A Direct C-H/Ar-H Coupling Approach to Oxindoles, Thio-oxindoles, 3,4-Dihydro-1 H-quinolin-2-ones, and 1,2,3,4-Tetrahydroquinolines

Article abstract of DOI:10.1002/chem.201403917

A copper(II)-catalysed approach to oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines via formal C-H, Ar-H coupling is described. In a new variant, copper(II) 2-ethylhexanoate has been identified as an inexpensive and efficient catalyst for this transformation, which utilises atmospheric oxygen as the re-oxidant. Copper(II) 2-ethylhexanoate: The synthesis of oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines from linear precursors by direct C-H, Ar-H coupling by using a single copper catalyst is reported (see scheme; DIPEA=diisopropylethylamine, EWG=electron-withdrawing group). The cyclisations are simple to perform, run open to the air, are moisture insensitive, and use an inexpensive catalyst.

Full text of DOI:10.1002/chem.201403917

DOI: 10.1002/chem.201403917
Full Paper
&
CÀH Coupling
A Direct CÀH/ArÀH Coupling Approach to Oxindoles,
Thio-oxindoles, 3,4-Dihydro-1H-quinolin-2-ones, and
1,2,3,4-Tetrahydroquinolines
Timothy E. Hurst,[a] Ryan M. Gorman,[a] Pauline Drouhin,[a] Alexis Perry,[b] and
Richard J. K. Taylor*[a]
Abstract: A copper(II)-catalysed approach to oxindoles, thio-
oxindoles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetra-
hydroquinolines via formal CÀH, ArÀH coupling is described.
In a new variant, copper(II) 2-ethylhexanoate has been iden-
tified as an inexpensive and efficient catalyst for this trans-
formation, which utilises atmospheric oxygen as the re-oxi-
dant.
Introduction
Nitrogen-containing heterocycles represent an important class
of biologically active molecules. In particular, the oxindole unit
is a common structural feature in both natural products and
pharmaceuticals,[1] such as the anticancer agent sunitinib[2] (1,
US sales in excess of $1 bn in 2012) and the vasopressin
V2 receptor antagonist satavaptan[3] (2, Figure 1). Remarkably,
the thio-oxindole ammosamide A (3) has been isolated from
a marine-derived Streptomyces strain.[4] The 3,4-dihydro-1H-qui-
nolin-2-one ring system has been shown to exhibit varied and
potent biological activities.[5] Some structurally diverse exam-
ples include the dopamine agonist aripiprazole (4, US sales of
$5.9 bn in 2012), the spirocyclic alkaloid trigolutesin A[6] (5),
and the monoterpenoid alkaloid meloscine[7] (6). The extensive
bioactivity of 1,2,3,4-tetrahydroquinolines, including antitu-
mour, antiviral, antibacterial, antimalarial, and antifungal activi-
ty is well documented.[8] The 1,2,3,4-tetrahydroquinoline
moiety is also present in many synthetic and naturally occur-
ring compounds, for example the potent thrombin inhibitor ar-
gatroban[9] (7) and the complex alkaloid strychnochromine[10]
(8). The development of efficient procedures for the prepara-
[a] Dr. T. E. Hurst, R. M. Gorman, P. Drouhin, Prof. R. J. K. Taylor
Department of Chemistry
Figure 1. Examples of synthetic and naturally occurring oxindoles, thio-oxin-
doles, 3,4-dihydro-1H-quinolin-2-ones, and 1,2,3,4-tetrahydroquinolines.
University of York
Heslington, York, YO10 5DD (UK)
Fax: (+44)1904324523
E-mail: richard.taylor@york.ac.uk
tion of these important heterocycles is therefore of considera-
ble interest.
[b] Dr. A. Perry
Transition-metal-catalysed formation of the C3ÀC3a bond
has emerged as a key method for the synthesis of 3,3-disubsti-
tuted oxindoles.[1a,11] In particular, cyclisation reactions of pre-
Physics and Medical Imaging
College of Engineering, Mathematics and Physical Sciences
University of Exeter
Physics Building
Stocker Road, Exeter, EX4 4QL (UK)
functionalised anilides have predominated in this area.[12]
A
range of more recent metal-catalysed[13] and metal-free[14] ap-
proaches have also been reported.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403917.
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Heck reaction,[27] Ni0-mediated reductive cross-coupling,[28] BiIII-
catalysed Friedel–Crafts cyclisation,[29] domino reaction from
benzyl azide and enamides,[30] and intramolecular radical cycli-
sation.[31] Although many of these methods involve a CÀH acti-
vation event in one of the coupling partners,[26a–c,29–31] the syn-
thesis of 1,2,3,4-tetrahydroquinolines by the direct coupling of
two CÀH bonds remains a challenge.
As part of our ongoing interest in the development of new
approaches for the synthesis of biologically relevant heterocy-
cles, we sought to establish a general method for the synthesis
of a range of nitrogen-containing heterocycles. We now dis-
close Cu(2-ethylhexanoate)2 as a new and efficient catalyst for
the synthesis of 3,3-disubstituted oxindoles, thio-oxindoles,
and related 6-membered ring systems—3,4-dihydro-1H-quino-
lin-2-ones and 1,2,3,4-tetrahydroquinolines—by direct CÀH,
ArÀH coupling.
Scheme 1. Previous copper(II)-mediated approaches to oxindoles by direct
CÀH, ArÀH coupling.
In 2009, the research groups of Kꢁndig[15] and Taylor[16] inde-
pendently reported the cyclisation of linear anilides by direct
CÀH, ArÀH coupling, obviating the need for pre-functionalised
substrates, using inexpensive copper salts as stoichiometric ox-
idants (CuCl2 and Cu(OAc)2·H2O, respectively, Scheme 1). This
efficient procedure was further improved by the research
group of Taylor with the discovery that catalytic Cu(OAc)2·H2O
Results and Discussion
Optimisation
may be used with air serving as the terminal re-oxidant.[17]
A
The initial aim was to further optimise our previously establish-
ed[17a] conditions for the copper(II)-catalysed synthesis of oxin-
doles from linear anilides, and then apply this catalyst to
a range of nitrogen-containing heterocycles. Repetition of the
cyclisation of anilide 15a with 10 mol% Cu(OAc)2·H2O in tolu-
ene at 1208C for 15 h under an atmosphere of air gave desired
oxindole 16a in 85% yield (Table 1, entry 1). After a brief
screen of copper salts (entries 2–4), commercially available
mechanism involving deprotonation, radical formation, and ho-
molytic aromatic substitution was proposed, initially supported
by deuterium labelling[15] and radical-clock experiments,[16] and
subsequently by DFT calculations carried out by the research
group of Kꢁndig.[18]
3,4-Dihydro-1H-quinolin-2-ones have also attracted much at-
tention from synthetic organic chemists. With respect to dis-
connection of the C4ÀC4a bond (Scheme 2), 3,4-dihydro-1H-
Table 1. Optimisation of the formation of oxindoles using catalytic
copper salts.[a]
Scheme 2. Generalised approach to the synthesis of 3,4-dihydro-1H-quino-
lin-2-ones and 1,2,3,4-tetrahydroquinolines by formation of the C4ÀC4a
bond.
Entry Catalyst
x
Base
y
T
Yield[d]
[equiv] [8C] [%]
[mol%]
1
2
3
4
5
6
7[c]
8[c]
9[c]
Cu(OAc)2·H2O
Cu(2-PC)2
CuOTf(MeCN)4
Cu(2-ethylhexanoate)2 10
Cu(2-ethylhexanoate)2
Cu(2-ethylhexanoate)2 0.1
Cu(2-ethylhexanoate)2 10
Cu(2-ethylhexanoate)2 10
Cu(2-ethylhexanoate)2 10
10
10
10
–
–
–
–
–
–
–
NaH
piperidine 10
DBU
DIPEA
DIPEA
–
–
–
–
–
–
–
2
120 85
120 46
120 73
120 quant.[b]
120 71
120 16
100 34
100 (5)
100 45
100 (22)
100 89
80 35
quinolin-2-ones have been prepared by PdII-catalysed Heck re-
actions,[19] Pd0-catalysed cyclopropane ring expansions,[20]
through multi-component reactions,[21] and from olefinated N-
nitrosamines.[22] Transition-metal-catalysed conjugate addition/
cyclisation strategies have also proved effective for the synthe-
sis of 3,4-dihydro-1H-quinolin-2-ones.[23] Of particular relevance
to this work, free-radical cyclisation of linear anilides has been
demonstrated by several groups.[24] Notably, the majority of
classical methods rely on the use of pre-functionalised sub-
strates, while direct activation of aromatic CÀH bonds is less
common.
1
10[c] Cu(2-ethylhexanoate)2 10
11[c] Cu(2-ethylhexanoate)2 10
12[c] Cu(2-ethylhexanoate)2 10
2
2
2
[a] reactions were performed using 0.4 mmol of 15a at a concentration
of 0.05m. [b] other solvents were also examined: DMF (37%), MeCN
(trace), 1,4-dioxane (trace), DMSO (trace). [c] 40 h reaction time. [d] Yields
were determined upon isolation; values in parentheses represent yields
determined from the 1H NMR spectrum of the crude reaction mixture
using 1,1,2,2-tetrachloroethane as internal standard. 2-PC=2-pyrazinecar-
boxylate. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene. DIPEA=diisopropyle-
thylamine, Tf=trifluoromethanesulfonyl.
1,2,3,4-Tetrahydroquinolines have also been the subject of
considerable interest, and their synthesis has been recently re-
viewed.[8] In terms of formation of the C4ÀC4a bond, some
recent representative examples include Pd0-catalysed cyclopro-
pane CÀH activation,[25] Povarov reaction,[26] intramolecular
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Cu(2-ethylhexanoate)2 was identified as a superior catalyst,
giving 16a in quantitative yield (entry 4). Other solvents (DMF,
MeCN, dioxane, DMSO) were found to be unsuitable, giving
poor conversions. Reduction in the catalyst loading to 1 mol%
gave a lower but still synthetically useful 71% yield of the de-
sired oxindole (entry 5), although 0.1 mol% catalyst was not as
efficient (entry 6). Lowering the temperature to 1008C signifi-
cantly reduced the yield to 34%, even after an extended reac-
tion time (entry 7). Addition of bases was therefore examined
in an attempt to increase the yield at this lower temperature
(entries 8–11). DIPEA was found to be the best base, giving
89% yield of 16a at 1008C (entry 11). However, a relatively
long reaction time (40 h) was still required. Lowering the tem-
perature still further to 808C led to a poor yield of product,
even with the addition of base (entry 12). After extensive
screening, the optimum conditions with respect to catalyst
loading, temperature, and time are therefore: Cu(2-ethylhexa-
noate)2 (10 mol%), toluene, 1208C, 15 h; or, if lower tempera-
ture is required then Cu(2-ethylhexanoate)2 (10 mol%), DIPEA
(2.0 equiv), toluene, 1008C, 40 h.
to 2 equivalents, with the addition of DIPEA, at elevated tem-
perature. Importantly, poor conversion to 16e was observed
when Cu(OAc)2·H2O was used as catalyst, clearly demonstrating
the superiority of the Cu(2-ethylhexanoate)2 system.
Although less common than oxindoles, thio-oxindoles are
useful synthetic intermediates.[32] Typically, they are prepared
from pre-formed oxindoles on treatment with Lawesson’s re-
agent. We sought to extend our methodology by applying it
to the de novo construction of the thio-oxindole motif. In the
event, treatment of linear thioanilides 15 f,g with 10–20 mol%
catalyst delivered thio-oxindoles 16 f,g in excellent yield, pro-
viding new access to this class of heterocycle. It is noteworthy
that the cyclisation to give 16 f was conducted on multi-gram
scale.
Synthesis of 3,4-dihydro-1H-quinolin-2-ones
Having successfully established an improved catalyst system
for the synthesis of oxindoles, preparation of the correspond-
ing 3,4-dihydro-1H-quinolin-2-ones was next examined. The re-
quired linear anilides, 20a–g, were rapidly accessed in 2 steps
from commercially available anilines 17 by acylation followed
by alkylation with an activated methylene compound, general-
ly in high yield (Scheme 4).
Synthesis of oxindoles and thio-oxindoles
With the optimised conditions established, a series of repre-
sentative oxindoles 16a–e were prepared to test the scope of
this new catalyst system (Scheme 3). As expected, various acti-
vating groups were well tolerated in the reaction, and the
yields obtained were similar or better than those obtained
under the previous Cu(OAc)2·H2O conditions. In some cases
(EWG=CN, P(O)(OEt)2), switching the solvent to mesitylene
and increasing the temperature to 1708C was required to
obtain oxindoles 16c,d in high yield. Cyclisation of an anilide
bearing a sulfone (EWG=SO2Ph) proved somewhat sluggish
by using the standard conditions. However, quantitative yield
of 16e was obtained by increasing the amount of copper salt
Scheme 4. Synthesis of 3,4-dihydro-1H-quinolin-2-one cyclisation precursors
20a–g.
Tsubusaki and Nishino have previously demonstrated the
cyclisation of anilides to give 3,4-dihydro-1H-quinolin-2-ones in
high yield using manganese(III) acetate as the oxidant.[24d]
However, stoichiometric amounts (3–10 equiv) of Mn(OAc)3
were required in refluxing acetic acid as solvent, potentially
limiting the scalability and substrate scope. Cyclisation of
model substrate 20a under our milder catalytic conditions
[10 mol% Cu(2-ethylhexanoate)2, toluene, 1208C, 19 h] led to
a disappointing 46% conversion to desired 3,4-dihydro-1H-qui-
nolin-2-one 21a (Scheme 5). Pleasingly, cyclisation of 20a with
added base delivered 21a in quantitative yield.
The scope of this copper(II)-catalysed synthesis of 3,4-dihy-
dro-1H-quinolin-2-ones was next investigated. As may be ex-
pected from the results obtained with the corresponding oxin-
doles, a tert-butyl ester activating group could be utilised in
the reaction to give 21b in 74% yield. A benzyl protecting
group on the nitrogen atom and electron-donating and elec-
tron-withdrawing groups on the aromatic ring were also well
Scheme 3. Synthesis of oxindoles 16a–e and thio-oxindoles 16 f–g. Reac-
tions were performed using 0.285 mmol of 15 with 10 mol% catalyst at
a concentration of 0.05m unless otherwise stated. [a] Mesitylene was used
as solvent at 1708C for 3 h. [b] 2 equiv Cu(2-ethylhexanoate)2 and 5 equiv
DIPEA were used in mesitylene at 1708C for 19 h. [c] 2ꢂ10 mol% catalyst
and 2.4 equiv DIPEA were used for 48 h. [d] Reaction was conducted on
13.9 mmol scale. [e] 2.4 equiv DIPEA was added.
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Scheme 6. One-pot synthesis of 3,4-dihydro-1H-quinolin-2-one 21a.
Synthesis of tetrahydroquinolines
Having demonstrated the efficient synthesis of oxindoles and
3,4-dihydro-1H-quinolin-2-ones, attention turned to application
of the copper(II) catalyst system to the preparation of 1,2,3,4-
tetrahydroquinolines. The required cyclisation precursors 24a–j
were readily accessible in 2 steps from 2-((aryl)methylamino)al-
cohols 22a–i by simple conversion to the iodide followed by
alkylation (Scheme 7).
Scheme 5. Synthesis of 3,4-dihydro-1H-quinolin-2-ones 21a–g. Reactions
were performed by using 0.165 mmol of 20 with 10 mol% catalyst and
2.4 equiv DIPEA at a concentration of 0.04m unless otherwise stated. [a] In
the absence of DIPEA, 46% conversion was observed based on the ratio of
1
anilide to product in the H NMR spectrum of the crude reaction mixture.
[b] Mesitylene was used as solvent at 1658C for 2 h. [c] Reaction was con-
ducted on 0.500 mmol scale with 1 equiv of Cu(2-ethylhexanoate)2 in mesi-
tylene at 1658C for 21 h.
Scheme 7. Synthesis of 1,2,3,4-tetrahydroquinoline cyclisation precursors
24a–j.
In general, cyclisation of the aniline-derived substrates 24
was slightly lower yielding than the corresponding anilides 20.
For example, treatment of model substrate 24a with 10 mol%
copper(II) 2-ethylhexanoate gave 1,2,3,4-tetrahydroquinoline
25a in 72% yield after 19 h (Scheme 8). Once again, improved
conversion to the desired product was observed on addition
of DIPEA. Likewise, Cu(OAc)2·H2O proved an inferior catalyst,
with only 40% conversion observed in the same timeframe. In
the case of nitrile 25b, 1 equivalent of the copper salt was re-
quired to obtain a modest 51% yield. Substitution in the ali-
phatic chain was well tolerated, giving access to hexahydroa-
cridine 25c in 75% yield. Electron-neutral and electron-poor
anilines proved generally more amenable to cyclisation.
Indeed, anilines bearing a halogen substituent (R=F, Cl)
proved good substrates, giving 25d,e in 71–79% yield. More
tolerated (21c–e). Introduction of an alkyl group at C-3 (R3 =
Me) was shown to hinder the reaction under the previous
Mn(OAc)3 conditions, delivering 21 f in 61% yield along with
28% yield of an over-oxidation by-product. However, a much
improved yield of 93% was obtained by using our copper(II)-
catalysed transformation. A more complex substrate based on
the 1-aminoanthraquinone scaffold was also successfully cy-
clised to give tetracycle 21g in 52% yield, with the lower than
expected yield owing to competing hydrolysis of the amide
during the reaction. Notably, for those 3,4-dihydro-1H-quinolin-
2-ones previously prepared by Nishino’s stoichiometric
Mn(OAc)3 procedure (21a, 21c–f), equal or superior yields
were obtained using the copper(II) method, which uses only
catalytic amounts of transition-metal salt under much milder
reaction conditions.
electron-rich anilines (R=Me) required
a stoichiometric
We have previously demonstrated a telescoped alkylation/
cyclisation sequence for the synthesis of oxindoles.[16a] It was
anticipated that a similar strategy could be applied to the one-
pot synthesis of 3,4-dihydro-1H-quinolin-2-ones. In the event,
treatment of 19a with diethyl malonate and KOtBu in toluene
at 608C for 6 h, followed by addition of copper(II) 2-ethylhexa-
noate and DIPEA and heating at 1208C for a further 18 h deliv-
ered 3,4-dihydro-1H-quinolin-2-one 21a in 58% unoptimised
yield (Scheme 6).
amount of copper to give a modest yield of 25 f, while incor-
poration of a para-methoxy group retarded the reaction com-
pletely, leading to complete decomposition of the starting ma-
terial. Assuming a similar mechanism to that proposed for the
synthesis of oxindoles is in operation, these results are some-
what incongruous given that homolytic aromatic substitution
should actually be preferred between an electron-rich aromatic
ring and the electron-deficient radical derived from a malonate.
To ensure that a radical mechanism was indeed in operation,
control reactions were carried out by performing the cyclisa-
tion of 24e and 24j in the presence of DIPEA but without cop-
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Scheme 8. Synthesis of tetrahydroquinolines 25a–j. Reactions were per-
formed using 0.30–1.00 mmol of 24 with 10 mol% catalyst and 2.2 equiv
DIPEA at a concentration of 0.1m unless otherwise stated. [a] In the absence
of DIPEA, 69% conversion was observed based on the ratio of aniline to
1
product in the H NMR spectrum of the crude reaction mixture.
[b] 100 mol% catalyst used. [c] 20 mol% catalyst used.
per(II) 2-ethylhexanoate. In both cases only starting material
was recovered, ruling out nucleophilic aromatic substitution as
a competing mechanism. Further support for a radical mecha-
nism was obtained by observing the regioselectivity in the cyc-
lisation of meta-substituted substrates 24h and 24j. In the
event, meta-methoxy substrate 24h gave a separable 2:1 mix-
ture of ortho- and para-cyclisation products (25h/25h’), while
the meta-nitro aniline 24j gave solely para-cyclised product
25j. Both these results may be rationalised by homolytic aro-
matic substitution to give preferentially the most stable radical,
as previously observed in the synthesis of oxindoles.[17b]
Scheme 9. Double copper(II)-catalysed cyclisation of linear 1,4-bis-anilides.
Firstly, cyclisation of linear bis-anilide 26 gave a separable
mixture of bis-oxindoles 27/27’ in 35% and 11% yield, respec-
tively, the structures of which were assigned based on HMBC
correlations.[35] Both 27 and 27’ were obtained as an insepara-
ble mixture of diastereomers, in a ratio of 3.5:1 and 1.4:1, re-
spectively. Furthermore, cyclisation of anilide 28 gave bis-3,4-
dihydro-1H-quinolin-2-one 29 as a single product in 59% yield.
Finally, a mixed linear precursor 30 corresponding to both the
oxindole and 3,4-dihydro-1H-quinolin-2-one ring systems was
prepared, giving tricyclic product 31 in good yield.
Double cyclisations to access fused tricyclic systems
Dihydropyrroloindolediones have recently been accessed by
a double Pummerer rearrangement,[33] and have been used to
prepare copolymers that have shown promise in organic elec-
tronics applications.[34] However, the substrates for the Pum-
merer rearrangement required multi-step synthesis. We envis-
aged an expeditious route to this class of heterocycle by using
our copper(II)-catalysed transformation. As such, the double
cyclisation of 1,4-diaminobenzene derivatives was examined
(Scheme 9).
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(Me), 23.5 ppm (Me). Physical and spectral data were found to be
consistent with those reported.[16a]
Conclusion
In summary, we report a simple copper(II) catalyst for the syn-
thesis of oxindoles, thio-oxindoles, 3,4-dihydro-1H-quinolin-2-
ones, and 1,2,3,4-tetrahydroquinolines from linear precursors
by direct CÀH, ArÀH coupling. The cyclisations are simple to
perform, are run open to the air, are moisture insensitive, and
use an inexpensive catalyst. Furthermore, our catalyst system
has been shown to be superior to existing methods, including
Cu(OAc)2·H2O and Mn(OAc)3. Applications involving double cyc-
lisations hold promise for future studies. Application of this
copper(II)-catalysed methodology in the total synthesis of nat-
ural products is also under investigation.
Diethyl 1,3-dimethyl-2-oxoindolin-3-ylphosphonate 16d: reac-
tion was conducted in mesitylene at 1708C for 3 h; colourless oil;
Rf =0.20 (EtOAc/petroleum ether 4:1); 1H NMR (400 MHz, CDCl3):
d=7.43 (d, J=7.9 Hz, 1H), 7.26 (tt, J=7.9, 1.5 Hz, 1H), 7.04 (t, J=
7.9 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 4.14 (dq, J=8.6(H,P), 7.1 Hz,
2H), 3.92 (ddq, J=10.2, 8.6(H,P), 7.1 Hz, 1H), 3.81 (ddq, J=10.2,
8.6(H,P), 7.1 Hz, 1H), 3.19 (s, 3H), 1.66 (d, J(H,P)=17.3 Hz, 3H), 1.31
(t, J=7.1 Hz, 3H), 1.02 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=174.7 (d, J(C,P)=2.5 Hz, C), 143.7 (d, J(C,P)=7.5 Hz, C),
128.8 (d, J(C,P)=2.8 Hz, CH), 127.9 (d, J(C,P)=6.0 Hz, C), 125.2 (d,
J(C,P)=3.7 Hz, CH), 122.7 (d, J(C,P)=3.0 Hz, CH), 108.1 (d, J(C,P)=
1.3 Hz, CH), 64.0 (d, J(C,P)=6.9 Hz, CH2), 63.2 (d, J(C,P)=7.5 Hz,
CH2), 50.0 (d, J(C,P)=136.9 Hz, C), 26.7 (Me), 18.6 (d, J(C,P)=6.2 Hz,
Me), 16.5 (d, J(C,P)=5.7 Hz, Me), 16.2 ppm (d, J(C,P)=5.6 Hz, Me);
IR (ATR): n˜ =1711 cmÀ1 (C=O); HRMS (ESI): m/z calcd for
C14H20NO4P+Na+: 320.1022 [M+Na+]; found: 320.1022. Physical
and spectral data were found to be consistent with those
reported.[16a]
Experimental Section
General procedure for the copper(II)-catalysed synthesis of
oxindoles 16a–e (Scheme 3)
A solution of the anilide 15 (0.285 mmol) and copper(II) 2-ethylhex-
anoate (10.0 mg, 10 mol%) in toluene (5 mL) was stirred at 1208C
for 19 h under a reflux condenser open to the air. After cooling to
rt, the toluene was removed under reduced pressure and EtOAc
(10 mL) was added. The organic phase was washed with saturated
NH4Cl (10 mL), and the aqueous layer back extracted with EtOAc
(10 mL). The combined organic layers were washed with 10%
NH4OH (10 mL) and saturated brine (2ꢂ10 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was puri-
fied by flash chromatography on silica gel, eluting with EtOAc/pe-
troleum ether (1:4), to afford the title compound.
1,3-Dimethyl-3-(phenylsulfonyl)indolin-2-one 16e: reaction was
conducted with 2 equiv of catalyst and with 5 equiv of DIPEA in
mesitylene at 1708C for 19 h; colourless solid; Rf =0.30 (EtOAc/pe-
1
troleum 1:1); m.p. 109–1118C; H NMR (500 MHz, CDCl3): d=7.64
(dd, J=7.6, 1.0 Hz, 1H), 7.56–7.50 (m, 3H), 7.37–7.29 (m, 3H), 7.15
(td, J=7.6, 1.0 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 2.91 (s, 3H),
1.90 ppm (s, 3H); 13C NMR (125 MHz, CDCl3): d=170.9 (C), 143.9
(C), 134.6 (C), 134.2 (CH), 130.6 (CH), 130.2 (CH), 128.3 (CH), 126.4
(CH), 124.1 (C), 123.3 (CH), 108.2 (CH), 70.9 (C), 26.4 (Me), 15.8 ppm
(Me); IR (ATR): n˜ =1718 cmÀ1 (C=O); HRMS (ESI): m/z calcd for
C16H15NO3S+Na+: 324.0665 [M+Na+]; found: 324.0659.
Ethyl 1,3-dimethyl-2-oxoindoline-3-carboxylate 16a: yellow oil;
Rf =0.21 (EtOAc/petroleum ether 1:4); 1H NMR (400 MHz, CDCl3):
d=7.30 (td, J=7.6, 1.2 Hz, 1H), 7.23 (dd, J=7.6, 1.2 Hz, 1H), 7.04
(td, J=7.6, 1.2 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.12 (dq, J=11.0,
7.1 Hz, 1H), 4.07 (dq, J=11.0, 7.1 Hz, 1H), 3.23 (s, 3H), 1.64 (s, 3H),
1.13 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=175.1
(C), 169.6 (C), 143.5 (C), 130.1 (C), 128.9 (CH), 122.8 (CH), 122.7 (CH),
108.3 (CH), 61.8 (CH2), 54.9 (C), 26.4 (Me), 20.0 (Me), 13.8 ppm (Me);
IR (ATR): n˜ =1729 (C=O), 1689 cmÀ1 (C=O); HRMS (ESI): m/z calcd
for C13H15NO3 +H+: 234.1125 [M+H+]; found: 234.1126. Physical
and spectral data were found to be consistent with those
reported.[16a]
Ethyl 1,3-dimethyl-2-thioxoindoline-3-carboxylate 16 f: A solu-
tion of ethyl 2-methyl-3-(methyl(phenyl)amino)-3-thioxopropanoate
15 f (3.50 g, 13.9 mmol), copper(II) 2-ethylhexanoate (0.486 g, 10
mol%), and DIPEA (5.81 mL, 33.4 mmol) in toluene (360 mL) was
stirred at 1208C for 24 h under a reflux condenser open to the air.
Further catalyst (0.486 g, 10 mol%) was added and stirring contin-
ued at 1208C for a further 24 h. After cooling to rt, the toluene
was removed under reduced pressure and EtOAc (100 mL) was
added. The organic phase was washed with 10% HCl (60 mL), 10%
NH4OH (60 mL), and saturated brine (60 mL), dried over MgSO4, fil-
tered, and concentrated in vacuo. The crude product was purified
by flash chromatography on silica gel, eluting with EtOAc/petrole-
um ether (3:17), to afford the title compound as an off-white
powder (2.69 g, 78%). Rf =0.23 (EtOAc/petroleum 2:5); m.p. 66–
678C; 1H NMR (400 MHz, CDCl3): d=7.38 (td, J=7.6, 1.2 Hz, 1H),
7.28 (dd, J=7.6, 1.2 Hz, 1H), 7.18 (td, J=7.6, 1.2 Hz, 1H), 7.04 (d,
J=7.6 Hz, 1H), 4.14 (dq, J=10.8, 7.1 Hz, 1H), 4.03 (dq, J=10.8,
7.1 Hz, 1H), 3.66 (s, 3H), 1.74 (s, 3H), 1.10 ppm (t, J=7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=203.9 (C), 169.2 (C), 145.1 (C), 134.7
(C), 128.9 (CH), 124.5 (CH), 122.9 (CH), 109.7 (CH), 65.2 (C), 61.9
(CH2), 31.5 (Me), 23.9 (Me), 13.8 ppm (Me); IR (ATR): n˜ =1736 (C=O),
1101 cmÀ1 (C=S); HRMS (ESI): m/z calcd for C13H15NO2S+Na+:
272.0896 [M+Na+]; found: 272.0905.
tert-Butyl 1,3-dimethyl-2-oxoindoline-3-carboxylate 16b: colour-
1
less oil; Rf =0.50 (EtOAc/petroleum ether, 1:1); H NMR (400 MHz,
CDCl3): d=7.29 (td, J=7.6, 1.0 Hz, 1H), 7.22 (dd, J=7.6, 1.0 Hz,1H),
7.03 (td, J=7.6, 1.0 Hz,1H), 6.83 (d, J=7.6 Hz,1H), 3.21 (s,3H), 1.59
(s, 3H), 1.32 ppm (s, 9H); 13C NMR (100 MHz, CDCl3): d=175.6 (C),
168.7 (C), 143.8 (C), 130.7 (C), 128.8 (CH), 122.8 (CH),122.8 (CH),
108.3 (CH), 82.3 (C), 56.1 (C), 27.7(Me), 26.5 (Me), 19.8 ppm (Me).
Physical and spectral data were found to be consistent with those
reported.[16a]
1,3-Dimethyl-2-oxoindoline-3-carbonitrile 16c: reaction was con-
ducted in mesitylene at 1708C for 3 h; pale yellow oil; Rf =0.60
(EtOAc/petroleum ether, 1:1); 1H NMR (400 MHz, CDCl3): d=7.41
(d, J=7.6 Hz, 1H), 7.39 (td, J=7.6, 1.0 Hz, 1H), 7.16 (td, J=7.6,
1.0 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 3.25 (s, 3H), 1.80 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=171.1 (C), 142.6 (C), 130.4 (CH),
126.9 (C), 124.0 (CH), 123.8 (CH), 117.8 (C), 109.3 (CH), 42.2 (C), 27.1
Ethyl 1-benzyl-3-methyl-2-thioxoindoline-3-carboxylate 16g: A
solution of ethyl 3-(benzyl(phenyl)amino)-2-methyl-3-thioxopropa-
noate 15g (0.107 g, 0.326 mmol), copper(II) 2-ethylhexanoate
(11.4 mg, 10 mol%), and DIPEA (0.136 mL, 0.782 mmol) in toluene
(8 mL) was stirred at 1208C for 15 h under a reflux condenser open
Chem. Eur. J. 2014, 20, 14063 – 14073
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to the air. After cooling to rt, the toluene was removed under re-
duced pressure and EtOAc (15 mL) was added. The organic phase
was washed with 10% HCl (2ꢂ15 mL), 10% NH4OH (2ꢂ15 mL),
and saturated brine (15 mL), dried over MgSO4, filtered, and con-
centrated in vacuo. The crude product was purified by flash chro-
matography on silica gel, eluting with EtOAc/petroleum ether (1:9),
to afford the title compound as a colourless powder. Rf =0.21
(EtOAc/petroleum ether 1:9); m.p. 76–788C; 1H NMR (400 MHz,
CDCl3): d=7.35–7.22 (m, 7H), 7.14 (t, J=7.5 Hz, 1H), 6.87 (d, J=
7.5 Hz, 1H), 5.79 (d, J=15.5 Hz, 1H), 5.17 (d, J=15.5 Hz, 1H), 4.24–
4.16 (m, 1H), 4.06–3.98 (m, 1H), 1.81 (s, 3H), 1.13 ppm (t, J=7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=204.7 (C), 169.2 (C), 144.3 (C),
134.6 (C), 134.3 (C), 128.9 (CH), 128.7 (CH), 127.7 (CH), 126.9 (CH),
124.4 (CH), 122.9 (CH), 110.6 (CH), 65.3 (C), 62.0 (CH2), 47.8 (CH2),
23.8 (Me), 13.7 ppm (Me); IR (ATR): n˜ =1738 (C=O), 1108 cmÀ1 (C=
S); HRMS (ESI): m/z calcd for C19H19NO2S+H+: 326.1209 [M+H+];
found: 326.1216.
