Palladium-catalyzed arylic/allylic aminations: Permutable domino sequences for the synthesis of dihydroquinolines from morita-baylis-hillman adducts

Article abstract of DOI:10.1021/ol401234v

An efficient palladium-catalyzed synthesis of 1,2-dihydroquinolines has been developed via the reaction between anilines and Morita-Baylis-Hillman adducts derived from o-bromobenzaldehyde. This new Pd(0)-catalyzed pseudo-domino type I sequence involves a Buchwald-Hartwig arylic amination and an allylic amination. When starting from an o-bromo allylic alcohol, the chronology is arylic amination/allylic arylation. However, the sequence reverses when the reaction is performed on the corresponding o-bromo allylic acetate.

Full text of DOI:10.1021/ol401234v

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Arylic/Allylic
Aminations: Permutable Domino
Sequences for the Synthesis of
Dihydroquinolines from
MoritaꢀBaylisꢀHillman Adducts
ꢀ
Melanie M. Lorion, Danila Gasperini, Julie Oble, and Giovanni Poli*
ꢀ
UPMC Univ. Paris 06, Sorbonne Universites, Institut Parisien de Chimie Moleculaire
(UMR CNRS 7201), case 183, 4 place Jussieu, 75005 Paris, France
ꢀ
giovanni.poli@upmc.fr
Received May 2, 2013
ABSTRACT
An efficient palladium-catalyzed synthesis of 1,2-dihydroquinolines has been developed via the reaction between anilines and
MoritaꢀBaylisꢀHillman adducts derived from o-bromobenzaldehyde. This new Pd(0)-catalyzed pseudo-domino type I sequence involves a
BuchwaldꢀHartwig arylic amination and an allylic amination. When starting from an o-bromo allylic alcohol, the chronology is arylic amination/
allylic arylation. However, the sequence reverses when the reaction is performed on the corresponding o-bromo allylic acetate.
Transition-metal-mediated domino reactions1 have re-
ached an important place in the arsenal of the organic
chemist, as they allow access to complex molecular struc-
tures in a single synthetic operation and often under mild
conditions. Such transformations may involve either a
single catalytic cycle entailing several elementary steps
(pure domino)2 or several sequential catalytic cycles
(pseudo-domino),3,4 driven by a single (type I)5 or several
catalysts (type II).6 Following our ongoing interest in these
domino transformations, as well as in the synthesis of
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Tietze, L. F. Chem.
Rev. 1996, 96, 115.
(2) Poli, G.; Giambastiani, G. Tetrahedron 2000, 56, 5959.
(3) (a) Prestat, G.; Poli, G. Chemtracts - Org. Chem. 2004, 17, 97. (b)
Poli, G.; Giambastiani, G. J. Org. Chem. 2002, 67, 9456.
(6) For representative examples of pseudo-domino type II, see: (a)
Zhang, L.; Sonaglia, L.; Stacey, J.; Lautens, M. Org. Lett. 2013, 15, 2128.
(b) Aksın-Artok, O.; Krause, N. Adv. Synth. Catal. 2011, 353, 385. (c)
€
(4) (a) Walsike, J.-C.; Obrey, J. O.; Baker, R. T.; Bazan, G. C. Chem.
Rev. 2005, 105, 1001. (b) Ajamian, A.; Gleason, J. L. Angew. Chem., Int.
Ed. 2004, 43, 3754. (c) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc.
Rev. 2004, 33, 302. (d) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev.
2004, 248, 2365.
(5) For representative examples of pseudo-domino type I sequences,
see: (a) Giboulot, S.; Liron, F.; Prestat, G.; Wahl, B.; Sauthier, M.;
Castanet, Y.; Mortreux, A.; Poli, G. Chem. Commun. 2012, 48, 5889. (b)
Mingoia, F.; Vitale, M.; Madec, D.; Prestat, G.; Poli, G. Tetrahedron
Lett. 2008, 49, 760. (c) Battistuzzi, G.; Bernini, R.; Cacchi, S.; De Salve,
I.; Fabrizi, G. Adv. Synth. Catal. 2007, 349, 297. (d) Maitro, G.; Vogel,
S.; Prestat, G.; Madec, D.; Poli, G. Org. Lett. 2006, 8, 5951. (e) Lemaire,
S.; Prestat, G.; Giambastiani, G.; Madec, D.; Pacini, B.; Poli, G.
J. Organomet. Chem. 2003, 687, 291. (f) Evans, P. A.; Robinson, J. E.
J. Am. Chem. Soc. 2001, 123, 4609. (g) Tietze, L. F.; Nordmann, G. Eur.
J. Org. Chem. 2001, 3247. (h) Poli, G.; Giambastiani, G.; Pacini, B.
Tetrahedron Lett. 2001, 42, 5179.
Kammerer, C.; Prestat, G.; Gaillard, T.; Madec, D.; Poli, G. Org. Lett.
2008, 10, 405. (d) Lebel, H.; Paquet, V. J. Am. Chem. Soc. 2004, 126,
1152. (e) Cossy, J.; Bargiggia, F.; Bouzbouz, S. Org. Lett. 2003, 5, 459. (f)
Son, S. U.; Park, K. H.; Chung, Y. K. J. Am. Chem. Soc. 2002, 124, 6838.
(g) Park, K. H.; Seung, U. S.; Chung, Y. K. Org. Lett. 2002, 4, 4361.
(h) Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem. Soc. 2000, 122, 10220.
(i) Grigg, R.; Sridharan, V.; York, M. Tetrahedron Lett. 1998, 39, 4139.
(j) Barnhart, R. W.; Bazan, G. C. J. Am. Chem. Soc. 1998, 120, 1082.
(k) Morken, J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J. Am.
Chem. Soc. 1994, 116, 3123.
(7) For recent examples, see: (a) Boutier, A.; Kammerer-Pentier, C.;
Krause, N.; Prestat, G.; Poli, G. Chem.;Eur. J. 2012, 18, 3840. (b)
Bantreil, X.; Prestat, G.; Moreno, A.; Madec, D.; Fristrup, P.; Norrby,
P. O.; Pregosin, P. S.; Poli, G. Chem.;Eur. J. 2011, 17, 2885. (c) Vogel,
S.; Bantreil, X.; Maitro, G.; Prestat, G.; Madec, D.; Poli, G. Tetrahedron
Lett. 2010, 51, 1459. (d) Kammerer, C.; Prestat, G.; Madec, D.; Poli, G.
Chem.;Eur. J. 2009, 15, 4224.
r
10.1021/ol401234v
XXXX American Chemical Society

nitrogen-based heterocycles,7 we have initiated a study
aimed at the development of a new palladium-catalyzed
sequence for the rapid construction of dihydroquinoline
frameworks, to be possibly adapted to pseudo-domino
conditions.
Quinolines and their fully or partially hydrogenated
derivatives are widely found in many biologically active
natural or synthetic products.8 In particular, 1,2-dihydro-
quinolines have received special attention because of their
numerous applications as pharmaceuticals and agrochem-
icals, as well as their use as intermediates in the synthesis of
other heterocycles of biological significance.9
chronologically switchable catalytic processes: an allylic
amination16 and a BuchwaldꢀHartwig arylic amination
reaction.17 The reaction, which starts from readily avail-
able MBH alcohol adducts, generates water and a halide
salt as the byproducts and can be run under pseudo-domino
conditions (Scheme 1).
Scheme 1. Domino Sequence to 1,2-Dihydroquinolines
Consequently, a number of strategies have been devel-
oped for the synthesis of these scaffolds including transition-
metal-10 or organo-catalyzed11 reactions, as well as one-pot
approaches from MoritaꢀBaylisꢀHillman (MBH) ad-
ducts. Indeed, the use of functionalized adducts derived
from the MBH reaction12 is a convenient synthetic ap-
proach for the construction of various quinoline deriva-
tives.13,14 However, to the best of our knowledge, there are
no reports concerning their one-pot synthesis directly from
MBH alcohol adducts.15
We began our study by focusing our attention on the
allylic amination of MBH adducts. In particular, we
selected, for this step, a poorly nucleophilic amine such
as aniline so as to avoid a competitive 1,4-addition on the
R,β-unsaturated ester.18
Recent studies have shown that combinations of
[PdCl(η3-C3H5)]2 with a large bite-angle ligand allow the
selective amination of allylic alcohols.16 Accordingly, we
decided to perform our first allylic amination tests on
the MBH adduct 1a lacking an o-halo substituent, using
Xantphos as the ligand in the presence of 1.5 equivalents
of aniline in 1,4-dioxane at 80 °C. While Pd(OAc)2 or
Pd(dba)2 as Pd source gave no reaction (Table 1, entries 1
and 2), the dimer [PdCl(η3-C3H5)]2 afforded the desired
allylic amine 2a in 98% yield (entry 3). DPEPhos (entry 4)
and dppf (entry 5) proved to be more efficient than
monophosphine ligands (entry 6). When the reaction was
carried out without either the precatalyst/ligand system
(entry 7) or the precatalyst (entry 8), we recovered the
unreacted starting material.19 These two last experiments
suggest that a transient η3-allyl palladium complex is likely
to be involved in this transformation and rule out an
alternative SN20 pathway.
Herein, we describe a palladium-catalyzed synthesis
of 1,2-dihydroquinolines through the formation of two
CꢀN bonds via two mechanistically independent and
(8) (a) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488. (b)
Sridharan, V.; Suryavanshi, P. A.; Menendez, C. Chem. Rev. 2011, 111,
7157. (c) Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J. Med. Chem.
2010, 45, 3245. (d) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166 and other
previous reports in this series.
(9) Jones, G. In: Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 5, p 167.
(10) (a) Wang, Z.; Li, S.; Yu, B.; Wu, H.; Wang, Y.; Sun, X. J. Org.
Chem. 2012, 77, 8615. (b) Kothandaraman, P.; Foo, S. J.; Chan, P. W. H.
J. Org. Chem. 2009, 74, 5947. (c) Liu, X.-Y.; Ding, P.; Huang, J.-S.; Che,
C. M. Org. Lett. 2007, 9, 2645. (d) Yi, C. S.; Yun, S. Y. J. Am. Chem. Soc.
2005, 127, 17000. (e) Williamson, N. M.; Ward, A. D. Tetrahedron 2005,
61, 155. (f) Lu, G.; Malinakova, H. C. J. Org. Chem. 2004, 69, 4701. (f)
Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M. Tetra-
hedron 2004, 60, 3017. (g) Pastine, S. J.; Youn, S.-W.; Sames, D.
Tetrahedron 2003, 59, 8859. (h) Ranu, B. C.; Hajra, A.; Dev, S. S.; Jana,
U. Tetrahedron 2003, 59, 813.
(11) (a) Li, H.; Wang, J.; Xie, H.; Zu, L.; Jiang, W.; Duesler, E. N.;
ꢀ
Submission of the chloro-substituted MBH adduct 1b to
the reaction conditions as previously optimized with 1a
gave cleanly the corresponding allylic amination product
2b (Table 1, entry 9). On the other hand, the corresponding
bromoester 2c could be obtained only when starting from
Wang, W. Org. Lett. 2007, 9, 965. (b) Sunden, H.; Rios, R.; Ibrahem, I.;
ꢀ
Zhao, G.-L.; Erikssson, L.; Cordova, A. Adv. Synth. Catal. 2007, 349,
827.
(12) For recent reviews, see: (a) Basavaiah, D.; Veeraraghavaiah, G.
Chem. Soc. Rev. 2012, 41, 68. (b) Basavaiah, D.; Reddy, B. S.; Badsara,
S. S. Chem. Rev. 2010, 110, 5447. (c) Declerck, V.; Martinez, J.; Lamaty,
F. Chem. Rev. 2009, 109, 1. (d) Basavaiah, D.; Rao, A. J.; Satyanarayana,
R. Chem. Rev. 2003, 103, 811.
20
the allylic acetate 1c0 (Table 1, entry 11), while no re-
action was obtained from the brominated MBH allylic
alcohol 1c (Table 1, entry 10).
These results strongly suggest that, under such condi-
tions, the reactivity scale of oxidative addition to Pd(0)
decreases in the order: allylic acetate > aryl bromide >
allylic alcohol > aryl chloride (Scheme 2).
(13) For SN20ꢀSNAr one-pot strategy from MBH acetate adducts,
see: (a) Napoleon, J. V.; Manheri, M. K. Synthesis 2011, 3379. (b) Kim,
J. N.; Lee, H. J.; Lee, K. Y.; Kim, H. S. Tetrahedron Lett. 2001, 42, 3737.
(c) Kim, J. N.; Im, Y. J.; Gong, J. H.; Lee, K. Y. Tetrahedron Lett. 2001,
42, 4195.
(14) For stepwise strategy involving SN20-palladium-catalyzed ami-
dation from MBH acetate adducts, see: Park, Y. S.; Cho, M. Y.; Kwon,
Y. B.; Yoo, B. W.; Yoon, C. M. Synth. Commun. 2007, 37, 2677.
(15) During the preparation of this manuscript, a copper-catalyzed
domino SN20-coupling reaction was reported from the MBH acetate
adducts: Niu, Q.; Mao, H.; Yuan, G.; Gao, J.; Liu, H.; Tu, Y.; Wang, X.;
Lv, X. Adv. Synth. Catal. 2013, 355, 1185.
(16) For recent reviews, see: (a) Sundararaju, B.; Achard, M.; Bruneau,
C. Chem. Soc. Rev. 2012, 41, 4467. (b) Bandini, M. Angew. Chem., Int.
Ed. 2011, 50, 994. (c) Bandini, M.; Tragni, M. Org. Biomol. Chem. 2009,
7, 1501. (d) Muzart, J. Eur. J. Org. Chem. 2007, 3077. (e) Tamaru, Y.
Eur. J. Org. Chem. 2005, 2647. (f) Muzart, J. Tetrahedron 2005, 61,
4179.
(17) For recent reviews, see: (a) Hartwig, J. F. Acc. Chem. Res. 2008,
41, 1534. (b) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
1599.
(18) Kaye, P. T.; Musa, M. A. Synth. Commun. 2003, 33, 1755.
(19) Toluene as a solvent also gave full conversion. However, this
solvent was highly detrimental for the domino process.
(20) This reaction was also described to occur without any catalyst.
See ref 14.
B
Org. Lett., Vol. XX, No. XX, XXXX

entry 1).21 However, other biphosphine ligands which
efficiently promoted the allylic amination gave lower yields
in this domino sequence (entries 2 and 3). Similarly, the use
of Cs2CO3 as the base led to a drop of yield (entry 4).
Interestingly, the 1,2-dihydroquinoline 3a could also be
obtained (81% yield) submitting the bromoacetate 1c0 to
the same reaction conditions as above (Table 2, entry 5).22
Finally, 3a could also be obtained (43% yield) starting
from the chloroalcohol 1b when working in the presence
of both Xantphos23 and Xphos23,24 (Table 2, entry 6).25
Indeed, while the former ligand turned out to be the
optimal one for the allylation step, the latter one is known
tobethe ligand of choice tofavor oxidative addition of aryl
chlorides to Pd(0).
Table 1. Optimization of the Palladium-Catalyzed Allylic
Amination of MBH Adducts with Anilinea
entry
R
X
catalyst
ligand
yield (%)
b
1
H
H
H
H
H
H
H
H
H
H
Ac
H
H
H
H
H
H
H
H
Cl
Br
Br
Pd(OAc)2
Xantphos
Xantphos
Xantphos
DPEPhos
dppf
no reaction
no reaction
2a, 98c
b
2
Pd(dba)2
3
[PdCl(η3-C3H5)]2
[PdCl(η3-C3H5)]2
[PdCl(η3-C3H5)]2
[PdCl(η3-C3H5)]2
4
2a, 81d
5
2a, 95d
2a, 50d
6
XPhose
Table 2. Palladium-Catalyzed Arylic/Allylic Amination
7
no reaction
no reaction
2b, 91c,f
Domino Sequence of MBH Adducts with Anilinea
8
Xantphos
Xantphos
Xantphos
Xantphos
9
[PdCl(η3-C3H5)]2
[PdCl(η3-C3H5)]2
[PdCl(η3-C3H5)]2
10
11
no reaction
2c, 56c
a Reaction conditions: 1 (1 equiv), PhNH2 (1.5 equiv), Pd cat. (5 mol %),
ligand (10 mol %), 1,4-dioxane (0.2 M). b 10 mol % of Pd cat. were used.
c Isolated yield. d Spectroscopic (1H NMR) yields using an internal
standard (1,3,5-trimethoxybenzene). e 20 mol % of ligand were used.
f Reaction time: 2 days.
entry
R
X
ligand
Xantphos
base
yield (%)
1
2
3
4
5
6
H
H
H
H
Ac
H
Br
Br
Br
Br
Br
Cl
K2CO3
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
65,b 58c
34b
DPEPhos
dppf
26b
Scheme 2. Oxidative Addition Preferences of o-Halo-MBH
Adducts
Xantphos
23b
Xantphos
81c
Xantphos and Xphos
43c,d
a Reaction conditions: 1c (1 equiv), PhNH2 (1.5 equiv), [PdCl(η3-
C3H5)]2 (5mol%), ligand(10mol%),K2CO3 (2 equiv), 1,4-dioxane (0.2 M).
b Spectroscopic (1H NMR) yields using an internal standard (1,3,5-
trimethoxybenzene). c Isolated yield. d Reaction time: 2 days.
As in the BuchwaldꢀHartwig reaction, a base is needed
to convert the amino complex ArPdXNH2R into the
corresponding amido complex ArPdNHR, we surmised
that the failure to react of 1c was very likely due to a
catalysis halt at the amino complex stage. We thus antici-
pated that generation of the desired dihydroquinoline in a
domino fashion could be obtained via two different chron-
ologies (allylation/arylation or vice versa) just by playing
with the nature of the allylic and the arylic leaving groups.
More precisely, we reasoned that in the case of the bromide
1c, addition of a base to the previously optimized reaction
conditions should trigger an initial BuchwaldꢀHartwig
arylic amination, and the thus generated secondary amine
may in turn undergo an intramolecular allylation, whereas
a reversed chronological sequence might be achieved either
from bromoacetate 1c0 or the chloroalcohol 1b.
With successful domino conditions in hands, we began
to explore the sequence on a series of aromatic amines
and various MBH adducts. In particular, we selected the
variant starting from the bromo alcohols MBH adducts as
it appears the most straightforward one (Scheme 3). In
the event, electron-donating (3b,3c, 3f) and electron-
withdrawing (3gꢀj) groups on the aromatic ring of the
amines were well tolerated and provided the target 1,2-
dihydroquinolines in good yields,26 except for the bulky
2,4,6-trimethylaniline (3d) and naphthalen-1-amine (3e).
(22) The yield of this domino process is better starting from acetate
1c0 than alcohol 1c. However, as the synthesis of the former requires an
unnecessary additional acylation step, the direct reaction from alcohol
1c appears synthetically preferable.
(23) For a review, see: Birkholz, M.-N.; Freixa, Z.; van Leeuwen,
P. W. N. M. Chem Soc Rev. 2009, 38, 1099.
(24) For a review, see: Surry, D. S.; Buchwald, S. L. Angew. Chem.,
As expected, when the reaction between 1c and aniline
was repeated in the presence of K2CO3, a 65% yield of the
desired 1,2-dihydroquinoline 3a was obtained (Table 2,
Int. Ed. 2008, 47, 6338.
(25) Conversion of 1b into 3a could also be obtained in two separated
(non domino) steps via isolation of 2b.
(26) Dihydroquinolines are quite unstable in both pure form and in
solution in CDCl3, and isomerization and/or oxidation to form the
corresponding quinolones can occur. For more details, see ref 13a.
(21) Under these conditions, the indanone derivative that could arise
from an intramolecular MizorokiꢀHeck coupling was not observed. (a)
Park, J. B.; Ko, S. H.; Hong, W. P.; Lee, K-J. Bull Korean Chem. Soc.
2004, 25, 927. (b) Gaudin, J.-M. Tetrahedron Lett. 1991, 32, 6113.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Scope of the Palladium-Catalyzed Arylic/Allylic
Amination Domino Sequence from Bromo Alcohol MBH
Adductsa
Scheme 4. Possible Mechanism and Chronologies of the
Palladium-Catalyzed Arylic/Allylic Amination Domino Sequence
a Isolated yields. Reaction conditions: MBH (1 equiv), ArNH2
(1.5 equiv), [PdCl(η3-C3H5)]2 (5 mol %), Xantphos (10 mol %),
K2CO3 (2 equiv), 1,4-dioxane (0.2 M).
The nature of the ester substituent had a minor effect on
the yield (compare 3k and 3l vs 3a).27 Finally, the 6,7-
benzo-1,2-dihydroquinoline (3m) could also be obtained,
albeit with a low yield.
sequence will reverse to arylic amination/allylic arylation
(Scheme 4, top from right to left).28ꢀ30
Coming back to the mechanistic details of this pseudo-
domino transformation, the results of our previous experi-
ments allow predicting the sequential chronology of the
NꢀC bond forming reactions as a function of the nature of
the leaving groups in the substrates. Indeed, starting from
the bromo-substituted allylic acetate, the selected sequence
will be allylic amination/arylic amination (Scheme 4, bott-
om from right to left, see also Table 1 entry 11, and Table 2
entry 5), while with bromo-substituted allylic alcohols the
In summary, we have developed a new pseudo-domino
type I sequence that allows the expeditious synthesis of 1,2-
dihydroquinolines from simple MBH alcohol adducts.
Two distinct Pd(0) processes are at play in this transforma-
tion: a BuchwaldꢀHartwig coupling and an allylic amina-
tion. Interestingly, the chronology of the two NꢀC bond
forming reactions can be selected as a function of the
nature of the leaving groups. Extension of this methodol-
ogy to other heterocycles and biologically relevant targets
are currently underway in our laboratory.
(27) The reaction with the MBH adduct derived from acrylonitrile
was unsuccessful, despite complete consumption of the starting material,
probably due to the rapid degradation of the desired quinoline in the
reaction conditions. The same issue was observed when aliphatic amines
(cyclohexylamine, allylamine, and tert-butylamine) or tosylamine were
employed.
(28) At the moment, no speculation on the step chronology can be
advanced for the chloroalcohol MBH adduct 1b when Xantphos and
Xphos are both added the outset of the experiment in the presence of
K2CO3.
Acknowledgment. This paper is dedicated to Prof. An-
ꢀ
ꢀ
dre Mortreux (UCCS, Universite Lille) on the occasion of
his 70th birthday. We thank Manuel Barday (IPCM) for
his contribution in preliminary experiments and Omar
Khaled (IPCM) for HRMS analyses. CNRS and UPMC
are acknowledged for financial support.
(29) For precedents of generation of η3-allyl complexes from the
acetate esters of MBH adducts and their reaction with amines see: (a)
Wang, Y.; Liu, L.; Wang, D.; Chen, Y.-J. Org. Biomol. Chem. 2012, 10,
6908. (b) Rajesh, S.; Banerji, B.; Iqbal, J. J. Org. Chem. 2002, 67, 7852.
See also: (c) Cao, H.; Vieira, T. O.; Alper, H. Org. Lett. 2011, 13, 11.
(30) In the latter sequence type, the intramolecular allylic amination
has, for geometric reasons, to take place on an anti configured
η3-allylpalladium complex.
Supporting Information Available. Experimental details
and characterization of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX