8c were comparable to those with boronic acid 6 (entries
7–9). Methyl tiglate, however, remained unreactive (entry 10). The
previously unsuccessful phenyl cinnamate gave a promising 48%
yield of 8e and the less electrophilic p-methoxycinnamate also gave
the desired dihydroquinolone 8g (entries 11 and 12). Dimethyl fu-
marate was found to still be poorly reactive, giving just a 7% yield of
the desired target 8f; we found however that this could be increased
to 40% if the catalyst loading was increased to 10% [Rh(cod)Cl]2
(entries 13 and 14). The latter reaction also gave a 10% yield of methyl
(2-oxo-2,3-dihydro-1H-indol-3-yl)acetate, theproductof ringclosure
totheproximalesteroftheintermediate2-(2-aminophenyl)succinate
derivative. Finally, the relatively electron-rich dehydroalanine methyl
ester 7h was converted to the 2-acetamidodihydroquinolinone 8h in
a pleasing 71% yield.
With the optimised reaction conditions (200 mol % KOH in aque-
ous dioxane) in hand, we next turned our attention to the synthesis of
a range of substituted dihydroquinolin-2-ones in parallel. Using
a Radleys GreenHouse parallel reactor, we treated pinacolboronate 9

9004
J. Horn et al. / Tetrahedron 65 (2009) 9002–9007
with methyl acrylate and eleven other
b
-substituted
a
,
b
-unsaturated
6 h) and slightly lower yields were generally observed with the tri-
fluoromethyl-substituted boronate 10 than the parent boronate 9,
likely reflecting the lower nucleophilicity of the reagent bearing the
electron-withdrawing group.
In summary, we have developed an efficient and convergent
one-step synthesis of substituted dihydroquinolin-2-ones from
a,b-
unsaturated esters and aminophenyl pinacolboronates under rho-
dium catalysis. The reaction is easily applicable in parallel synthesis
format and provides convenient access to this pharmaceutically-
relevant motif.
esters under the standard reaction conditions. To probe the influence
of substitution in the ring of the boronate nucleophile, we also pre-
pared the 4-trifluoromethyl-2-aminophenyl pinacolboronate 1012 by
palladium-catalysed cross-coupling of the corresponding aryl bro-
mide with pinacolborane using the method of Baudoin,17 and in-
vestigated its reaction with eight representative Michael acceptors
using the GreenHouse. The aim of the series was to establish the
generality of the protocol and no attempt was made to optimise in-
dividual reactions. The results are summarised in Table 3.
Table 3
3. Experimental section
3.1. General information
Synthesis of diverse 4-substituted dihydroquinolin-2-onesa
R1
O
B
O
All experiments were conducted under an atmosphere of ni-
trogen unless otherwise stated. Column chromatography was car-
ried out using Fisher Matrix silica gel 60. Aluminium-backed plates,
pre-coated with silica gel 60 (UV254), were used for thin layer
chromatography and were visualized by UV and staining either
with anisaldehyde, KMnO4, vanillin or phosphomolybdate.
1H and 13C NMR spectra have chemical shift values reported in
ppm relative to residual protic solvent as internal standards unless
otherwise stated.
CO2Me
+
R1
R2
NH2
R2
N
H
O
9 R2 = H
7
8
10 R2 = CF3
Entry
Boronate
Enoate
R1
R2
Product
Yield, %
1
2
3
4
5
6
7
8
9
9
9
9
9
9
9
9
9
7a
7c
7e
7g
7i
7j
7k
7l
7m
7n
7o
7p
7a
7c
7e
7g
7m
7n
7o
7p
H
Me
Ph
H
H
H
H
H
H
H
H
H
H
H
H
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
8a
8c
8e
8g
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
8t
8u
8v
8w
8x
64
46
58
30
37
37
34
29
39
39
38
49
50
39
43
46
0
4-MeOC6H4
4-NO2C6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
N-Et-Indol-3-yl
3-Quinolinyl
2-Thienyl
2-Pyridyl
H
3.2. General experimental procedures
3.2.1. General procedure A: (Table 1)
To a suspension of chloro(1,5-cyclooctadiene)rhodium(I) dimer
(8 mg, 0.015 mmol, 0.03 equiv), 2-aminophenylboronic acid pinacol
9
10
11
12
13
14a
15
16
17
18
19
20
9
9
9
boronate (219 mg,1.00 mmol, 2.00 equiv) and
(0.50 mmol, 1.00 equiv) in dioxane (1.4 mL, ca. 0.33 M) was added
2.5 M KOH (24 L, 0.12 mmol, 0.25 equiv). The mixture was heated
a,b-unsaturated ester
10
10
10
10
10
10
10
10
m
Me
Ph
under reflux conditions for 2 h. The solvent was removed in vacuo.
The residue was dissolved in EtOAc and washed with 1 N HCl
(twice), satd NaHCO3, brine and then dried (MgSO4). The organic
layer was concentrated in vacuo to give the crude product which
was purified by flash column chromatography.
4-MeOC6H4
N-Et-Indol-3-yl
3-Quinolinyl
2-Thienyl
2-Pyridyl
47
19
33
a
Reaction conditions: 1 equiv 7, 2 equiv 9 or 10, 3% [Rh(cod)Cl]2, 200% KOH, 14:1
3.2.2. General procedure B: (Table 3)
dioxane/water, reflux, 6–20 h.
Reactions were carried out in a Radleys GreenHouse Parallel
Synthesiser. To a suspension of chloro(1,5-cyclooctadiene)rhodium(I)
dimer (8 mg, 0.015 mmol, 0.03 equiv), 2-aminoarylboronic acid
pinacol ester (9: 219 mg or 10: 287 mg, 1.00 mmol, 2.00 equiv) and
We were pleased to find a 95% success rate for the reactions, with
significant quantities of product being formed in all cases except one
(the reaction of 10 with methyl N-ethylindol-3-yl acrylate 7m, entry
17). We repeated this latter reaction using a round-bottomed flask
and condenser and again observed none of the desired product,
confirming that this is a result of poorly matched reactivity rather
than an artefact of the experimental set-up. Amongst the successful
reactions, the following trends emerged. Firstly, the reaction of
methyl cinnamate 7e provides a benchmark for the reaction against
a standard experimental set-up. From this, we see that the experi-
ment in the GreenHouse reactor is slightly lower yielding at 58%
(Table 3, entry 3) compared with 65% under standard conditions
(Table 2, entry 2) but that the difference is small. Secondly, a wide
range of substituents are tolerated on the ester. For both nucleophiles
9 and 10 the unsubstituted Michael acceptor methyl acrylate is most
reactive (entries 1 and 13), but both alkyl- and aryl-substituted
electrophiles participate successfully. The aryl substituents can be
electron-donating (entries 4 and 16), electron-withdrawing (entry 5)
or heteroaryl (entries 9–12 and 18–20). Additionally, the rhodium
catalyst tolerates the presence of aryl bromide substituents of any
regiochemistry (entries 6–8), generating products that could po-
tentially be further functionalised under, for example, palladium
catalysis. Finally, with respect to the aminophenyl boronate nucleo-
phile, a longer reaction time was found to be required (20 h versus
a,b-unsaturated ester (0.50 mmol, 1 equiv) in dioxane (1.4 mL, ca.
0.33 M) was added 10 M KOH (0.1 mL,1 mmol, 2 equiv). The mixture
was heated at reflux temperature for 6 h (entries 1–12) or 20 h (en-
tries 13–20). The solvent was removed in vacuo give the crude
product which was purified by flash column chromatography.
3.3. Compound data
3.3.1. 3,4-Dihydro-1H-quinolin-2-one 8a
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as brown oil. This was purified by column
chromatography (3:1 to 3:2 petrol–ethyl acetate) to yield 8a as pale
yellow crystals (45 mg, 64%). 1H NMR (300 MHz, CDCl3)
d: 9.21 (1H,
br s, NH), 7.17 (1H, t, J¼7.5 Hz, C7-H), 7.15 (1H, d, J¼7.5 Hz, C5-H), 6.98
(1H, dt, J¼1.2, 7.5 Hz, C6-H), 6.85 (1H, d, J¼7.5 Hz, C8-H), 2.97 (2H, t,
J¼7.5 Hz, C3-H2), 2.65 (2H, t, J¼7.5 Hz, C4-H2); 13C NMR (75 MHz,
CDCl3) d: 172.6, 137.8, 128.3, 127.9, 124.0, 123.5, 116.0, 31.2, 25.6;
ESIHRMS for C9H9NONa ([MþNa]þ): calcd 170.0576; found
170.0570; melting point¼160–162 ꢀC (CH2Cl2/Et2O), (lit.,18 mp¼163–
164 ꢀC; EtOH/H2O); IR (NaCl, thin film): nmax 3400, 1643, 1492, 1463,
1384,1340,1281,1246 cmꢁ1.1H and 13C NMR data are consistent with
the reported values.19

J. Horn et al. / Tetrahedron 65 (2009) 9002–9007
9005
3.3.2. 4-Methyl-3,4-dihydro-1H-quinolin-2-one 8b
ester: 1H NMR (300 MHz, CDCl3)
d: 8.85 (1H, br s, NH), 7.22 (2H, m,
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:1 to 3:2 petrol/ethyl acetate) to yield 8b as pale
C6-H and C4-H), 7.00 (1H, dt, J¼1.2, 7.5 Hz, C5-H), 6.90 (1H, d,
J¼7.8 Hz, C7-H), 3.82 (1H, dd, J¼7.9, 4.5 Hz, C3-H), 3.70 (3H, s,
COOMe), 3.09 (1H, dd, J¼17.1, 4.5 Hz, C-HA), 2.83 (1H, dd, J¼17.1,
yellow crystals (37 mg, 46%).1H NMR (300 MHz, CDCl3)
d:8.55(1H, brs,
7.9 Hz, C-HB); 13C NMR (75 MHz, CDCl3)
d: 178.1, 170.1, 140.6, 127.7,
NH), 7.19–7.13 (2H, m, C7-H and C5-H), 6.95 (1H, t, J¼7.5 Hz, C6-H), 6.80
(1H, d, J¼7.5 Hz, C8-H), 3.00 (1H, dd, J¼15.0, 6.0 Hz, C4-HA), 2.74–2.62
(2H, m, C4-HB and C3-H),1.30 (3H, d, J¼6.5 Hz, CH3); 13C NMR (75 MHz,
127.3, 123.1, 121.5, 108.9, 51.0, 41.3, 33.6; ESIHRMS for C11H12NO3
([MþH]þ) and C11H11NO3MNa ([MþNa]þ): calcd 206.0812,
228.0631; found 206.0805, 228.0621; melting point¼186–187 ꢀC
(CH2Cl2/MeOH), (lit.,22 mp¼187–188 ꢀC; MeOH); IR (NaCl, thin
film): nmax 3224, 1710, 1625 cmꢁ1. 1H and 13C NMR data consistent
with reported values.22
CDCl3) d: 173.5, 136.2, 127.1, 126.4, 122.6, 121.9, 114.1, 34.0, 32.5, 14.3;
ESIHRMS for C10H12NO ([MþH]þ) and C10H11NONa ([MþNa]þ): calcd
162.0913, 184.0733; found 162.0913, 184.0741; melting point¼128–
129 ꢀC (CH2Cl2), (lit.,20 mp¼126–127 ꢀC); IR (NaCl, thin film): nmax
3434, 2955, 1686, 1593, 1487, 1379, 1339, 1311 cmꢁ1. 1H and 13C NMR
data are consistent with the reported values.20
3.3.6. 4-(4-Methoxyphenyl)-3,4-dihydro-1H-quinolin-2-one 8g
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
3.3.3. 4-Methyl-3,4-dihydro-1H-quinolin-2-one 8c
chromatography (3:2 petrol/ethyl acetate) to yield 8g as pale brown
I
Synthesised according to general procedure A on a 0.1 mmol
scale. The crude product was purified by flash column chroma-
tography to yield 8c as colourless crystals (8 mg, 48%). 1H NMR
crystals (38 mg, 30%). H NMR (300 MHz, CDCl3)
d: 9.25 (1H, br s,
NH), 7.18 (1H, dt, J¼2.1, 7.5 Hz, C7-H), 7.11 (2H, d, J¼8.4 Hz,
methoxyphenyl C2-H), 6.98–6.88 (3H, m, C8-H, C6-H and C5-H),
6.86 (2H, dt, J¼8.4 Hz, methoxyphenyl C3-H), 4.24 (1H, t, J¼7.5 Hz,
C4-H), 3.78 (3H, s, OCH3), 2.90 (2H, app. d, J¼7.5 Hz, C3-H2); 13C NMR
(300 MHz, CDCl3)
d
: 8.88 (1H, br s, NH), 7.19 (1H, d, J¼7.8 Hz, C5-H),
7.18 (1H, t, J¼7.5 Hz, C7-H), 7.02 (1H, t, J¼7.5 Hz, C6-H), 6.83 (1H, d,
J¼7.8 Hz, C8-H), 3.17–3.10 (1H, m, C4-H), 2.74 (1H, dd, J¼15.9,
6.0 Hz, C3-HA), 2.43 (1H, dd, J¼15.9, 7.2 Hz, C3-HB), 1.32 (3H, d,
(75 MHz, CDCl3) d: 171.8,159.1,137.5,134.0,129.2,128.5,127.6,123.7,
116.3,114.7,114.3, 55.7, 41.6, 39.0; ESIHRMS for C16H16NO2 ([MþH]þ)
and C16H15NO2Na ([MþNa]þ): calcd 254.1176, 276.0995; found
254.1168, 276.0986; melting point¼184–185 ꢀC (CH2Cl2/MeOH); IR
J¼6.9 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d: 171.9, 136.9, 129.2,
127.9, 126.9, 123.7, 116.0, 38.8, 33.1, 20.2; ESIHRMS for C10H12NO
([MþH]þ) and C10H11NONa ([MþNa]þ): calcd 162.0913, 184.0733;
found 162.0917, 184.0739; melting point¼98–99 ꢀC (CH2Cl2), (lit.,20
mp¼92–95 ꢀC); IR (NaCl, thin film): nmax 3434, 2964, 2923, 1674,
1593, 1487, 1379, 1332, 1312, 1282, 1245,1219 cmꢁ1. 1H and 13C NMR
data are consistent with the reported values.20
(NaCl, thin film): nmax 3429, 1673, 1512, 1485, 1377, 1250 cmꢁ1
.
3.3.7. N-(2-Oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide 8h
Synthesised according to general procedure A on a 0.5 mmol
scale. The product precipitated from the reaction solution when
ethyl acetate was added. The product was filtered off from the so-
lution and washed with diethyl ether to give 8h as a white solid
3.3.4. 4-Phenyl-3,4-dihydro-1H-quinolin-2-one 8e
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:1 petrol/ethyl acetate) to yield 8e as pale yellow
(72 mg, 71%). 1H NMR (300 MHz, DMSO)
d: 10.30 (1H, br s, 1N-H),
8.17 (1H, d, J¼7.8 Hz, C3-NH), 7.19 (1H, d, J¼7.6 Hz, C5-H), 7.17 (1H, t,
J¼7.6 Hz, C7-H), 6.94 (1H, t, J¼7.6 Hz, C6-H), 6.87 (1H, d, J¼7.6 Hz,
C8-H), 4.45 (1H, app. q, J¼7.1 Hz, C3-H), 3.02 (1H, dd, J¼15.3, 6.6 Hz,
C4-HA), 2.86 (1H, app. t, J¼15.3 Hz, C4-HB),1.91 (3H, s, CH3); 13C NMR
crystals (65 mg, 58%). 1H NMR (300 MHz, CDCl3)
d: 8.48 (1H, br s,
NH), 7.37–7.18 (6H, m, phenyl C3-H, phenyl C2-H, C7-H and C6-H),
6.99–6.84 (3H, m, phenyl C4-H, C8-H and C5-H), 4.30 (1H, t,
J¼7.5 Hz, C4-H), 2.96–2.92 (2H, app. dd, J¼8.5, 6.0 Hz, C3-H2); 13C
(75 MHz, DMSO) d: 169.6, 169.1, 137.9, 128.4, 127.9, 122.8, 122.5,
115.4, 48.2, 31.9, 22.9; ESIHRMS for C11H12N2O2Na ([MþNa]þ): calcd
227.0791; found 227.0787; melting point¼227–229 ꢀC (CH2Cl2/
MeOH); IR (NaCl, thin film): nmax 3434, 1683, 1639, 1535, 1491, 1437,
NMR (75 MHz, CDCl3) d: 170.6, 141.5, 137.1, 128.9, 128.4, 128.0, 127.8,
127.2, 126.8, 123.4, 115.6, 42.1, 38.4; ESIHRMS for C15H14NO
([MþH]þ): calcd 224.1070; found 224.1061; melting point¼181–
182 ꢀC (CH2Cl2/MeOH), (lit.,20 mp¼177–178 ꢀC); IR (NaCl, thin film):
1402, 1341, 1293, 1266, 1243, 1219 cmꢁ1
.
nmax 3429, 1648, 1485, 1376 cmꢁ1
.
1H and 13C NMR data are con-
3.3.8. 4-(4-Nitrophenyl)-3,4-dihydro-1H-quinolin-2-one 8i
sistent with the reported values.21
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8i as yellow solid
3.3.5. 2-Oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid methyl
ester 8f and (2-oxo-2,3-dihydro-1H-indol-3-yl)-acetic
(50 mg, 37%). 1H NMR (300 MHz, CDCl3)
d: 8.79 (1H, br s, NH), 8.18
acid methyl ester
(2H, d, J¼8.7 Hz, nitrophenyl C3-H), 7.36 (2H, d, J¼8.7 Hz, nitro-
phenyl C2-H), 7.26 (1H, dt, J¼1.2, 7.6 Hz, C7-H,), 7.02 (1H, dt, J¼1.2,
7.6 Hz, C6-H), 6.94 (1H, d, J¼7.6 Hz, C5-H), 6.92 (1H, d, J¼7.6 Hz, C8-
H), 4.43 (1H, t, J¼6.9 Hz, C4-H), 3.03 (1H, dd, J¼16.2, 6.3 Hz, C3-HA),
Synthesis according to general procedure A but using 10 mol %
[Rh(cod)Cl]2 and 200 mol % KOH on a 0.5 mmol scale gave the crude
products as a brown oil. Purification by column chromatography
(3:2 petrol/ethyl acetate) yielded 8f as pale yellow crystals (41 mg,
40%) and (2-oxo-2,3-dihydro-1H-indol-3-yl)-acetic acid methyl
ester as a pale yellow oil (12 mg, 10%). Date for 8f: 1H NMR
2.91 (1H, dd, J¼16.2, 7.5 Hz, C3-HB); 13C NMR (75 MHz, CDCl3)
d:
170.0,149.5,147.6,137.4,130.3,129.2,128.8,125.2,124.6,124.2,116.5,
42.3, 38.5; ESIHRMS for C15H12N2O3Na ([MþNa]þ): calcd 291.0740;
found 291.0736; melting point¼203–204 ꢀC (CH2Cl2/MeOH); IR
(300 MHz, CDCl3) d: 9.08 (1H, br s, NH), 7.21–7.13 (2H, m, C7-H and
C5-H), 6.94 (1H, dt, J¼0.9, 7.5 Hz, C6-H), 6.81 (1H, dd, J¼7.8, 0.9 Hz,
C8-H), 3.88 (1H, dd, J¼6.8, 4.1 Hz, C4-H), 3.63 (3H, s, COOMe), 2.91
(1H, dd, J¼16.5, 4.1 Hz, C3-HA), 2.71 (1H, dd, J¼16.5, 6.8 Hz, C3-HB);
(NaCl, thin film): nmax 3434, 1641, 1219 cmꢁ1
.
3.3.9. 4-(4-Bromophenyl)-3,4-dihydro-1H-quinolin-2-one 8j
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8j as pale brown
13C NMR (75 MHz, CDCl3)
d: 171.0, 169.7, 136.2, 129.1, 128.9, 123.2,
119.0, 115.1, 51.5, 45.4, 33.1; ESIHRMS for C11H12NO3 ([MþH]þ) and
C11H11NO3Na ([MþH]þ): calcd 206.0812, 228.0631; found 206.0815,
228.0621; melting point¼168–170 ꢀC (CH2Cl2/MeOH), (lit.,22
mp¼170–171 ꢀC; DMSO); IR (NaCl, thin film): nmax 3446, 1740, 1661,
1617 cmꢁ1. 1H and 13C NMR data consistent with reported values.22
Data for (2-oxo-2,3-dihydro-1H-indol-3-yl)-acetic acid methyl
crystals (56 mg, 37%). 1H NMR (300 MHz, CDCl3)
d: 8.93 (1H, br s,
NH), 7.45 (2H, d, J¼8.4 Hz, bromophenyl C3-H), 7.22 (1H, dd, J¼7.5,
1.5 Hz, C7-H), 7.06 (2H, d, J¼8.4 Hz, bromophenyl C2-H), 6.98 (1H, dt,
J¼1.5, 7.5 Hz, C6-H), 6.89 (2H, m, C8-H and C5-H), 4.26 (1H, dd, J¼7.8,

9006
J. Horn et al. / Tetrahedron 65 (2009) 9002–9007
6.8 Hz, C4-H), 2.95 (1H, dd, J¼16.2, 6.8 Hz, C3-HA), 2.86 (1H, dd,
CDCl3) d: 9.68 (1H, br s, NH), 8.87 (1H, br s, quinoline C2-H), 8.10
J¼16.2, 7.8 Hz, C3-HB); 13C NMR (75 MHz, CDCl3)
d: 170.8, 140.9,
(1H, d, J¼8.1 Hz, quinoline C8-H), 7.86 (1H, s, quinoline C4-H), 7.73–
7.49 (3H, m, quinoline C5-H, C6-H and C7-H), 7.24 (1H, t, J¼7.8 Hz,
C7-H), 6.98–6.97 (3H, m, C8-H, C6-H and C5-H), 4.53 (1H, t,
J¼6.8 Hz, C4-H), 3.07–3.05 (2H, app. d, J¼6.8 Hz, C3-H2); 13C NMR
137.4,132.5,130.0,128.7,126.4,123.9,121.6,116.3, 42.0, 38.7; 12 of 13
expected signals observed; EIHRMS for C15H1279/81BrNO ([M]þ):
calcd 301.0102, 303.0082; found 301.0109, 303.0087; melting
point¼184–185 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film): nmax 3435,
(75 MHz, CDCl3) d: 170.9, 151.3, 147.9, 137.7, 134.7, 134.6, 129.9,
1644, 1486, 1377 cmꢁ1
.
129.6, 129.0, 128.6, 128.3, 128.1, 127.4, 125.6, 124.0, 116.6, 40.2, 38.5;
ESIHRMS for C18H15N2O ([MþH]þ): calcd 275.1179; found 275.1176;
melting point¼182–183 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film):
3.3.10. 4-(3-Bromophenyl)-3,4-dihydro-1H-quinolin-2-one 8k
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8k as pale brown
nmax 3434, 1644, 1488, 1420, 1376, 1245 cmꢁ1
.
3.3.14. 4-Thien-2-yl-3,4-dihydro-1H-quinolin-2-one 8o
crystals (51 mg, 34%). 1H NMR (300 MHz, CDCl3)
d
: 9.51 (1H, br s,
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8o as pale yellow
NH), 7.39 (1H, dt, J¼7.8, 1.5 Hz, bromophenyl C4-H), 7.33 (1H, t,
J¼1.8 Hz, bromophenyl C2-H), 7.25–7.16 (2H, m, C7-H and bromo-
phenyl C5-H and C7-H), 7.11 (1H, dt, J¼7.5, 1.2 Hz, bromophenyl C6-
H), 6.97 (1H, dt, J¼1.2, 7.5 Hz, C6-H), 6.94–6.89 (2H, m, C8-H and
C5-H), 4.26 (1H, t, J¼7.8 Hz, C4-H), 2.96 (1H, dd, J¼16.2, 6.3 Hz, C3-
crystals (43 mg, 38%). 1H NMR (300 MHz, CDCl3)
d: 9.22 (1H, br s,
NH), 7.23–7.17 (2H, m, C7-H and thienyl C5-H), 7.12 (1H, d, J¼7.5 Hz,
C5-H), 7.02 (1H, dt, J¼1.2, 7.5 Hz, C6-H), 6.92 (1H, dd, J¼5.1, 3.6 Hz,
thienyl C4-H), 6.88 (1H, dd, J¼7.5,1.3 Hz, C8-H), 6.82 (1H, d, J¼3.6 Hz,
thienyl C3-H), 4.54 (1H, t, J¼6.3 Hz, C4-H), 3.01 (1H, d, J¼6.3 Hz, C3-
HA), 2.86 (1H, dd, J¼16.2, 8.1 Hz, C3-HB); 13C NMR (75 MHz, CDCl3)
d:
171.2,144.4,137.5,131.3,130.9,130.8,128.8,128.7,126.9,126.1,123.9,
123.4, 116.5, 42.2, 38.8; ESIHRMS for C15H1379/81BrNO ([MþH]þ) and
C15H12Br79/81NONa ([MþNa]þ): calcd 302.0175/304.1555, 323.9994/
325.9992; found 302.0176/304.0160, 323.9987/325.9980; melting
point¼162–164 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film): nmax 3434,
HA), 3.01 (1H, d, J¼6.8 Hz, C3-HB); 13C NMR (75 MHz, CDCl3)
d: 170.8,
145.5, 137.0, 128.9, 128.5, 127.4, 126.7, 125.3, 125.0, 123.9, 116.4, 39.2,
38.0; ESIHRMS for C13H12NOS ([MþH]þ) and C13H11NONaS
([MþNa]þ): calcd 230.0634, 252.0454; found 230.0638, 252.0457;
melting point¼175–176 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film): nmax
1675, 1649, 1594, 1486, 1428, 1376, 1245, 1219 cmꢁ1
.
3434, 1643, 1490, 1434, 1389, 1311, 1269, 1252 cmꢁ1
.
3.3.11. 4-(2-Bromophenyl)-3,4-dihydro-1H-quinolin-2-one 8l
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8l as pale brown
3.3.15. 4-Pyridin-2-yl-3,4-dihydro-1H-quinolin-2-one 8p
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate to neat ethyl acetate) to
yield 8p as pale yellow crystals (55 mg, 49%). 1H NMR (300 MHz,
crystals (43 mg, 29%). 1H NMR (300 MHz, CDCl3)
d: 8.89 (1H, br s,
NH), 7.62 (1H, dd, J¼7.8, 1.5 Hz, bromophenyl C3-H), 7.26–7.19 (2H,
m, bromophenyl C5-H and C7-H), 7.12 (1H, dt, J¼1.8, 7.8 Hz, bro-
mophenyl C4-H), 7.01–6.95 (2H, m, bromophenyl C6-H and C6-H),
6.94–6.89 (2H, m, C8-H and C5-H), 4.84 (1H, t, J¼7.2 Hz, C4-H), 2.94
CDCl3)
d
: 8.84 (1H, br s, NH), 8.54 (1H, ddd, J¼4.8,1.8, 0.9 Hz, pyridyl
C6-H), 7.59 (1H, dt, J¼1.8, 7.5 Hz, pyridyl C4-H), 7.20 (1H, dt, J¼1.8,
7.5 Hz, C7-H), 7.15 (1H, ddd, J¼7.5, 4.8, 0.9 Hz, pyridyl C5-H), 7.08–
6.95 (3H, m, C6-H, C5-H and pyridyl C3-H), 6.87 (1H, d, J¼7.5 Hz,
C8-H), 4.44 (1H, t, J¼6.6 Hz, C4-H), 3.22 (1H, dd, J¼16.2, 6.3 Hz, C3-
HA), 2.97 (1H, dd, J¼16.2, 6.6 Hz, C3-HB); 13C NMR (75 MHz, CDCl3)
(2H, app. dd, J¼7.5, 6.9 Hz, C3-H2); 13C NMR (75 MHz, CDCl3)
d:
170.3, 140.6, 137.5, 133.4, 129.1, 128.8, 128.5, 128.4, 128.1, 125.3,
124.5, 123.6, 115.8, 41.2, 37.2; ESIHRMS for C15H1279/81BrNONa
([MþNa]þ): calcd 323.9994/325.9992; found 323.9980/325.9982;
melting point¼216–217 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film):
d: 171.3, 161.4, 150.3, 137.6, 137.2, 129.0, 128.7, 125.6, 123.7, 122.5,
116.3, 44.5, 36.8; 13 of 14 expected signals observed; ESIHRMS for
C14H13N2O ([MþH]þ): calcd 225.1022; found 225.1020; melting
point¼178–179 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film): nmax 3434,
nmax 3435, 1676, 1487, 1437, 1379, 1247 cmꢁ1
.
3.3.12. 4-(1-Ethyl-1H-indol-3-yl)-3,4-dihydro-1H-quinolin-
2-one 8m
1671, 1593, 1487, 1433, 1378, 1219 cmꢁ1
.
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate to neat ethyl acetate) to
yield 8m as pale yellow crystals (56 mg, 39%). 1H NMR (300 MHz,
3.3.16. 7-Trifluoromethyl-3,4-dihydro-1H-quinolin-2-one 8q
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8q as pale yel-
CDCl3)
d
: 8.47 (1H, br s, NH), 7.52 (1H, d, J¼7.8 Hz, indolyl C4-H or
low crystals (54 mg, 50%). 1H NMR (500 MHz, CDCl3)
d: 9.72 (1H, br
indolyl C7-H), 7.34 (1H, d, J¼8.1 Hz, indolyl C4-H or indolyl C7-H),
7.24–7.16 (2H, m, C7-H and indolyl C5/C6-H), 7.11–7.06 (2H, m, C5-H
and indolyl C5/C6-H), 6.93 (1H, dt, J¼0.9, 7.6 Hz, C6-H), 6.85 (1H, d,
J¼7.8 Hz, C8-H), 6.80 (1H, s, indolyl C2-H), 4.63 (1H, dd, J¼8.7,
6.0 Hz, C4-H), 4.09 (2H, q, J¼7.2 Hz, N-CH2), 3.11 (1H, dd, J¼16.1,
8.7 Hz, C3-HA), 2.95 (1H, dd, J¼16.1, 6.0 Hz, C3-HB), 1.41 (3H, t,
s, NH), 7.27 (1H, d, J¼8.0 Hz, C6-H), 7.24 (1H, d, J¼8.0 Hz, C5-H), 7.10
(1H, s, C8-H), 3.03 (2H, t, J¼7.7 Hz, C3-H2), 2.69 (2H, t, J¼7.7 Hz, C4-
H2); 13C NMR (75 MHz, CDCl3)
d
: 172.6, 138.4, 130.5 (q, J¼33 Hz, C7),
128.8, 127.9, 124.2 (q, J¼271 Hz, CF3), 120.1, 112.8, 30.6, 25.6;
EIHRMS for C10H8F3NO ([M]þ): calcd 215.0558; found 215.0551;
melting point¼149–150 ꢀC (CH2Cl2); IR (NaCl, thin film): nmax 3412,
J¼7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d
: 171.7,137.2,136.9,128.7,
1683, 1642, 1492, 1439, 1408, 1385, 1331, 1234 cmꢁ1
.
128.1, 127.5, 127.2, 125.3, 123.7, 122.1, 119.8, 119.5, 115.9, 114.9, 110.0,
41.3, 38.3, 34.3, 15.8; ESIHRMS for C19H18N2ONa ([MþNa]þ): calcd
313.1311; found 313.1315; melting point¼182–183 ꢀC (CH2Cl2/
3.3.17. 4-Methyl-7-trifluoromethyl-3,4-dihydro-1H-quinolin-
2-one 8r
MeOH); IR (NaCl, thin film): nmax 3434, 1641, 1379, 1219 cmꢁ1
.
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8r as pale yellow
3.3.13. 30,40-Dihydro-10H-[3,40]biquinolinyl-20-one 8n
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate to neat ethyl acetate) to
yield 8n as pale yellow crystals (53 mg, 39%). 1H NMR (300 MHz,
crystals (45 mg, 39%). 1H NMR (500 MHz, CDCl3)
d: 9.62 (1H, br s,
NH), 7.31 (1H, d, J¼8.3 Hz, C6-H), 7.28 (1H, d, J¼8.3 Hz, C5-H), 7.11
(1H, s, C8-H), 3.23–3.17 (1H, m, C4-H), 2.78 (1H, dd, J¼16.0, 5.5 Hz,
C3-HA), 2.48 (1H, dd, J¼16.0, 7.0 Hz, C3-HB), 1.35 (3H, d, J¼7.0 Hz,

J. Horn et al. / Tetrahedron 65 (2009) 9002–9007
9007
C4-CH3); 13C NMR (75 MHz, CDCl3)
d
: 172.0, 137.5, 132.9, 130.5 (q,
C3-H2); 13C NMR (100 MHz, CDCl3)
d
: 171.0, 145.2, 138.7, 132.1, 132.5
J¼33 Hz, C7), 127.5, 124.2 (q, J¼270 Hz, CF3), 120.4, 112.9, 38.2, 31.2,
20.0; ESIHRMS for C11H11F3NO ([MþH]þ) and C11H10F3NONa
([MþNa]þ): calcd 230.0787, 252.0607; found 230.0788, 252.0617;
melting point¼158–159 ꢀC (CH2Cl2); IR (NaCl, thin film): nmax 3412,
(q, J¼33 Hz, C7), 130.4, 128.7, 126.9, 126.7, 125.4 (q, J¼280 Hz, CF3),
121.8, 114.2, 39.9, 39.1; ESIHRMS for C14H11F3NOS ([MþH]þ): calcd
320.0327; found 320.0323; melting point¼179–180 ꢀC (CH2Cl2/
MeOH); IR (NaCl, thin film): nmax 3413, 1642, 1333, 1219 cmꢁ1
.
1682, 1637, 1485, 1405, 1377, 1339, 1219 cmꢁ1
.
3.3.22. 4-Pyridin-2-yl-7-trifluoromethyl-3,4-dihydro-1H-quinolin-
2-one 8x
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate to neat ethyl acetate) to
yield 8x as pale yellow crystals (52 mg, 33%). 1H NMR (500 MHz,
3.3.18. 4-Phenyl-7-trifluoromethyl-3,4-dihydro-1H-quinolin-
2-one 8s
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (1:3 petrol/diethyl ether) to yield 8s as pale yellow
crystals (62 mg, 43%).1H NMR (500 MHz, CDCl3)
d: 9.76 (1H, br s, NH),
CDCl3)
d
: 9.35 (1H, br s, NH), 8.59 (1H, d, J¼4.5 Hz, pyridyl C6-H),
7.37–7.28 (3H, m, phenyl C2-H and C6-H), 7.21–7.18 (3H, m, phenyl
C3-H and phenyl C4-H), 7.16 (1H, s, C8-H), 7.02 (1H, d, J¼7.5 Hz, C5-H),
4.34 (1H, t, J¼7.5 Hz, C4-H), 2.97 (2H, app. d, J¼7.5 Hz, C3-H2); 13C
7.64 (1H, dt, J¼1.5, 7.0 Hz, pyridyl C4-H), 7.23 (1H, d, J¼7.0 Hz,
pyridyl C3-H), 7.19 (1H, ddd, J¼7.0, 4.5, 1.5 Hz, pyridyl C5-H), 7.13–
7.11 (3H, m, C8-H, C6-H and C5-H), 4.49 (1H, t, J¼6.5 Hz, C4-H), 3.25
(1H, dd, J¼16.5, 6.5 Hz, C3-HA), 2.98 (1H, dd, J¼16.5, 6.5 Hz, C3-HB);
NMR (75 MHz, CDCl3)
d
: 171.6, 147.1, 140.9, 130.5 (q, J¼38 Hz, C7),
130.3, 129.6, 129.3, 128.2, 128.0, 124.1 (q, J¼270 Hz, CF3), 120.4, 113.1,
42.4, 38.3; ESIHRMS for C16H12F3NONa ([MþNa]þ): calcd 314.0763;
found 314.0756; melting point¼153–154 ꢀC (CH2Cl2/MeOH); IR
13C NMR (75 MHz, CDCl3)
d: 171.0, 160.0, 150.1, 137.8, 137.0, 130.7 (q,
J¼33 Hz, C7), 129.0, 123.9 (q, J¼271 Hz, CF3), 122.4, 122.1, 119.9,
119.7, 112.8, 43.9, 35.9; ESIHRMS for C15H12F3N2O ([MþH]þ): calcd
293.0896; found 293.0897; melting point¼186–187 ꢀC (CH2Cl2/
(NaCl, thin film): nmax 3400, 1685, 1638, 1481, 1332, 1219 cmꢁ1
.
MeOH); IR (NaCl, thin film): nmax 3429, 2099, 1642, 1473,1331 cmꢁ1
.
3.3.19. 4-(4-Methoxyphenyl)-7-trifluoromethyl-3,4-dihydro-1H-
quinolin-2-one 8t
Acknowledgements
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (1:3 petrol/diethyl ether) to yield 8t as pale yellow
We thank the EPSRC and GlaxoSmithKline for support through
grant EP/E020712/1. S.P.M. is a Royal Society Industry Fellow 2008–
2010.
crystals (74 mg, 46%). 1H NMR (500 MHz, CDCl3)
d: 9.45 (1H, br s,
NH), 7.21 (1H, d, J¼8.0 Hz, C6-H), 7.13–7.10 (3H, m, methoxyphenyl
C2-H and C8-H), 7.03 (1H, d, J¼8.0 Hz, C7-H), 6.89 (2H, d, J¼8.5 Hz,
methoxyphenyl C3-H), 4.30 (1H, t, J¼7.5 Hz, C4-H), 3.04 (3H, s,
References and notes
OCH3), 2.95–2.93 (2H, m, C3-H2); 13C NMR (75 MHz, CDCl3)
d: 171.4,
1. Morita, S.; Irie, Y.; Saitoh, Y.; Kohri, H. Biochem. Pharmacol. 1976, 25, 1836.
2. Nishi, T.; Tabusa, F.; Tanaka, T.; Shimizu, T.; Kanbe, T.; Kimura, Y.; Nakagawa, K.
Chem. Pharm. Bull. 1983, 31, 1151.
159.4,138.0,132.8,131.9 (q, J¼33 Hz, C7),131.5,131.3,129.3,124.1 (q,
J¼271 Hz, CF3), 120.4, 114.9, 113.0, 55.7, 41.6, 38.5; ESIHRMS for
C17H14F3NONa ([MþNa]þ): calcd 344.0869; found 344.0853;
melting point¼184–186 ꢀC (CH2Cl2/MeOH); IR (NaCl, thin film):
3. Semba, J.; Watanabe, A.; Kito, S.; Toru, M. Neuropharmacology 1995, 34, 785.
4. Bernauer, K.; Englert, G.; Vetter, W.; Weiss, E. Helv. Chim. Acta 1969, 52, 1886.
5. Uchida, R.; Imasoto, R.; Shiomi, K.; Tomoda, H.; Omura, S. Org. Lett. 2005, 7, 5701.
6. (a) Jones, G. In Comprehensive Heterocyclic Chemistry; Boulton, A. J., McKillop, A.,
Eds.; Pergamon: Oxford, 1984; Vol. 2, Chapter 8; (b) Johnston, K. M. Tetrahedron
1968, 24, 5595; (c) Li, K.; Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70, 2881.
7. Fujita, K.-i.; Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org. Lett.
2004, 6, 2785.
8. Clark, A. J.; Jones, K.; McCarthy, C.; Storey, J. M. D. Tetrahedron Lett.1991, 32, 2829.
9. (a) Wu, Y. L.; Chuang, C. P.; Lin, P. Y. Tetrahedron 2000, 56, 6209; (b) Binot, G.;
Zard, S. Z. Tetrahedron Lett. 2005, 46, 7503.
10. (a) Chapman, O. L.; Adams, W. R. J. Am. Chem. Soc. 1968, 90, 2333; (b) Ogata, Y.;
Takagi, K.; Ishino, I. J. Org. Chem. 1971, 36, 3975; (c) For a recent example uti-
lising Ugi condensation to establish the photocyclisation precursor, see: Akri-
topolou-Zanze, I.; Whitehead, A.; Waters, J. E.; Henry, R. F.; Djuric, S. W.
Tetrahedron Lett. 2007, 48, 3549.
11. (a) El Ali, B.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am. Chem. Soc. 1996, 118, 4264;
(b) Okuro, K.; Kai, H.; Alper, H. Tetrahedron: Asymmetry 1997, 8, 2307.
12. Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org. Lett. 2008, 10,
4117.
13. For examples of heterocycle formation from aminophenylboronates or N-pro-
tected derivatives by Suzuki coupling/condensation, see: (a) Siddiqui, M. A.;
Snieckus, V. Tetrahedron Lett. 1988, 29, 5463; (b) Cochennec, C.; Rocca, P.;
Marsais, F.; Godard, A.; Queguiner, G. J. Chem. Soc., Perkin Trans. 1 1995, 979; (c)
Chamoin, S.; Houldsworth, S.; Kruse, C. G.; Bakker, W. I.; Snieckus, V. Tetrahe-
dron Lett. 1998, 39, 4179; (d) Hodgetts, K. J.; Kershaw, M. T. Org. Lett. 2003, 5,
2911; (e) Gug, F.; Blondel, M.; Desban, M.; Bouaziz, S.; Vierfond, J.-M.; Galons, H.
Tetrahedron Lett. 2005, 46, 3725.
nmax 3434, 1642, 1331, 1254 cmꢁ1
.
3.3.20. 70-Trifluoromethyl-30,40-dihydro-10H-[3,40]biquinolinyl-20-
one 8v
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate to neat ethyl acetate) to
yield 8v as pale yellow crystals (82 mg, 47%). 1H NMR (300 MHz,
CDCl3)
d
: 9.63 (1H, br s, NH), 8.86 (1H, d, J¼2.4 Hz, quinolinyl C2-H),
8.12 (1H, d, J¼8.4 Hz, quinolinyl C8-H), 7.88 (1H, d, J¼2.4 Hz, qui-
nolinyl C4-H), 7.78–7.70 (2H, m, quinolinyl C5-H and C6/C7-H), 7.56
(1H, t, J¼7.6 Hz, quinolinyl C6/C7-H), 7.26 (1H, s, C8-H), 7.22 (1H, d,
J¼8.1 Hz, C6-H), 7.10 (1H, d, J¼8.1 Hz, C5-H), 4.59 (1H, t, J¼7.2 Hz,
C4-H), 3.09 (2H, d, J¼7.2 Hz, C3-CH2); 13C NMR (100 MHz, CDCl3)
d:
171.9, 152.2, 149.3, 139.5, 135.9, 134.9, 132.7 (q, J¼33 Hz, C7), 131.5,
131.0, 130.5, 130.3, 130.1, 129.5, 129.4, 125.3 (q, J¼271 Hz, CF3), 121.9,
114.6, 41.4, 39.3; ESIHRMS for C19H14F3N2O ([MþH]þ): calcd
343.1053; found 343.1039; melting point¼190–191 ꢀC (CH2Cl2/
MeOH); IR (NaCl, thin film): nmax 3401, 1638, 1331, 1331, 1219 cmꢁ1
.
14. Jones, G. In Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. W. F., Eds.; Pergamon: Oxford, 1996; Vol. 5, pp 167–243; For a recent
mechanistic study on this reaction, see: Denmark, S. E.; Venkataraman, S. J. Org.
Chem. 2006, 71, 1668.
3.3.21. 4-Thien-2-yl-7-trifluoromethyl-3,4-dihydro-1H-quinolin-2-
one 8w
15. (a) Itooka, R.; Iguchi, Y.; Miyaura, N. J. Org. Chem. 2003, 68, 6000; (b) Hayashi, T.;
Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052.
16. Navarro, C.; Morena, A.; Csaky, A. G. J. Org. Chem. 2009, 74, 466.
Synthesis according to general procedure B on a 0.5 mmol scale
gave the crude product as a brown oil. This was purified by column
chromatography (3:2 petrol/ethyl acetate) to yield 8was pale yellow
´
´
17. Baudoin, O.; Guenard, D.; Guerrite, F. J. Org. Chem. 2000, 65, 9268.
18. Koltunov, K. Y.; Prakash, G. K.; Rasul, G.; Olah, G. A. Heterocycles 2004, 62, 757.
19. Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218.
crystals (23 mg, 19%). 1H NMR (500 MHz, CDCl3)
d: 8.35 (1H, br s,
NH), 7.29–7.24 (3H, m, C5-H, C6-H and thienyl C5-H), 7.07 (1H, s, C8-
H), 6.96 (1H, dd, J¼5.0, 3.5 Hz, thienyl C4-H), 6.85 (1H, d, J¼3.5 Hz,
thienyl C3-H), 4.61 (1H, t, J¼6.5 Hz, C4-H), 3.04 (2H, app. d, J¼6.5 Hz,
20. Dong, C.; Alper, H. Tetrahedron: Asymmetry 2004, 15, 35.
21. Paquin, J. F.; Stephenson, C. R.; Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7, 3821.
´
22. Becerril, E. R.; Herna´ndez, N. P.; Nathan, P. J.; Rıos, M. S. Heterocycles 2007, 68,1459.