7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=169.0 (C), 166.8 (C),
138.9 (C), 136.4 (C), 129.3 (CH), 128.7 (CH), 128.1 (CH), 127.1 (CH),
126.4 (CH), 123.3 (CH), 122.7 (C), 116.2 (CH), 62.5 (CH2), 57.0 (C),
45.9 (CH2), 38.1 (CH2), 13.9 ppm (Me); IR (ATR): n˜ =1757 (C=O),
1724 (C=O), 1678 cmÀ1 (C=O); HRMS (ESI): m/z calcd for
C22H23NO5 +Na+: 404.1468 [M+Na+]; found: 404.1465. Physical
and spectral data were found to be consistent with those repor-
ted.[24d]
Diethyl
6-methoxy-1-methyl-2-oxo-2,3-dihydroquinoline-
4,4(1H)-dicarboxylate 21d: yellow oil; Rf =0.38 (EtOAc/petroleum
1
ether 1:1); H NMR (400 MHz, CDCl3): d=6.95–6.91 (m, 1H), 6.89–
6.84 (m, 2H), 4.31–4.19 (m, 4H), 3.77 (s, 3H), 3.28 (s, 3H), 3.18 (s,
2H), 2.25 ppm (t, J=7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
168.8 (C), 166.3 (C), 155.3 (C), 133.4 (C), 123.8 (C), 116.2 (CH), 114.1
(CH), 113.7 (CH), 62.4 (CH2), 56.9 (C), 55.5 (Me), 38.0 (CH2), 29.7
(Me), 13.9 ppm (Me); IR (ATR): n˜ =1730 (C=O), 1675 cmÀ1(C=O);
HRMS (ESI): m/z calcd for C17H21NO6 +Na+: 358.1261 [M+Na+];
found: 358.1258. Physical and spectral data were found to be con-
sistent with those reported.[24d]
General procedure for the copper(II)-catalysed synthesis of
3,4-dihydro-1H-quinolin-2-ones 21a–g (Scheme 5)
To a solution of the anilide 20 (0.165 mmol) and copper(II) 2-ethyl-
hexanoate (5.8 mg, 10 mol%) in toluene (4 mL) was added DIPEA
(69.0 mL, 0.432 mmol). The reaction mixture was stirred at 1208C
for 15 h under a reflux condenser open to the air. After cooling to
rt, the toluene was removed under reduced pressure and EtOAc
(10 mL) was added. The organic phase was washed with 10% HCl
(10 mL), 10% NH4OH (10 mL), and saturated brine (10 mL), dried
over MgSO4, filtered, and concentrated in vacuo. The crude prod-
uct was purified by flash chromatography on silica gel, eluting
with EtOAc/petroleum ether (1:3 to 2:3), to afford the title com-
pound.
Diethyl 1-methyl-6-nitro-2-oxo-2,3-dihydroquinoline-4,4(1H)-di-
carboxylate 21e: yellow solid; Rf =0.23 (EtOAc/petroleum ether
2:3); m.p. 82–848C (lit. 898C); H NMR (400 MHz, CDCl3): d=8.30–
1
8.23 (m, 2H), 7.13 (d, J=8.9 Hz, 1H), 4.32–4.22 (m, 4H), 3.39 (s,
3H), 3.27 (s, 2H), 1.31–1.27 ppm (m, 6H); 13C NMR (100 MHz,
CDCl3): d=167.9 (C), 166.3 (C), 145.2 (C), 142.8 (C), 125.2 (CH),
124.0 (CH), 123.0 (C), 115.4 (CH), 63.0 (CH2), 56.3 (C), 37.3 (CH2),
30.0 (Me), 13.9 ppm (Me); IR (ATR): n˜ =1731 (C=O), 1696 cmÀ1(C=
O); HRMS (ESI): m/z calcd for C16H18N2O7 +Na+: 373.1006
[M+Na+]; found: 373.1000. Physical and spectral data were found
to be consistent with those reported.[24d]
Diethyl 1-methyl-2-oxo-2,3-dihydroquinoline-4,4(1H)-dicarboxy-
late 21a: colourless powder; Rf =0.23 (EtOAc/petroleum ether
3:10); m.p. 80–818C (lit. 86–878C); H NMR (400 MHz, CDCl3): d=
Diethyl 1,3-dimethyl-2-oxo-2,3-dihydroquinoline-4,4(1H)-dicar-
boxylate 21 f: colourless solid; Rf =0.45 (EtOAc/petroleum ether
1:1); m.p. 59–618C (lit. 60–618C); 1H NMR (400 MHz, CDCl3): d=
7.53 (dd, J=7.6, 1.2 Hz, 1H), 7.36–7.31 (m, 1H), 7.10 (td, J=7.6,
1.2 Hz, 1H), 6.98 (dd, J=7.6, 1.2 Hz, 1H), 4.30–4.07 (m, 4H), 3.33 (s,
3H), 3.30 (q, J=7.2 Hz, 1H), 1.23 (t, J=7.1 Hz, 3H), 1.21 (t, J=
7.2 Hz, 3H), 1.21 ppm (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=169.9 (C), 169.1 (C), 167.7 (C), 139.6 (C), 129.5 (CH),
129.2 (CH), 123.0 (CH), 121.5 (C), 114.9 (CH), 62.1 (CH2), 61.7 (CH2),
60.6 (C), 41.3 (CH), 29.8 (Me), 13.9 (Me), 13.8 (Me), 12.5 ppm (Me);
IR (ATR): n˜ =1706 (C=O), 1659 cmÀ1 (C=O); HRMS (ESI): m/z calcd
for C17H21NO5 +Na+: 342.1312 [M+Na+]; found: 342.1309. Physical
and spectral data were found to be consistent with those repor-
ted.[24d]
1
7.35 (ddd, J=8.0, 7.2, 1.6 Hz, 1H), 7.28 (dd, J=8.0, 1.6 Hz, 1H), 7.09
(td, J=7.6, 1.2 Hz, 1H), 7.01 (dd, J=8.0, 1.2 Hz, 1H), 4.28–4.21 (m,
4H), 3.32 (s, 3H), 3.22 (s, 2H), 1.25 ppm (t, J=7.2 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=169.1 (C), 166.8 (C), 140.0 (C), 129.5 (CH),
127.9 (CH), 123.3 (CH), 122.7 (C), 115.4 (CH), 62.5 (CH2), 57.0 (C),
38.1 (CH2), 29.7 (Me), 14.0 ppm (Me); IR (ATR): n˜ =1729 (C=O),
1658 cmÀ1 (C=O); HRMS (ESI): m/z calcd for C16H19NO5 +H+:
306.1336 [M+H+]; found: 306.1336. Physical and spectral data
were found to be consistent with those reported.[24d]
Di(tert-butyl) 1-methyl-2-oxo-2,3-dihydroquinoline-4,4(1H)-dicar-
boxylate 21b: reaction was conducted in mesitylene at 1658C for
2 h; colourless solid; Rf =0.58 (EtOAc/petroleum 1:1); m.p. 69–
1
718C; H NMR (400 MHz, CDCl3): d=7.39 (dd, J=7.7, 1.5 Hz, 1H),
4,4-Diethyl 1-methyl-2,7,12-trioxo-1,2,3,4,7,12-hexahydro-1-aza-
tetraphene-4,4-dicarboxylate 21g: reaction was conducted with
1 equiv of catalyst and with 2.2 equiv of DIPEA in mesitylene at
1658C for 21 h; yellow solid; Rf =0.50 (EtOAc/CH2Cl2 1:9); m.p.
160.5–162.58C; 1H NMR (400 MHz, CDCl3): d=8.26–8.24 (m, 1H),
8.21–8.18 (m, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.83–7.76 (m, 2H), 7.71
(d, J=8.0 Hz, 1H), 4.36–4.24 (m, 4H), 3.30 (s, 2H), 3.11 (s, 3H),
1.29 ppm (t, J=7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=182.6
(C), 182.4 (C), 168.0 (C), 167.4 (C), 142.5 (C), 135.3 (C), 135.0 (C),
134.5 (CH), 133.9 (CH), 133.7 (C), 132.3 (C), 131.9 (CH), 127.2 (CH),
126.9 (CH), 124.3 (C), 123.3 (CH), 63.0 (CH2), 57.1 (C), 38.1 (CH2),
37.9 (Me), 14.0 ppm (Me); IR (ATR): n˜ =1732 (C=O), 1695 (C=O),
1669 cmÀ1 (C=O); HRMS (ESI): m/z calcd for C24H21NO7 +Na+:
458.1210 [M+Na+]; found: 458.1229.
7.34 (ddd, J=8.1, 7.5, 1.5 Hz, 1H), 7.10 (td, J=7.6, 1.2 Hz, 1H), 7.01
(dd, J=8.2, 1.0 Hz, 1H), 3.33 (s, 3H), 3.10 (s, 2H), 1.47 ppm (s,
18H); 13C NMR (100 MHz, CDCl3): d=168.1(C), 167.2 (C), 139.9 (C),
129.0 (CH), 127.5 (CH), 123.6 (C), 123.0 (CH), 115.2 (CH), 82.9 (C),
57.8 (C), 38.4 (CH2), 29.6 (Me), 27.7 ppm (Me); IR (ATR): n˜ =1728 (C=
O), 1686 cmÀ1 (C=O); HRMS (ESI): m/z calcd for C20H27NO5 +Na:
384.1718 [M+Na]; found: 384.1788.
Diethyl 1-benzyl-2-oxo-2,3-dihydroquinoline-4,4(1H)-dicarboxy-
late 21c: colourless crystals; Rf =0.50 (EtOAc/petroleum ether 1:1);
m.p. 80–818C (lit. 96–978C); 1H NMR (400 MHz, CDCl3): d=7.34–
7.14 (m, 7H), 7.05 (td, J=7.6, 1.2 Hz, 1H), 6.92 (dd, J=8.2, 1.0 Hz,
1H), 5.17 (s, 2H), 4.32–4.21 (m, 4H), 3.36 (s, 2H), 1.27 ppm (t, J=
Chem. Eur. J. 2014, 20, 14063 – 14073
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One-pot synthesis of diethyl 1-methyl-2-oxo-2,3-dihydroquino-
line-4,4(1H)-dicarboxylate 21a from 2-bromo-N-methyl-N-phe-
nylacetamide 19a (Scheme 6): To a stirred solution of diethylmalo-
nate (66.0 mL, 0.432 mmol) in toluene (4 mL) was added KOtBu
(54.0 mg, 0.482 mmol) and the reaction mixture stirred at rt for
10 min. 2-Bromo-N-methyl-N-phenylacetamide 19a (0.100 g,
0.438 mmol) in toluene (2 mL) was then added by cannula and stir-
ring maintained at 608C for 6 h under an atmosphere of air. Cop-
per(II) 2-ethylhexanoate (15.0 mg, 10 mol%) and DIPEA (0.182 mL,
1.05 mmol) were added and the solution stirred at 1208C for 18 h.
The reaction mixture was worked up and purified as outlined in
the general procedure to afford the title compound (77.0 mg,
58%) as a colourless powder. Data as above.
(ATR): n˜ =1735 (C=O), 1716 cmÀ1 (C=O); HRMS (ESI): m/z calcd for
C20H27NO4 +H+: 346.2013 [M+H+]; found: 346.2009.
Diethyl
6-fluoro-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicar-
boxylate 25d: colourless solid; Rf =0.31 (EtOAc/petroleum ether
1:9); m.p. 44–45.58C; 1H NMR (400 MHz, CDCl3): d=7.03 (dd, J=
9.9, 3.0 Hz, 1H), 6.91 (ddd, J=9.0, 7.8, 3.0 Hz, 1H), 6.57 (dd, J=9.0,
4.7 Hz, 1H), 4.29–4.18 (m, 4H), 3.18–3.16 (m, 2H), 2.86 (s, 3H),
2.53–2.50 (m, 2H), 1.27 ppm (t, J=7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3): d=171.0 (C), 154.7 (d, J(C,F)=237 Hz, C), 143.0 (d, J(C,F)=
1.5 Hz, C), 118.7 (d, J(C,F)=7.1 Hz, C), 117.0 (d, J(C,F)=23.4 Hz, CH),
115.8 (d, J(C,F)=21.8 Hz, CH), 112.7 (d, J(C,F)=7.4 Hz, CH), 62.1
(CH2), 57.1 (d, J(C,F)=1.1 Hz, C), 47.9 (CH2), 39.8 (Me), 29.8 (CH2),
14.1 ppm (Me); IR (ATR): n˜ =1725 cmÀ1 (C=O); HRMS (ESI): m/z
calcd for C16H20FNO4 +H+: 310.1449 [M+H+]; found: 310.1459.
General procedure for the copper(II)-catalysed synthesis of
1,2,3,4-tetrahydroquinolines 25a–j (Scheme 8)
To a solution of the diethyl 2-(2-(methyl(aryl)amino)ethyl)malonate
24 (1.00 mmol) and copper(II) 2-ethylhexanoate (35.0 mg, 10
mol%) in toluene (10 mL) was added DIPEA (0.383 mL, 2.20 mmol).
The reaction mixture was heated at 1208C for 19 h under a reflux
condenser open to the air. After cooling to rt, saturated NH4Cl
(20 mL) was added and the aqueous phase extracted with EtOAc
(3ꢂ20 mL). The combined organics were washed with 10% NH4OH
(20 mL) and saturated brine (20 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The crude product was purified by
flash chromatography on silica gel, eluting with EtOAc/petroleum
ether (1:49 to 1:19), to afford the title compound.
Diethyl
6-chloro-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicar-
boxylate 25e: colourless solid; Rf =0.25 (EtOAc/petroleum ether
1:9); m.p. 71–738C; 1H NMR (400 MHz, CDCl3): d=7.22 (d, J=
2.5 Hz, 1H), 7.11 (dd, J=8.9, 2.5 Hz, 1H), 6.55 (d, J=8.9 Hz, 1H),
4.30–4.18 (m, 4H), 3.22–3.19 (m, 2H), 2.88 (s, 3H), 2.51–2.48 (m,
2H), 1.27 ppm (t, J=7.4 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
170.8 (C), 144.6 (C), 130.0 (CH), 128.8 (CH), 120.8 (C), 118.8 (C),
112.8 (CH), 61.9 (CH2), 56.8 (C), 47.4 (CH2), 39.3 (Me), 29.3 (CH2),
13.9 ppm (Me); IR (ATR): n˜ =1727 cmÀ1 (C=O); HRMS (ESI): m/z
calcd for C16H20ClNO4 +H+: 326.1154 [M+H+]; found: 326.1150.
Diethyl 1,6-dimethyl-2,3-dihydroquinoline-4,4(1H)-dicarboxylate
25 f: reaction was conducted with 1 equiv of catalyst; colourless
oil; Rf =0.31 (EtOAc/petroleum ether 1:9); 1H NMR (400 MHz,
CDCl3): d=7.06 (d, J=1.9 Hz, 1H), 7.00 (ddd, J=8.4, 1.9, 0.6 Hz,
1H), 6.59 (d, J=8.4 Hz, 1H), 4.29–4.17 (m, 4H), 3.18–3.15 (m, 2H),
2.86 (s, 3H), 2.54–2.51 (m, 2H), 2.24 (s, 3H), 1.27 ppm (t, J=7.1 Hz,
6H); 13C NMR (100 MHz, CDCl3): d=171.5 (C), 144.0 (C), 130.8 (CH),
129.7 (CH), 125.3 (C), 117.7 (C), 112.0 (CH), 61.7 (CH2), 57.0 (C), 47.8
(CH2), 39.4 (Me), 29.8 (CH2), 20.4 (Me), 14.0 ppm (Me); IR (ATR): n˜ =
1725 cmÀ1 (C=O); HRMS (ESI): m/z calcd forC17H23NO4 +H+:
306.1700 [M+H+]; found: 306.1687.
Diethyl
1-methyl-2,3-dihydroquinoline-4,4(1H)-dicarboxylate
25a: colourless solid; Rf =0.28 (EtOAc/petroleum ether 1:9); m.p.
44.5–45.58C; H NMR (400 MHz, CDCl3): d=7.25 (dd, J=7.7, 1.6 Hz,
1
1H), 7.19 (ddd, J=8.3, 7.3, 1.6 Hz, 1H), 6.69 (dd, J=7.3, 1.2 Hz, 1H),
6.67 (td, J=8.3, 1.2 Hz, 1H), 4.30–4.17 (m, 4H), 3.24–3.21 (m, 2H),
2.90 (s, 3H), 2.55–2.52 (m, 2H), 1.27 ppm (t, J=7.2 Hz, 6H);
13C NMR (100 MHz, CDCl3): d=171.4 (C), 145.9 (C), 130.4 (CH),
129.0 (CH), 117.6 (C), 116.1 (CH), 111.7 (CH), 61.7 (CH2), 56.9 (CH2),
47.6 (C), 39.2 (Me), 29.6 (CH2), 13.9 ppm (Me); IR (ATR): n˜ =
1717 cmÀ1 (C=O); HRMS (ESI): m/z calcd for C16H21NO4 +H+
:292.1543 [M+H+]; found: 292.1539.
1-Methyl-2,3-dihydroquinoline-4,4(1H)-dicarbonitrile 25b: reac-
tion was conducted with 1 equiv of catalyst; colourless solid; Rf =
0.13 (EtOAc/petroleum ether 1:9); m.p. 70–728C; 1H NMR
(400 MHz, CDCl3): d=7.46 (dd, J=7.9, 1.5 Hz, 1H), 7.29 (ddd, J=
8.4, 7.3, 1.5 Hz, 1H), 6.79 (td, J=7.6, 1.1 Hz, 1H), 6.68 (dd, J=8.4,
0.8 Hz, 1H), 3.51–3.48 (m, 2H), 2.96 (s, 3H), 2.66–2.64 ppm (m, 2H);
13C NMR (100 MHz, CDCl3): d=144.5 (C), 131.7 (CH), 128.7 (CH),
117.5 (CH), 115.6 (C), 112.6 (CH), 111.1 (C), 46.1 (CH2), 38.8 (Me), 33.9
(C), 31.9 ppm (CH2); IR (ATR): n˜ =2241 cmÀ1 (CꢀN); HRMS (ESI): m/z
calcd for C12H11N3 +H+: 198.1026 [M+H+]; found: 198.1021.
Diethyl 5-methoxy-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicar-
boxylate 25h: colourless oil; Rf =0.14 (EtOAc/petroleum ether 1:9);
1H NMR (400 MHz, CDCl3): d=7.13 (dd, J=8.4, 8.2 Hz, 1H), 6.32
(dd, J=8.4, 0.8 Hz, 1H), 6.29 (dd, J=8.2, 0.8 Hz, 1H), 4.27–4.11 (m,
4H), 3.72 (s, 3H), 3.16–3.13 (m, 2H), 2.89 (s, 3H), 2.51–2.48 (m, 2H),
1.23 ppm (t, J=7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=171.7
(C), 158.3 (C), 146.3 (C), 129.1 (CH), 108.1 (C), 105.0 (CH), 100.2 (CH),
61.1 (CH2), 55.6 (Me), 54.6 (C), 47.5 (CH2), 39.4 (Me), 30.2 (CH2),
13.9 ppm (Me); IR (ATR): n˜ =1723 cmÀ1 (C=O); HRMS (ESI): m/z
calcd for C17H23NO5 +H+: 322.1649 [M+H+]; found: 322.1649.
Diethyl 10-methyl-1,3,4,4a,9a,10-hexahydroacridine-9,9(2H)-di-
carboxylate 25c: colourless solid; Rf =0.44 (EtOAc/petroleum ether
1:9); m.p. 57–598C; 1H NMR (400 MHz, CDCl3): d=7.16 (ddd, J=
8.2, 7.3, 1.6 Hz, 1H), 6.89 (dd, J=7.9, 1.6 Hz, 1H), 6.62–6.58 (m, 2H),
4.39–4.25 (m, 2H), 4.20–4.08 (m, 2H), 3.06 (td, J=11.0, 3.5 Hz, 1H),
2.92 (s, 3H), 2.38–2.32 (m, 1H), 2.15 (td, J=11.0, 3.8 Hz, 1H), 1.90–
1.75 (m, 4H), 1.42–1.08 (m, 3H), 1.32 (t, J=7.0 Hz, 3H), 1.18 ppm (t,
J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=171.1 (C), 169.8 (C),
145.5 (C), 128.7 (CH), 127.4 (CH), 122.1 (C), 115.5 (CH), 112.8 (CH),
61.4 (CH2), 61.3 (CH2), 61.0 (C), 58.8 (CH), 46.2 (CH), 36.3 (Me), 33.3
(CH2), 27.8 (CH2), 26.2 (CH2), 24.7 (CH2), 14.1 (Me), 14.0 ppm (Me); IR
Diethyl 7-methoxy-1-methyl-2,3-dihydroquinoline-4,4(1H)-dicar-
boxylate 25h’: colourless oil; Rf =0.19 (EtOAc/petroleum ether
1:9); 1H NMR (400 MHz, CDCl3): d=7.18 (d, J=8.6 Hz, 1H), 6.26
(dd, J=8.6, 2.5 Hz, 1H), 6.17 (d, J=2.5 Hz, 1H), 4.28–4.15 (m, 4H),
3.78 (s, 3H), 3.22–3.19 (m, 2H), 2.88 (s, 3H), 2.50–2.47 (m, 2H),
1.26 ppm (t, J=7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=171.6
(C), 160.3 (C), 147.2 (C), 131.5 (CH), 110.4 (C), 101.4 (CH), 97.7 (CH),
61.7 (CH2), 56.3 (C), 55.0 (Me), 47.6 (CH2), 39.3 (Me), 29.7 (CH2),
14.0 ppm (Me); IR (ATR): n˜ =1725 cmÀ1 (C=O); HRMS (ESI): m/z
calcd for C17H23NO5 +H+: 322.1649 [M+H+]; found: 322.1645.
Chem. Eur. J. 2014, 20, 14063 – 14073
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Diethyl 1-methyl-6-nitro-2,3-dihydroquinoline-4,4(1H)-dicarbox-
ylate 25i: reaction was conducted with 20 mol% catalyst; yellow
solid; Rf =0.06 (EtOAc/petroleum ether 1:9); m.p. 82.5–84.58C;
1H NMR (400 MHz, CDCl3): d=8.16 (d, J=2.7 Hz, 1H), 8.00 (dd, J=
9.4, 2.7 Hz, 1H), 6.52 (d, J=9.4 Hz, 1H), 4.24 (q, J=7.2 Hz, 4H),
3.39–3.36 (m, 2H), 3.01 (s, 3H), 2.49–2.46 (m, 2H), 1.26 ppm (t, J=
7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=170.0 (C), 150.0 (C),
136.4 (C), 126.7 (CH), 125.6 (CH), 116.3 (C), 110.0 (CH), 62.2 (CH2),
56.3 (C), 47.2 (CH2), 39.1 (Me), 28.1 (CH2), 13.8 ppm (Me); IR (ATR):
n˜ =1726 cmÀ1 (C=O); HRMS (ESI): m/z calcd for C16H20N2O6 +H+:
337.1394 [M+H+]; found: 337.1392.
major), 107.9 (CH, minor), 62.3 (CH2, minor), 62.2 (CH2, major), 55.7
(C, major), 55.4 (C, minor), 27.0 (Me, minor), 26.9 (Me, major), 20.8
(Me, major), 17.7 (Me, minor), 13.85 (Me, minor), 13.77 ppm (Me,
major); IR (ATR): n˜ =1733 (C=O), 1710 cmÀ1 (C=O); HRMS (ESI): m/z
calcd for C20H24N2O6 +Na+: 411.1527 [M+Na+]; found: 411.1530.
Tetraethyl 1,6-dimethyl-2,7-dioxo-1,2,3,6,7,8-hexahydropyrido-
[2,3g]quinoline-4,4,9,9-tetracarboxylate 29: colourless solid; Rf =
0.26 (EtOAc/petroleum ether 1:1); m.p. 177–1798C; 1H NMR
(400 MHz, CDCl3): d=7.04 (s, 2H), 4.33–4.23 (m, 8H), 3.30 (s, 6H),
3.21 (s, 4H), 1.28 ppm (t, J=7.0 Hz, 12H); 13C NMR (100 MHz,
CDCl3): d=168.5 (C), 166.0 (C), 135.6 (C), 123.2 (C), 115.3 (CH), 62.7
(CH2), 56.5 (C), 37.8 (CH2), 29.7 (Me), 14.0 ppm (Me); IR (ATR): n˜ =
1748 (C=O), 1727 (C=O), 1672 cmÀ1 (C=O); HRMS (ESI): m/z calcd
for C26H32N2O10 +H+: 533.2130 [M+H+]; found:533.2139.
Diethyl 1-methyl-7-nitro-2,3-dihydroquinoline-4,4(1H)-dicarbox-
ylate 25j: yellow solid; Rf =0.14 (EtOAc/petroleum ether 1:9); m.p.
1
83.5–85.58C; H NMR (400 MHz, CDCl3): d=7.46 (dd, J=8.5, 2.3 Hz,
1H), 7.42 (d, J=2.3 Hz, 1H), 7.34 (d, J=8.5 Hz, 1H), 4.31–4.18 (m,
4H), 3.32–3.29 (m, 2H), 2.99 (s, 3H), 2.53–2.50 (m, 2H), 1.27 ppm (t,
J=7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=170.3 (C), 148.7 (C),
146.3 (C), 131.0 (CH), 123.6 (C), 110.1 (CH), 105.7 (CH), 62.2 (CH2),
56.9 (C), 47.1 (CH2), 39.1 (Me), 28.7 (CH2), 13.9 ppm (Me); IR (ATR):
n˜ =1741 (C=O), 1720 (C=O), 1348 cmÀ1 (NÀO); HRMS (ESI): m/z
calcd for C16H20N2O6 +H+: 337.1394 [M+H+]; found: 337.1384.
Triethyl
1,3,5-trimethyl-2,6-dioxo-1,2,3,5,6,7-hexahydro-8H-
pyrrolo[2,3g]quinoline-3,8,8-tricarboxylate 31: colourless solid;
Rf =0.29 (EtOAc/petroleum ether 1:1); m.p. 153.5–1558C; 1H NMR
(400 MHz, CDCl3): d=6.94 (s, 1H), 6.79 (s, 1H), 4.31–4.24 (m, 4H),
4.22–4.14 (m, 1H), 4.11–4.03 (m, 1H), 3.30 (s, 3H), 3.21 (s, 3H), 3.18
(s, 2H), 1.65 (s, 3H), 1.28 (t, J=7.1 Hz, 3H), 1.27 (t, J=7.1 Hz, 3H),
1.17 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=174.5
(C), 169.2 (C), 168.71 (C), 168.69 (C), 166.1 (C), 139.1 (C), 135.9 (C),
131.0 (C), 123.2 (C), 111.0 (CH), 107.7 (CH), 62.6 (CH2), 62.2 (CH2),
56.9 (C), 55.1 (C), 37.8 (CH2), 30.0 (Me), 26.6 (Me), 20.3 (Me), 13.9
(Me), 13.8 ppm (Me); IR (ATR): n˜ =1745 (C=O), 1726 (C=O), 1711
(C=O), 1674 cmÀ1 (C=O); HRMS (ESI): m/z calcd for C23H28N2O8 +H+:
461.1918 [M+H+]; found:461.1904.
General procedure for the copper(II)-catalysed double cycli-
sation of linear anilides 26, 28, and 30 (Scheme 9)
To a solution of the anilide (0.605 mmol) and copper(II) 2-ethylhex-
anoate (42.0 mg, 20 mol% or 0.106 g, 50 mol%) in toluene (6 mL)
was added DIPEA (0.464 mL, 2.66 mmol). The reaction mixture was
heated at 1208C for 18–40 h under a reflux condenser open to the
air. After cooling to rt, saturated NH4Cl (20 mL) was added and the
aqueous phase extracted with EtOAc (3ꢂ20 mL). The combined or-
ganics were washed with 10% NH4OH (20 mL) and saturated brine
(20 mL), dried over MgSO4, filtered, and concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel,
eluting with EtOAc/petroleum ether (1:3 to 1:1), to afford the title
compound.
Acknowledgements
We thank the University of York Wild Fund for postgraduate
support (P. D.) and the EPSRC for postdoctoral support (T. E. H.,
EP/J000124/1). We also thank CHEM21 for postgraduate sup-
port (R. M. G.). The research for this work has received funding
from the Innovative Medicines Initiative joint undertaking proj-
ect CHEM21 (https://www.chem21.eu/) grant agreement
no. 115360, resources of which are composed of financial con-
tribution from the European Union’s Seventh Framework Pro-
gramme (FP7/2007–2013) and EFPIA companies in kind contri-
bution.
3,7-Diethyl 1,3,5,7-tetramethyl-2,6-dioxo-1H,2H,3H,5H,6H,7H-
pyrrolo[2,3-f]indole-3,7-dicarboxylate 27: 3.5:1 mixture of diaste-
reomers; colourless solid; Rf =0.25 (EtOAc/petroleum ether 1:1);
m.p. 223.5–225.58C; 1H NMR (400 MHz, CDCl3): d=6.78 (s, 1.6H,
major), 6.77 (s, 0.4H, minor), 4.20–4.03 (m, 4H, both), 3.21 (s, 6H,
both), 1.64 (s, 1.3H, minor), 1.63 (s, 4.7H, major), 1.152 (t, J=
7.1 Hz, 4.7H, major), 1.150 ppm (t, J=7.1 Hz, 1.3H, minor); 13C NMR
(100 MHz, CDCl3): d=174.4 (C, both), 169.5 (C, minor), 169.4 (C,
major), 139.2 (C, both), 130.39 (C, major), 130.36 (C, minor), 104.4
(CH, major), 104.3 (CH, minor), 62.1 (CH2, both), 55.3 (C, both), 26.7
(Me, both), 20.4 (Me, major), 20.2 (Me, minor), 13.83 (Me, minor),
13.81 ppm (Me, major); IR (ATR): n˜ =1738 (C=O), 1698 cmÀ1 (C=O);
HRMS (ESI): m/z calcd for C20H24N2O6 +Na+: 411.1527 [M+Na+];
found: 411.1532.
Keywords: dihydroquinolinones
oxindoles · tetrahydroquinolines
·
catalysis
·
copper
·
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Received: June 11, 2014
Published online on September 11, 2014
Chem. Eur. J. 2014, 20, 14063 – 14073
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14073
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim