[1,5]-hydride transfer/cyclization of ortho-amino alkynyl fischer carbene complexes: A useful tool for the synthesis of quinoline derivatives

Article abstract of DOI:10.1002/ejoc.201001717

An efficient method for the synthesis of compounds containing a quinoline moiety by using o-aminophenyl alkynyl Fischer carbene complexes as starting materials is described. The reaction is based on a cascade process involving [1,5]-hydride transfer/cycli

Full text of DOI:10.1002/ejoc.201001717

FULL PAPER
DOI: 10.1002/ejoc.201001717
[1,5]-Hydride Transfer/Cyclization of ortho-Amino Alkynyl Fischer Carbene
Complexes: A Useful Tool for the Synthesis of Quinoline Derivatives
José Barluenga,*[a] Martín Fañanás-Mastral,[a] Amadeo Fernández,[a] and Fernando Aznar[a]
Keywords: Domino reactions / Carbenes / Chromium / Heterocycles / Hydride transfer
An efficient method for the synthesis of compounds contain-
ing a quinoline moiety by using o-aminophenyl alkynyl Fi-
scher carbene complexes as starting materials is described.
The reaction is based on a cascade process involving [1,5]-
hydride transfer/cyclization to afford new alkenylcarbene
complexes with quinoline moiety 2. The reaction of alkenyl
complexes 2 with unsaturated substrates such as electron-
poor alkynes afford furo[2Ј,3Ј-3,4]cyclopenta[1,2-c]quinol-
inone derivatives 6 and (1,2-dihydroquinolin-3-ylvinyl)-
malonates 12 when propiolic aldehydes and propiolates are
used, respectively. The reactivity of the alkenylcarbene com-
plexes was also studied by using 1,3-dienes to afford cy-
clohepta[c]quinolinones 17 when Danishefsky’s diene is used
and 3-pirimidinylquinoline derivatives 21 when 4-amino-1-
azadienes are employed.
Introduction
Quinoline derivatives, such as 1,2-dihydroquinolines and
1,2,3,4-tetrahydroquinolines, are important structural com-
ponents in naturally occurring alkaloids and synthetic ana-
logues with interesting biological activities.[1] Therefore, the
development of new and efficient synthetic routes for the
preparation of their analogues is of importance to both syn-
thetic organic chemistry and medicinal chemistry.[2,3] We
have recently described a novel [1,5]-hydride transfer/cycli-
zation process of ortho-amino alkynyl Fischer carbene com-
plexes 1 that leads to 1,2-dihydroquinolynylcarbene com-
plexes 2 (Scheme 1).[4] Considering the synthetic versatility
of Fischer carbene complexes,[5] compounds 2 offer the pos-
sibility to manipulate the 1,2-dihydroquinoline moiety to
introduce different functionalities or incorporate more com-
plex cyclic systems to this structure. In our recent communi-
cation, we reported the reaction between chromium ortho-
amino alkynyl Fischer carbene complexes 1 and alkynes 3,
Scheme 1. Synthesis of 5,6-dihydrophenantridines 3 through a
[1,5]-hydride transfer/cyclization/Dötz benzannulation cascade pro-
cess.
which affords 5,6-dihydrophenantridine derivatives
4
Results and Discussion
through a novel [1,5]-hydride transfer/cyclization/Dötz
benzannulation cascade process (Scheme 1).[4]
We decided to start studying the behavior of Fischer carb-
ene complexes 1 with electron-deficient alkynes. The treat-
ment of alkynylcarbene complexes 1 with propiolaldehydes
5 (6 equiv.) in THF at 90 °C in a sealed tube gave rise to
bicyclic lactones 6 in good yield and with total diastereo-
selectivity (Table 1). The structure and the relative configu-
ration of the stereogenic centers of new compounds 6 were
determined by 1D and 2D NMR spectroscopic analysis and
unequivocally ascertained by X-ray diffraction analysis car-
ried out with compound 6d.[6]
Encouraged by these results and aiming to evaluate the
scope of the reaction, we next decided to explore the behav-
ior of Fischer carbene complexes 1 with other unsaturated
substrates. Herein we present some new cascade processes
of chromium ortho-amino alkynyl Fischer carbene com-
plexes which lead to the formation of different structures
derived from the 1,2-dihydroquinoline core.
[a] Instituto Universitario de Química Organometálica “Enrique
Moles”, Unidad Asociada al CSIC, Universidad de Oviedo,
Julián Clavería 8, 33006 Oviedo, Spain
The formation of bicyclic lactones 6 can be explained as
a result of the cascade process depicted in Scheme 2. Alken-
ylcarbene complex 2 formed from the 1,5-hydride transfer/
cyclization process could undergo regioselective [2+2] cyclo-
Fax: +34-985-103450
E-mail: barluenga@uniovi.es
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001717.
Eur. J. Org. Chem. 2011, 1961–1967
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1961

J. Barluenga, M. Fañanás-Mastral, A. Fernández, F. Aznar
FULL PAPER
Table 1. Synthesis of bicyclic lactones 5.
Carbene
R1
R3 Aldehyde
R4
Product Yield [%][a]
1a
1a
1a
1d
1d
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
H
H
H
Cl
Cl
5a
5b
5c
5a
5b
TMS
Ph
C5H11
TMS
Ph
6a
6b
6c
6d
6e
72
73
61
78
75
Ph
[a] Isolated yield based on alkynylcarbene complex 1.
addition of the propiolaldehyde to form intermediate 7, fol-
lowed by an electrocyclic ring-opening step to afford non-
stabilized Fischer carbene complex 8. Then, insertion of a
carbonyl ligand would give rise to cross-conjugated ketene
intermediate 9, which would evolve through a van Halban–
White-type double cyclization[7] to furo[2Ј,3Ј-3,4]cyclo-
penta[1,2-c]quinolinone derivatives 6, after decoordination
of the metal fragment. To understand the complete dia-
stereoselectivity observed in compound 6, we carried out
DFT-based computational modeling of the van Halban–
White double cyclization. According to our calculations,
the cyclization takes place in an asynchronous concerted
manner, in which the new C–O bond is highly developed in
transition state TS-10. The formation of diastereoisomer 6
is clearly favored when compared with unobserved 6Ј,
which features the R1 group in a trans relationship with
the benzylic hydrogen atom. Indeed, an energy difference of
3.6 kcal/mol was obtained between both transition states
TS-10 and TS-10Ј. This energy difference can be under-
stood by inspection of the molecular models. In TS-10, the
steric interactions between R1 and the rest of the molecule
are minimized when compared with TS-10Ј (Scheme 2). A
more detailed discussion is provided in the Supporting In-
formation.
Scheme 2. Proposed mechanism for the formation of compounds
6.
Table 2. Synthesis of 1,2-dihydroquinolines 12.
We then turned our attention to other electron-deficient
alkynes such as propiolates 11. When alkynyl Fischer
carbene complexes 1 were treated with this type of alkynes
in a 1:6 molar ratio using a 9:1 mixture of THF/R5OH un-
der the same reaction conditions as those described above,
we could isolate, after workup, 1,2-dihydroquinoline deriva-
tives 12 as single diastereoisomers in good yields
(Table 2).[8]
Carbene
R1
R3 Propiolate R5
Product Yield [%][a]
1a
1a
1b
1a
4-MeC6H4
4-MeC6H4
Ph
H
H
11a
11b
11c
11d
Me
Et
12a
12b
12c
12d
78
79
73
81
Me
H
Me
allyl
4-MeC6H4
[a] Isolated yield based on alkynylcarbene complex 1.
The structure of 1,2-dihydroquinolines 12 was deter-
mined by 1D and 2D NMR spectroscopic analysis. The
stereochemistry of the double bond was determined by a tween one hydrogen of the enol ether moiety Hb (δ =
NOESY experiment carried out with compound 12a, show- 5.21 ppm) and the hydrogen over the C-4 of the quinoline
ing two determinant cross-peaks. One cross-peak appears moiety Hc (δ = 6.81 ppm, Figure 1).
between the α-hydrogen atom of the 1,3-dicarbonyl moiety
To explain this different chemical behavior observed in
Ha (δ = 4.55 ppm) and the methyl group of the methoxy the reaction of carbene complexes 1 with propiolic esters,
group in the enol ether (δ = 3.48 ppm) and the other be- we proposed a mechanism to account for the formation of
1962
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Eur. J. Org. Chem. 2011, 1961–1967

[1,5]-Hydride Transfer/Cyclization of ortho-Amino Alkynyl Fischer Carbenes
dition reaction,[10] we observed that complexes 1 do not re-
act with Danishefsky’s diene 16 at room temperature. This
fact allowed us to carry out the one-pot reaction without
observing any side product derived from the reaction of the
alkynylcarbene complex and the diene. Thus, when alk-
ynylcarbene complexes 1 and Danishefsky’s diene 16 were
dissolved in THF and heated at 90 °C in a sealed tube, we
obtained, after workup, tetrahydrocyclohepta[c]quinol-
inones 17 in good yields and with total diastereoselectivity
(Scheme 4). Formation of compounds 17 can be considered
as a [1,5]-hydride transfer/cyclization/[4+3] cycloaddition
cascade process.
Figure 1. Determinant NOEs in compound 12a.
compounds 12 shown in Scheme 3. Alkenylcarbene com-
plexes 2 initially formed through 1,5-hydride transfer/cycli-
zation could undergo regioselective [2+2] cyclization with
one molecule of propiolate to give intermediates 13. In this
case, the regiochemistry of the insertion is the opposite to
that observed in the case where propargylic aldehydes were
used, probably due to the use of a terminal alkyne moiety.
Subsequent electrocyclic ring opening would afford carbene
complexes 14 as the Z isomer, avoiding the steric hindrance
between the metal fragment and the quinoline moiety.
Complexes 14 could further undergo a CO insertion reac-
tion to furnish ketene intermediates 15. Finally, nucleo-
philic attack of a molecule of alcohol would lead to the
formation of (1,2-dihydroquinolin-3-ylvinyl)malonates 12,
after metal decoordination.[8]
Scheme 4. Synthesis of tetrahydrocyclohepta[c]quinolinones 17
through a [1,5]-hydride transfer/cyclization/[4+3] cycloaddition cas-
cade process.
The formation of compound 17 could be explained
through the mechanism depicted in Scheme 5. Thus, the re-
action would start with 1,2 nucleophilic addition of the ter-
minal carbon of the enol ether moiety of the dienic system
to alkenylcarbene complex 2 to form zwitterionic intermedi-
ate 18. This intermediate could undergo intramolecular
Michael addition of the allylchromate to the unsaturated
oxonium moiety to afford seven-membered intermediate 19.
The approach of the unsaturated oxonium moiety to the
allylchromate from the opposite face to where the R1 group
on the quinoline moiety is placed could be responsible for
the resulting complete diastereoselectivity. Further hydroly-
sis and metal decoordination furnish tetrahydrocyclohepta-
quinolinones 17. Alternatively, the reaction to form 17
could first give a cyclopropane intermediate and then un-
dergo Cope rearrangement.[9d,11]
Scheme 3. Proposed mechanism for the formation of (1,2-dihy-
droquinolin-3-ylvinyl)malonates 12.
Dienic systems are also good substrates for the reaction
with alkenyl Fischer carbene complexes.[9] Thus, we tried to
develop cascade processes in the presence of such unsatu-
rated substrates. As a first approach, we decided to start
our studies by employing electron-rich dienes, and we chose
Danishefsky’s diene 16. Although this diene reacts with alk-
Scheme 5. Proposed mechanism for the reactivity of alkenyl com-
plexes 6 and electron-rich dienes to give tetrahydrocycloheptaquin-
ynyl Fischer carbene complex through a [4+2] cycload- olinones 17.
Eur. J. Org. Chem. 2011, 1961–1967
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1963

J. Barluenga, M. Fañanás-Mastral, A. Fernández, F. Aznar
FULL PAPER
We were also able to accomplish a cascade process of tives.[15] We assume first that 1,2-nucleophilic addition of
alkynylcarbene complexes 1 by using electron-poor dienes the iminic nitrogen atom of aminoazadiene 20 to carbene
such as 4-amino-1-azadienes 20. As alkynyl Fischer carbene complex 2 occurs, which gives rise to zwitterionic interme-
complexes react at low temperatures with this type of hetero- diate 22. In the following step, intermediate 22 would evolve
diene,[12] first we had to develop the [1,5]-hydride transfer/ into imino carbene complex 23 by elimination of a molecule
cyclization at 90 °C, and then, cool the reaction mixture to of methanol. This complex would experience nucleophilic
room temperature and add the heterodiene. After workup intramolecular attack of the enaminic nitrogen atom to give
of the reaction, we obtained 3-pyrimidinylquinoline deriva- chromate complex 24. 1,3-Hydrogen shift, giving hy-
tives 21 in good yields (Scheme 6).[13] This transformation dridechromium complex 25, followed by reductive elimi-
can be considered as a formal [1,5]-hydride transfer/cycliza- nation would furnish dihydropyrimidine derivative 26. A fi-
tion/[5+1] cycloaddition cascade process.
nal aromatization step would lead to the formation of 3-
pyrimidinylquinoline derivative 21.
Conclusions
In conclusion, we have described a new and efficient
method for the synthesis of quinoline derivatives from easily
available
o-benzylaminophenylalkynylchromiumcarbene
complexes and alkyne or diene derivatives. The reaction is
based on an original [1,5]-hydride transfer/cyclization/[3+2],
[4+2], or [5+1] cascade process. Using this strategy, highly
substituted phenantridines, furo[2Ј,3Ј-3,4]cyclopenta[1,2-c]-
quinolinones,
(1,2-dihydroquinolin-3-ylvinyl)malonates,
Scheme 6. Synthesis of 3-pirimidinylquinoline derivatives 21
through a [1,5]-hydride transfer/cyclization/[5+1] cycloaddition cas-
cade process.
tetrahydrocyclohepta[c]quinolinones, and 3-pyrimidinyl-
quinoline derivatives are easily available in a simple way.
Moreover, the quinoline systems obtained through this
strategy are nature-like structural motifs that might be of
value in the discovery of biologically active molecular
agents.
The formation of compounds 21 can be explained by the
reaction of alkenylcarbene complexes 2 generated in the
first step of the transformation with aminoazadiene 20. It
is important to note that the behavior of carbene complexes
2 is completely different than that of standard α,β-unsatu-
rated Fischer carbene complexes, which afford azepines in
their reaction with 4-amino-1-azadienes.[14]
Experimental Section
General Methods: 1H NMR spectra were recorded with a Bruker
AV-600 (600 MHz), Bruker AMX-400 (400 MHz), or Bruker DPX-
300 (300 MHz). Chemical shifts are reported in ppm from tet-
ramethylsilane with the residual solvent resonance as the internal
standard (CHCl3: δ = 7.26 ppm). Data are reported as follows:
chemical shift, multiplicity (s: singlet, d: doublet, dd: double doub-
let, td: triplet of doublets, t: triplet, q: quartet, br.: broad, m: mul-
tiplet), coupling constants (J in Hz), integration, and assignment.
13C NMR spectra were recorded with a Bruker AV-600 (150 MHz),
Bruker AMX-400 (100 MHz), or Bruker DPX-300 (75 MHz) with
complete proton decoupling. Chemical shifts are reported in ppm
from tetramethylsilane with the solvent resonance as internal stan-
dard (CDCl3: δ = 76.95 ppm). 2D NMR experiments (COSY,
HSQCED, HMBC, and NOESY) were recorded with a Bruker
AMX-400 (400 MHz). High-resolution mass spectrometry was car-
ried out with a Finnigan-Mat 95 spectrometer. All reactions were
conducted in dried glassware under an inert atmosphere of argon.
Tetrahydrofuran used as solvent was dried and deoxygenated with
a PureSolv column system before used.
In Scheme 7 we propose a tentative mechanism that ac-
counts for the formation of 3-pirimidinylquinoline deriva-
General Procedure for the Synthesis of Bicyclic Lactone Derivatives
6: A solution of alkynyl carbene complex 1 (0.5 mmol) and alde-
hyde 5 (3 mmol) in THF (10 mL) was heated in a sealed tube under
an argon atmosphere at 90 °C for 4 h. Then, the reaction was al-
lowed to reach room temperature, hexane (30 mL) was added, and
the mixture was exposed to air and light. Finally, the mixture was
filtered through a pad of Celite, solvents were removed under re-
duced pressure, and the crude product was purified by column
Scheme 7. Proposed mechanism for the formation of 3-pyrimidin-
ylquinoline derivatives 21.
1964
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Eur. J. Org. Chem. 2011, 1961–1967

[1,5]-Hydride Transfer/Cyclization of ortho-Amino Alkynyl Fischer Carbenes
chromatography on silica gel (hexane/ethyl acetate, 7:1) to afford
CH), 122.8 (C), 122.6 (C), 120.7 (C), 113.5 (CH), 89.7 (CH), 60.4
lactones 6.
(OCH3), 58.2 (NCH), 53.8 (NCH2), 43.3 (CH), –1.3 [Si-
(CH3)3] ppm. HRMS (EI): calcd. for C31H31NO3 477.2662; found
465.2663.
(6S*,10aS*,10bR*)-7-Methoxy-5-(4-methylbenzyl)-6-(4-methyl-
phenyl)-8-(trimethylsilyl)-10a,10b-dihydro-5H-furo[2Ј,3Ј-3,4]cyclo-
penta[1,2-c]quinolin-9(6H)-one (6a): Yield: 72%. Colorless oil. Rf =
(6S*,10aS*,10bR*)-5-Benzyl-2-chloro-7-methoxy-6,8-diphenyl-
10a,10b-dihydro-5H-furo[2Ј,3Ј-3,4]cyclopenta[1,2-c]quinolin-9(6H)-
one (6e): Yield: 75%. Colorless oil. Rf = 0.32 (hexane/AcOEt, 7:1).
1H NMR (400 MHz, CDCl3): δ = 7.77–7.73 (m, 2 H), 7.58–7.19
(m, 13 H), 6.62 (d, J = 8.9 Hz, 1 H), 5.56 (s, 1 H), 5.23 (d, J =
4.0 Hz, 1 H), 4.73 (d, J = 17.3 Hz, 1 H), 4.36 (d, J = 17.3 Hz, 1
H), 3.82 (d, J = 4.1 Hz, 1 H), 3.60 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 173.2 (C), 159.7 (C), 146.2 (C), 142.6 (C),
140.6 (C), 137.2 (C), 131.8 (C), 131.6 (C), 130.8 (C), 130.6 (C),
130.0 (C), 129.1 (2 CH), 128.8 (2 CH), 128.7 (CH), 128.6 (CH),
128.6 (2 CH), 128.4 (2 CH), 128.1 (CH), 128.0 (CH), 126.3 (2 CH),
126.0 (2 CH), 122.28 (CH), 113.37 (CH), 87.35 (CH), 60.62
(OCH3), 58.57 (NCH), 53.69 (NCH2), 43.31 (CH) ppm. HRMS
(EI): calcd. for C34H26ClNO3 531.1601; found 531.1612.
1
0.35 (hexane/AcOEt, 7:1). H NMR (400 MHz, CDCl3): δ = 8.15
(d, J = 7.6 Hz, 1 H), 7.30 (d, J = 7.6 Hz, 2 H), 7.15 (d, J = 7.6 Hz,
2 H), 7.13 (t, J = 7.8 Hz, 1 H), 6.99 (d, J = 8.2 Hz, 2 H), 6.96 (d,
J = 8.2 Hz, 2 H), 6.91 (t, J = 7.4 Hz, 1 H), 6.70 (t, J = 8.1 Hz, 1
H), 5.60 (s, 1 H), 5.47 (s, 1 H), 4.55 (d, J = 14.8 Hz, 1 H), 4.34 (d,
J = 14.8 Hz, 1 H), 3.32 (s, 3 H), 2.85–2.77 (m, 2 H), 2.75–2.66 (m,
2 H), 2.36 (s, 3 H), 2.25 (s, 3 H), 1.30 (t, J = 7.3 Hz, 1 H), 1.23 (t,
J = 7.3 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 147.6
(C), 147.0 (C), 145.4 (C), 136.9 (C), 136.8 (C), 136.7 (C), 135.5 (C),
135.0 (C), 131.1 (C), 129.4 (C), 129.3 (2 CH), 128.8 (2 CH), 128.3
(CH), 127.9 (2 CH), 127.6 (2 CH), 125.5 (CH), 123.8 (C), 118.5
(CH), 117.6 (C), 115.3 (CH), 61.8 (NCH), 59.1 (OCH3), 53.1
(NCH2), 21.2 (CH3), 21.1 (CH3), 20.1 (CH2), 20.0 (CH2), 15.7
(CH3), 14.5 (CH3) ppm. HRMS (EI): calcd. for C33H35NO3Si
521.2386; found 521.2389.
General Procedure for the Synthesis of 1,2-Dihydroquinolines 12: A
solution of alkynyl carbene complex 1 (0.5 mmol) and the corre-
sponding propiolate 11 (3 mmol) in THF (9 mL) and R5OH (1 mL)
was heated in a sealed tube under an argon atmosphere at 90 °C
for 4 h. Then, the reaction was allowed to reach room temperature,
hexane (30 mL) was added, and the mixture was exposed to air and
light. Finally, the mixture was filtered through a pad of Celite, the
solvents were removed under reduced pressure, and the crude prod-
uct was purified by column chromatography on silica gel (hexane/
ethyl acetate, 5:1) to afford 1,3-dicarbonyl compounds 12.
(6S*,10aS*,10bR*)-7-Methoxy-5-(4-methylbenzyl)-6-(4-methyl-
phenyl)-8-phenyl-10a,10b-dihydro-5H-furo[2Ј,3Ј-3,4]cyclopenta-
[1,2-c]quinolin-9(6H)-one (6b): Yield: 73%. Colorless Oil. Rf = 0.32
1
(hexane/AcOEt, 7:1). H NMR (400 MHz, CDCl3): δ = 7.81–7.71
(m, 2 H), 7.49 – 7.32 (m, 4 H), 7.22–7.09 (m, 9 H), 6.82 (t, J =
7.3 Hz, 1 H), 6.70 (d, J = 8.3 Hz, 1 H), 5.53 (s, 1 H), 5.25 (d, J =
3.9 Hz, 1 H), 4.72 (d, J = 17.1 Hz, 1 H), 4.32 (d, J = 17.1 Hz, 1
H), 3.88 (d, J = 3.8 Hz, 1 H), 3.58 (s, 3 H), 2.35 (s, 3 H), 2.34 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 173.6 (C), 160.5 (C),
145.8 (C), 144.1 (C), 138.0 (C), 137.5 (C), 136.7 (C), 134.6 (C),
132.4 (C), 129.8 (C), 129.7 (2 CH), 129.4 (2 CH), 128.8 (C), 128.7
(CH), 128.6 (2 CH), 128.4 (2 CH), 128.3 (CH), 126.4 (2 CH), 126.1
(2 CH), 120.8 (C), 119.2 (C), 117.5 (CH), 112.0 (CH), 87.8 (CH),
60.6 (OCH3), 58.2 (NCH), 53.0 (NCH2), 43.5 (CH3), 21.1 (CH3),
21.0 (CH3) ppm. HRMS (EI): calcd. for C36H31NO3 525.2304;
found 525.2298.
(Z)-Dimethyl 2-{2-methoxy-2-[1-(4-methylbenzyl)-2-(4-methyl-
phenyl)-1,2-dihydroquinolin-3-yl]vinyl}malonate (12a): Yield: 46%.
Yellow oil. Rf = 0.29 (hexane/AcOEt, 5:1). 1H NMR (400 MHz,
CDCl3): δ = 7.18 (d, J = 7.8 Hz, 2 H), 7.13 (d, J = 7.9 Hz, 4H),
7.08 (d, J = 7.2 Hz, 1 H), 7.05–7.02 (m, 3 H), 6.81 (s, 1 H), 6.66
(t, J = 7.3 Hz, 1 H), 6.46 (d, J = 8.1 Hz, 1 H), 5.21 (d, J = 9.2 Hz,
1 H), 5.18 (s, 1 H), 4.56 (d, J = 9.2 Hz, 1 H), 4.51 (d, J = 16.1 Hz,
1 H), 4.20 (d, J = 16.1 Hz, 1 H), 3.72 (s, 3 H), 3.65 (s, 3 H), 3.48
(s, 3 H), 2.35 (s, 3 H), 2.30 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ =168.6 (C), 168.6 (C), 156.2 (C), 144.0 (C), 137.8 (C),
137.4 (C), 136.7 (C), 134.3 (C), 130.0 (CH), 129.3 (2 CH), 129.0 (2
CH), 128.7 (C), 128.2 (CH), 127.0 (2 CH), 126.8 (2 CH), 124.7
(CH), 121.5 (C), 116.9 (CH), 111.2 (CH), 106.2 (CH), 62.7 (CH),
59.3 (CH3), 52.7 (CH3), 52.6 (CH3), 51.6 (CH2), 49.0 (CH), 21.1
(2 CH3) ppm. HRMS (EI): calcd. for C32H33NO5 511.2353; found
511.2370.
(6S*,10aS*,10bR*)-7-Methoxy-5-(4-methylbenzyl)-6-(4-methyl-
phenyl)-8-pentyl-10a,10b-dihydro-5H-furo[2Ј,3Ј-3,4]cyclopenta-
[1,2-c]quinolin-9(6H)-one (6c): Yield: 61%. Colorless oil. Rf = 0.30
1
(hexane/AcOEt, 7:1). H NMR (400 MHz, CDCl3): δ = 7.37 (d, J
= 7.4 Hz, 1 H), 7.18–7.06 (m, 9H), 6.78 (t, J = 7.0 Hz, 1 H), 6.65
(d, J = 8.3 Hz, 1 H), 5.44 (s, 1 H), 5.11 (d, J = 4.0 Hz, 1 H), 4.68
(d, J = 17.2 Hz, 1 H), 4.28 (d, J = 17.2 Hz, 1 H), 3.83 (s, 2 H),
3.68 (d, J = 3.7 Hz, 1 H), 2.35 (s, 3 H), 2.31 (s, 3 H), 1.67–1.16 (m,
8 H), 0.86 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 175.5 (C), 160.9 (C), 145.7 (C), 144.1 (C), 138.2 (C), 137.3 (C),
136.6 (C), 134.6 (C), 129.5 (2 CH), 129.4 (CH), 129.3 (2 CH), 128.5
(CH), 128.2 (CH), 126.3 (CH), 126.0 (CH), 121.1 (C), 212.0 (CH),
117.3 (CH), 111.8 (CH), 88.0 (CH), 60.2 (OCH3), 58.2 (NCH), 52.9
(NCH2), 43.2 (CH), 31.4 (CH2), 27.8 (C), 24.9 (C), 22.3 (CH2), 21.0
(2 CH3), 13.9 (CH3) ppm. HRMS (EI): calcd. for C35H36ClNO3
553.2384; found 553.2384.
(Z)-Diethyl 2-{2-methoxy-2-[1-(4-methylbenzyl)-2-(4-methylphenyl)-
1,2-dihydroquinolin-3-yl]vinyl}malonate (12b): Yield: 51%. Yellow
1
oil. Rf = 0.39 (hexane/AcOEt, 5:1). H NMR (400 MHz, CDCl3):
δ = 7.18 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 7.9 Hz, 4 H), 7.08 (d, J
= 7.5 Hz, 1 H), 7.03–7.01 (m, 3 H), 6.83 (s, 1 H), 6.66 (t, J =
7.3 Hz, 1 H), 6.45 (d, J = 8.2 Hz, 1 H), 5.22 (d, J = 9.3 Hz, 1 H),
5.17 (s, 1 H), 4.52 (d, J = 9.3 Hz, 1 H), 4.50 (d, J = 16.0 Hz, 1 H),
(6S*,10aS*,10bR*)-5-Benzyl-2-chloro-7-methoxy-6-phenyl-8-(tri- 4.21 (d, J = 16.0 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 4.09 (q, J =
methylsilyl)-10a,10b-dihydro-5H-furo[2Ј,3Ј-3,4]cyclopenta[1,2-c]-
quinolin-9(6H)-one (6d)Yield: 78%. White solid. M.p. 146–158 °C.
Rf = 0.36 (hexane/AcOEt, 7:1). H NMR (400 MHz, CDCl3): δ =
7.49–7.04 (m, 10 H), 6.64 (d, J = 8.9 Hz, 1 H), 5.53 (s, 1 H), 5.06
(d, J = 4.0 Hz, 1 H), 4.76 (d, J = 17.0 Hz, 1 H), 4.35 (d, J =
17.0 Hz, 1 H), 3.80 (s, 3 H), 0.34 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 177.4 (C), 175.9 (C), 147.2 (C), 142.5 (C),
7.1 Hz, 2 H), 3.49 (s, 3 H), 2.34 (s, 3 H), 2.28 (s, 3 H), 1.24 (t, J =
7.1 Hz, 3 H), 1.13 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ =168.2 (C), 168.2 (C), 156.0 (C), 143.9 (C), 137.7 (C),
137.4 (C), 136.7 (C), 134.3 (C), 129.9 (CH), 129.3 (2 CH), 129.1 (2
CH), 128.7 (C), 128.2 (CH), 127.0 (2 CH), 126.8 (2 CH), 124.5
(CH), 121.6 (C), 116.9 (CH), 111.3 (CH), 106.6 (CH), 62.6 (CH),
61.6 (CH2), 61.5 (CH2), 59.5 (CH3), 51.6 (CH2), 49.5 (CH), 21.1 (2
1
140.3 (C), 137.2 (C), 132.2 (C), 129.0 (2 CH), 128.8 (2 CH), 128.5 CH3), 14.0 (CH3), 13.8 (CH3) ppm. HRMS (EI): calcd. for
(CH), 128.1 (CH), 127.8 (CH), 127.3 (CH), 126.4 (2 CH), 126.0 (2 C34H37NO5 539.2666; found 539.2665.
Eur. J. Org. Chem. 2011, 1961–1967
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1965

J. Barluenga, M. Fañanás-Mastral, A. Fernández, F. Aznar
FULL PAPER
(Z)-Dimethyl 2-[2-(1-benzyl-2-phenyl-1,2-dihydroquinolin-3-yl)-2-
methoxyvinyl]malonate (12c): Yield: 48%. Yellow oil. Rf = 0.27
(hexane/AcOEt, 5:1). H NMR (400 MHz, CDCl3): δ = 7.33–7.25
(d, J = 15.1 Hz, 1 H), 3.63 (s, 3 H), 3.57 (d, J = 15.1 Hz, 1 H),
3.54–3.50 (m, 2 H), 2.74 (d, J = 6.8 Hz, 1 H), 2.71 (d, J = 6.8 Hz,
1 H), 1.00 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =206.2
1
(m, 5 H), 7.23–7.20 (m, 5 H), 6.92 (d, J = 1.4 Hz, 1 H), 6.85 (dd, (C), 146.4 (C), 144.4 (C), 142.1 (C), 127.6 (CH), 127.4 (2 CH),
J = 8.2, 1.4 Hz, 1 H), 6.80 (s, 1 H), 6.36 (d, J = 8.2 Hz, 1 H), 5.20
(d, J = 9.4 Hz, 1 H), 5.18 (s, 1 H), 4.55 (d, J = 9.4 Hz, 1 H), 4.51
(d, J = 16.3 Hz, 1 H), 4.25 (d, J = 16.3 Hz, 1 H), 3.72 (s, 3 H),
3.63 (s, 3 H), 3.47 (s, 3 H), 2.24 (s, 3 H) ppm. 13C NMR (100 MHz,
127.3 (2 CH), 127.0 (CH), 125.5 (CH), 120.4 (C), 120.4 (C), 115.7
(CH), 112.0 (CH), 82.1 (CH), 60.3 (CH2), 59.1 (CH), 57.1 (CH3),
56.4 (CH3), 46.4 (CH2), 44.7 (CH2), 40.8 (CH), 35.1 (C), 28.2 (3
CH3) ppm. HRMS (EI): calcd. for C27H33NO3 419.2460; found
CDCl3): δ =168.6 (C), 168.5 (C), 156.1 (C), 141.7 (C), 140.7 (C), 419.2451.
137.6 (C), 130.5 (CH), 128.8 (CH), 128.7 (C), 128.6 (2 CH), 128.4
General Procedure for the Synthesis of 1,2-Dihydroquinoline Deriva-
(2 CH), 127.8 (CH), 127.0 (2 CH), 126.8 (2 CH), 126.1 (C), 124.8
(CH), 121.5 (C), 111.3 (CH), 106.3 (CH), 63.2 (CH), 59.3 (CH3),
52.7 (CH3), 52.6 (CH3), 52.2 (CH2), 49.0 (CH), 20.2 (CH3) ppm.
HRMS (EI): calcd. for C31H30NO5 [M – H]+ 496.2118; found
496.2113.
tives 21: A solution of alkynyl carbene complex 1 (0.5 mmol) and
azadiene 20 (3 mmol) in THF (10 mL) was heated in a sealed tube
under an argon atmosphere at 90 °C for 2 h. Then, the reaction
was allowed to reach room temperature, and the azadiene (3 mmol)
was added. The mixture was stirred at room temperature until com-
(Z)-Diallyl 2-{2-Methoxy-2-[1-(4-methylbenzyl)-2-(p-tolyl)-1,2-dihy- plete loss of the characteristic carbene color (dark violet). Then,
droquinolin-3-yl]vinyl}malonate (12d): Yield: 57%. Yellow oil. Rf =
0.44 (hexane/AcOEt, 5:1). H NMR (400 MHz, CDCl3): δ = 7.18
(d, J = 8.0 Hz, 2 H), 7.14–7.05 (m, 6 H), 7.01 (d, J = 7.9 Hz, 2 H),
hexane (30 mL) was added, and the mixture was exposed to air and
light. Finally, the mixture was filtered through a pad of Celite, the
solvents were removed under reduced pressure, and the crude prod-
1
6.83 (s, 1 H), 6.66 (t, J = 7.4 Hz, 1 H), 6.46 (d, J = 8.2 Hz, 1 H), uct was purified by column chromatography on silica gel (hexane/
5.87 (ddt, J = 17.1, 10.5, 5.6 Hz, 1 H), 5.76 (ddt, J = 17.2, 10.5,
5.6 Hz, 1 H), 5.30 (dd, J = 17.2, 1.4 Hz, 1 H), 5.24 (d, J = 9.2 Hz,
1 H), 5.25–5.19 (m, 3 H), 5.17 (s, 1 H), 4.62 (d, J = 5.6 Hz, 2 H),
4.61 (d, J = 9.3 Hz, 1 H), 4.54 (d, J = 5.6 Hz, 2 H), 4.50 (d, J =
16.1 Hz, 1 H), 4.20 (d, J = 16.1 Hz, 1 H), 3.50 (s, 3 H), 2.35 (s, 3
H), 2.29 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =167.8 (C),
167.7 (C), 156.3 (C), 143.9 (C), 137.6 (C), 137.4 (C), 136.7 (C),
134.3 (C), 131.6 (CH), 131.5 (CH), 129.9 (CH), 129.3 (2 CH), 129.1
(2 CH), 128.6 (C), 128.2 (CH), 127.0 (2 CH), 126.7 (2 CH), 124.7
(CH), 121.6 (C), 118.4 (CH2), 118.3 (CH2), 116.9 (CH), 111.3
(CH), 106.1 (CH), 66.1 (CH2), 66.0 (CH2), 62.6 (CH), 59.4 (CH3),
51.6 (CH2), 49.3 (CH), 21.1 (2 CH3) ppm. HRMS (EI): calcd. for
C36H37NO5 563.2672; found 563.2673.
triethylamine, 10:1) to afford compounds 21.
3-(4-Cyclopropylpyrimidin-2-yl)-1-neopentyl-2-phenyl-1,2-dihydro-
quinoline (21a): Yield: 59%. Yellow oil. Rf = 0.34 (hexane/NEt3,
1
10:1). H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 5.1 Hz, 1 H),
7.90 (s, 1 H), 7.35–7.33 (m, 2 H), 7.19–7.15 (m, 3 H), 7.13 (d, J =
8.4, 1.4 Hz, 1 H), 6.93 (d, J = 5.1 Hz, 1 H), 6.75 (d, J = 8.4 Hz, 1
H), 6.62 (t, J = 7.3 Hz, 1 H), 6.12 (s, 1 H), 3.54 (d, J = 15.1 Hz, 1
H), 2.98 (d, J = 15.1 Hz, 1 H), 1.97–1.90 (m, 1 H), 1.28–1.23 (m,
1 H), 1.18–1.13 (m, 1 H), 1.09–1.03 (m, 2 H), 1.02 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ =170.9 (C), 163.0 (C), 155.6 (CH),
146.3 (C), 142.5 (C), 131.9 (C), 130.1 (CH), 129.5 (CH), 129.4
(CH), 128.1 (2 CH), 127.3 (CH), 127.1 (2 CH), 122.3 (C), 116.3
(CH), 116.0 (CH), 112.0 (CH), 62.1 (CH), 57.8 (CH2), 35.2 (C),
28.3 (3 CH3), 16.9 (CH), 11.0 (CH2), 10.9 (CH2) ppm. HRMS (EI):
calcd. for C27H29N3 395.2361; found 395.2370.
General Procedure for the Synthesis of Compounds 17: A solution
of alkynyl carbene complex 1 (0.5 mmol) and Danishefsky’s diene
16 (1.5 mmol) in THF (10 mL) was heated in a sealed tube under
an argon atmosphere at 90 °C for 4 h. Then, the reaction was al-
lowed to reach room temperature and hydrolyzed by adding SiO2.
Finally, the solvents were removed under reduced pressure, and the
crude product was purified by column chromatography on silica
gel (hexane/ethyl acetate 7:1) to afford compounds 17.
1-Benzyl-3-(4-cyclopropylpyrimidin-2-yl)-6-methyl-2-phenyl-1,2-di-
hydroquinoline (21b): Yield: 52%. Yellow oil. Rf = 0.31 (hexane/
NEt3, 10:1). 1H NMR (400 MHz, CDCl3): δ = 8.40 (d, J = 5.1 Hz,
1 H), 8.00 (s, 1 H), 7.38–7.17 (m, 10 H), 7.08 (d, J = 1.8 Hz, 1 H),
6.88 (dd, J = 8.3, 1.8 Hz, 1 H), 6.87 (d, J = 5.1 Hz, 1 H), 6.36 (t,
J = 8.3 Hz, 1 H), 5.98 (s, 1 H), 4.52 (d, J = 16.2 Hz, 1 H), 4.38 (d,
(11S*,11aR*)-7,11-Dimethoxy-5-(4-methylbenzyl)-6-(4-methyl- J = 16.2 Hz, 1 H), 2.26 (s, 3 H), 1.90–1.82 (m, 1 H), 0.99–0.93 (m,
phenyl)-8,10,11,11a-tetrahydro-5H-cyclohepta[c]quinolin-9(6H)-one
(17a): Yield: 48%. Brown oil. Rf = 0.39 (hexane/AcOEt, 3:1). 1H
NMR (300 MHz, CDCl3): δ = 7.18–7.00 (m, 10 H), 6.70 (td, J =
7.4, 0.8 Hz, 1 H), 6.68 (d, J = 8.2 Hz, 1 H), 5.70 (s, 1 H), 4.69 (d,
J = 16.5 Hz, 1 H), 4.21 (d, J = 16.5 Hz, 1 H), 4.15 (td, J = 7.1,
4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =170.9 (C), 162.7 (C),
155.4 (CH), 142.7 (C), 141.8 (C), 138.0 (C), 132.8 (C), 131.1 (CH),
129.6 (CH), 129.0 (CH), 128.5 (2 CH), 128.1 (2 CH), 127.4 (2 CH
+ CH), 127.1 (2 CH), 126.8 (CH), 125.8 (C), 122.0 (C), 116.2 (CH),
111.5 (CH), 62.1 (CH), 52.2 (CH2), 20.3 (CH3), 16.9 (CH), 11.1
3.2 Hz, 1 H), 3.61 (d, J = 3.2 Hz, 1 H), 3.58 (dd, J = 8.6, 7.1, Hz, (CH2), 10.6 (CH2) ppm. HRMS (EI): calcd. for C30H27N3
1 H), 3.51 (dd, J = 8.6, 7.1 Hz, 1 H), 3.38 (s, 3 H), 2.80 (s, 3 H), 429.2205; found 429.2210.
2.75 (d, J = 6.7 Hz, 1 H), 2.33 (s, 3 H), 2.33 (d, J = 6.7 Hz, 1 H),
3-(4-Cyclopropylpyrimidin-2-yl)-1-(4-methylbenzyl)-2-(4-methyl-
2.29 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =206.3 (C), 145.5
phenyl)-1,2-dihydroquinoline (21c): Yield: 67%. Yellow oil. Rf = 0.29
(C), 145.1 (C), 139.5 (C), 136.3 (C), 135.5 (C), 135.4 (C), 129.2 (2
1
(hexane/NEt3, 10:1). H NMR (400 MHz, CDCl3): δ = 8.39 (d, J
CH), 128.1 (2 CH), 127.7 (2 CH), 127.6 (CH), 127.5 (CH), 126.8
= 5.1 Hz, 1 H), 7.99 (s, 1 H), 7.26 (d, J = 7.9 Hz, 2 H), 7.23 (dd,
(2 CH), 121.3 (C), 121.1 (C), 116.6 (CH), 112.1 (CH), 81.9 (CH),
J = 7.4, 1.5 Hz, 1 H), 7.21 (d, J = 7.9 Hz, 2 H), 7.12 (d, J = 7.9 Hz,
58.6 (CH), 57.1 (CH3), 56.4 (CH3), 53.2 (CH2), 46.3 (CH2), 45.0
2 H), 7.05 (td, J = 7.8, 1.5 Hz, 1 H), 7.00 (d, J = 7.9 Hz, 1 H), 6.86
(CH2), 41.7 (CH), 21.1 (2 CH3) ppm. HRMS (EI): calcd. for
(d, J = 5.1 Hz, 1 H), 6.67 (t, J = 7.3 Hz, 1 H), 6.44 (d, J = 8.3 Hz,
C31H33NO3 467.2460; found 467.2463.
1 H), 5.96 (s, 1 H), 4.50 (d, J = 16.0 Hz, 1 H), 4.32 (d, J = 16.0 Hz,
(11S*,11aR*)-7,11-Dimethoxy-5-neopentyl-6-phenyl-8,10,11,11a- 1 H), 2.34 (s, 3 H), 2.26 (s, 3 H), 1.89–1.83 (m, 1 H), 1.00–0.94 (m,
tetrahydro-5H-cyclohepta[c]quinolin-9(6H)-one (17b): Yield: 65%.
Brown oil. Rf = 0.50 (hexane/AcOEt, 3:1). 1H NMR (300 MHz,
CDCl3): δ = 7.18–7.05 (m, 7 H), 6.98 (d, J = 8.3 Hz, 1 H), 6.63 (t,
4 H) ppm. 13C NMR (100 MHz, CDCl3): δ =170.9 (C), 162.7 (C),
155.4 (CH), 144.9 (C), 138.9 (C), 137.1 (C), 136.5 (C), 134.6 (C),
132.7 (C), 130.5 (CH), 129.2 (2 CH), 129.1 (CH), 128.8 (2 CH),
J = 7.3 Hz, 1 H), 5.87 (s, 1 H), 4.10 (td, J = 7.1, 3.4 Hz, 1 H), 3.74 127.4 (2 CH), 127.1 (2 CH), 122.0 (C), 116.7 (CH), 116.3 (CH),
1966
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1961–1967

[1,5]-Hydride Transfer/Cyclization of ortho-Amino Alkynyl Fischer Carbenes
J. Organomet. Chem. 2005, 690, 5900–5911; e) J. W. Herndon,
Coord. Chem. Rev. 2006, 250, 1889–1964.
[6] CCDC-784348 (for 6d) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[7] For examples of van Halban–White cyclizations on alkenyl Fi-
scher carbene complexes, see: a) T. A. Brandvold, W. D. Wulff,
A. L. Rheingold, J. Am. Chem. Soc. 1990, 112, 1645–1647; b)
M. L. Waters, T. A. Brandvold, L. Isaacs, W. D. Wulff, Organo-
metallics 1998, 17, 4298–4308.
[8] For a similar reaction using alkyl Fischer carbene complexes,
see: A. Yamashita, T. A. Scahill, Tetrahedron Lett. 1982, 23,
3765–3768.
[9] a) W. D. Wulff, W. E. Bauta, R. W. Kaesler, P. J. Lankford,
R. A. Miller, C. K. Murray, D. C. Yang, J. Am. Chem. Soc.
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111.4 (CH), 61.5 (CH), 51.7 (CH2), 21.1 (2 CH3), 16.9 (CH), 11.1
(CH2), 10.6 (CH2) ppm. HRMS (EI): calcd. for C31H29N3
443.2361; found 443.2363.
Supporting Information (see footnote on the first page of this arti-
cle): Selected NMR spectra, computational modeling of the
van Halban–White cyclization, including Cartesian coordinates.
Acknowledgments
We gratefully acknowledge financial support from the Ministerio
de Ciencia e Innovación (MICINN) (CTQ2007-61048/BQU) and
Principado de Asturias (PRINCAST) (IB08-088). M.F.-M. also ac-
knowledges the Ministerio de Educación y Ciencia (MEC) for a
grant. We also acknowledge Prof. F.J. Fañanás and Prof. C. Valdés
for helpful discussions and assistance in the computational model-
ing.
[10] For some examples, see: a) W. D. Wulff, D. C. Yang, J. Am.
Chem. Soc. 1984, 106, 7565–7567; b) J. Barluenga, F. Aznar, S.
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M. Fañanás-Mastral, F. Aznar, Chem. Eur. J. 2008, 14, 7508–
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[15] For a similar procedure for the synthesis of dihydropyrimid-
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Received: December 22, 2010
Published Online: February 22, 2011
Eur. J. Org. Chem. 2011, 1961–1967
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1967