Lewis acid catalyzed formation of tetrahydroquinolines via an intramolecular redox process

Article abstract of DOI:10.1021/ol802519r

Polycyclic tetrahydroquinolines were prepared by an efficient Lewis acid catalyzed 1,5-hydride shift, ring closure sequence. Gadolinium triflate was identified as a catalyst that is superior to scandium triflate as well as other Lewis acids. An approach t

Full text of DOI:10.1021/ol802519r

ORGANIC
LETTERS
2009
Vol. 11, No. 1
129-132
Lewis Acid Catalyzed Formation of
Tetrahydroquinolines via an
Intramolecular Redox Process
Sandip Murarka, Chen Zhang, Marlena D. Konieczynska, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New
Jersey, Piscataway, New Jersey 08854
seidel@rutchem.rutgers.edu
Received October 30, 2008
ABSTRACT
Polycyclic tetrahydroquinolines were prepared by an efficient Lewis acid catalyzed 1,5-hydride shift, ring closure sequence. Gadolinium triflate
was identified as a catalyst that is superior to scandium triflate as well as other Lewis acids. An approach toward a catalytic enantioselective
variant is also described.
Tetrahydroquinolines have attracted considerable attention
due to their diverse array of biological activities.1 Common
Scheme 1
.
Tetrahydroquinoline Synthesis via Redox Neutral
methods for the synthesis of tetrahydroquinolines1 include
the Povarov reaction2 and various reductions of quinolines.3
An underutilized approach to polycyclic tetrahydroquinolines,
not readily available by other means, is outlined in Scheme
1. Tertiary anilines 1 with an appropriate acceptor group in
the ortho position rearrange to tetrahydroquinolines 2 under
thermal conditions. In this process, a C-H bond R to the
tertiary amine nitrogen is replaced by a C-C bond that
becomes part of the newly formed tetrahydroquinoline ring
system.4 Harsh reaction conditions are typically required for
this transformation, therefore resulting in limited synthetic
C-H Bond Functionalization
use. Here we report an efficient Lewis acid catalyzed
approach that readily proceeds at room temperature and
significantly enhances the applicability of this rearrangement.
(1) For a comprehensive review, see: Katritzky, A. R.; Rachwal, S.;
Rachwal, B. Tetrahedron 1996, 52, 15031–15070.
The thermal rearrangement of 1 (Z ) Z′ ) CN) was
(2) For a recent review on the Povarov reaction, see: Glushkov, V. A.;
Tolstikov, A. G. Russ. Chem. ReV. 2008, 77, 137–159.
originally reported in 1984 by Reinhoudt et al.,5 and variants
(3) For recent examples, see: (a) Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683–3686. (b) Zhou,
Y.-G. Acc. Chem. Res. 2007, 40, 1357–1366. (c) Chan, S. H.; Lam, K. H.;
Li, Y.-M.; Xu, L.; Tang, W.; Lam, F. L.; Lo, W. H.; Yu, W. Y.; Fan, Q.;
Chan, A. S. C. Tetrahedron: Asymmetry 2007, 18, 2625–2631. (d) Guo,
Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759–762. (e)
Mrsic, N.; Lefort, L.; Boogers, J. A. F.; Minnaard, A. J.; Feringa, B. L.; de
Vries, J. G. AdV. Synth. Catal. 2008, 350, 1081–1089. (f) Wang, X.-B.;
Zhou, Y.-G. J. Org. Chem. 2008, 73, 5640–5642, and references cited
therein.
(4) Due to this unusual reactivity, reactions of this type have been
described by the term “tert-amino effect.” For reviews, see: (a) Meth-Cohn,
O.; Suschitzky, H. AdV. Heterocycl. Chem. 1972, 14, 211–278. (b) Verboom,
W.; Reinhoudt, D. N. Recl. TraV. Chim. Pays-Bas 1990, 109, 311–324. (c)
Meth-Cohn, O. AdV. Heterocycl. Chem. 1996, 65, 1–37. (d) Quintela, J. M.
Recent Res. DeVel. Org. Chem. 2003, 7, 259–278. (e) Matyus, P.; Elias,
O.; Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-Dajka, B. Synthesis 2006,
2625–2639.
10.1021/ol802519r CCC: $40.75
Published on Web 12/09/2008
2009 American Chemical Society

of this reaction have been reported.6 In some examples, the
benzene ring has been replaced by different heterocycles,7
and one of the acceptors (Z) can also be a heterocycle.8
Scheme 2. Proposed Lewis Acid Catalyzed Process
While microwave acceleration of the thermal rearrange-
ment has been reported,9 surprisingly little effort has focused
on using Lewis acids to accelerate this reaction.10 Lewis acids
such as zinc chloride and boron trifluoride-diethyl ether have
been used in stoichiometric amounts, with heating still being
required to induce the rearrangement.10
As part of a program to develop intramolecular redox
reactions of broad synthetic applicability,11 we decided to
explore the use of Lewis acids for the rearrangement of 1a
to 2a (Scheme 2).12 We speculated that alkylidene malonates
represent ideal acceptor moieties that are susceptible to
activation by a Lewis acid catalyst capable of chelation to
the malonate subunit. This interaction is expected to increase
the hydride acceptor capability of the conjugated double
bond. The dipolar intermediate resulting from hydride
transfer is expected to readily undergo ring closure to form
2a.
Indeed, catalytic amounts of various Lewis acids facilitate
rearrangement of 1a to 2a at room temperature (Table 1).
(5) Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org.
Chem. 1984, 49, 269–276.
Table 1. Evaluation of Potential Catalystsa
(6) (a) Nijhuis, W. H. N.; Verboom, W.; Reinhoudt, D. N.; Harkema,
S. J. Am. Chem. Soc. 1987, 109, 3136–3138. (b) Nijhuis, W. H. N.;
Verboom, W.; Reinhoudt, D. N. Synthesis 1987, 641–645. (c) Groenen,
L. C.; Verboom, W.; Nijhuis, W. H. N.; Reinhoudt, D. N.; Van Hummel,
G. J.; Feil, D. Tetrahedron 1988, 44, 4637–4644. (d) Nijhuis, W. H. N.;
Verboom, W.; Abu El-Fadl, A.; Harkema, S.; Reinhoudt, D. N. J. Org.
Chem. 1989, 54, 199–209. (e) Nijhuis, W. H. N.; Verboom, W.; Abu El-
Fadl, A.; Van Hummel, G. J.; Reinhoudt, D. N. J. Org. Chem. 1989, 54,
209–216. (f) Nijhuis, W. H. N.; Leus, G. R. B.; Egberink, R. J. M.;
Verboom, W.; Reinhoudt, D. N. Recl. TraV. Chim. Pays-Bas 1989, 108,
172–178. (g) Kelderman, E.; Noorlander-Bunt, H. G.; Van Eerden, J.;
Verboom, W.; Reinhoudt, D. N. Recl. TraV. Chim. Pays-Bas 1991, 110,
115–123. (h) Tverdokhlebov, A. V.; Gorulya, A. P.; Tolmachev, A. A.;
Kostyuk, A. N.; Chernega, A. N.; Rusanov, E. B. Tetrahedron 2006, 62,
9146–9152. (i) Rabong, C.; Hametner, C.; Mereiter, K.; Kartsev, V. G.;
Jordis, U. Heterocycles 2008, 75, 799–838. (j) Ryabukhin, S. V.; Plaskon,
A. S.; Volochnyuk, D. M.; Pipko, S. E.; Tolmachev, A. A. Synth. Commun.
2008, 38, 3032–3043.
yield
(%)
entry
catalyst
Mg(OTf)2
Mg(ClO4)2
Mg(ClO4)2·6H2O
InCl3
mol %
solvent
time
24 h
20 h
24 h
24 h
24 h
24 h
24 h
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
20
20
10
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
20b
83
trace
66b
72b
55
Zn(OTf)2
Cu(OTf)2
Ni(ClO4)2·6H2O
FeCl3·6H2O
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
La(OTf)3
28b
trace
84
(7) (a) Verboom, W.; Verboom, C.; Eissink, I. M.; Lammerink, B. H. M.;
Reinhoudt, D. N. Recl. TraV. Chim. Pays-Bas 1990, 109, 481–484. (b) Ojea,
V.; Peinador, C.; Quintela, J. M. Synthesis 1992, 798–802. (c) Ojea, V.;
Peinador, C.; Vilar, J.; Quintela, J. M. Synthesis 1993, 152–157. (d) Ojea,
V.; Maestro, M. A.; Quintela, J. M. Tetrahedron 1993, 49, 2691–2700. (e)
Matyus, P.; Fuji, K.; Tanaka, K. Heterocycles 1994, 37, 171–174. (f) Ojea,
V.; Muinelo, I.; Figueroa, M. C.; Ruiz, M.; Quintela, J. M. Synlett 1995,
622–624. (g) Wamhoff, H.; Kramer-Hoss, V. Liebigs Ann./Recueil 1997,
1619–1625. (h) Ojea, V.; Muinelo, I.; Quintela, J. M. Tetrahedron 1998,
54, 927–934. (i) Devi, I.; Baruah, B.; Bhuyan, P. J. Synlett 2006, 2593–
2596. (j) Dajka-Halasz, B.; Foldi, A. A.; Ludanyi, K.; Matyus, P. ARKIVOC
2008, 102–126. (k) Ivanov, I. C.; Glasnov, T. N.; Belaj, F. J. Heterocycl.
Chem. 2008, 45, 177–180.
24 h
9
2.5 h
30 min
1 h
4 h
22 h
45 min
15 min
15 min
50 min
10
11
12
13
14
15
16
17
86
93
93
83
86
93
90
75
10
10
5
Gd(OTf)3
Gd(OTf)3
Gd(OTf)3
5
(8) (a) Tverdokhlebov, A. V.; Gorulya, A. P.; Tolmachev, A. A.;
Kostyuk, A. N.; Chernega, A. N.; Rusanov, E. B. Synthesis 2005, 2161–
2170. (b) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.; Shivanyuk,
A. N.; Tolmachev, A. A. Synthesis 2007, 2872–2886.
a Reactions were performed in a given solvent (0.1 M) on a 0.25 mmol
scale and were run to full conversion as judged by TLC analysis.
b
1
Conversion by H NMR.
(9) (a) Kaval, N.; Dehaen, W.; Matyus, P.; Van der Eycken, E. Green
Chem. 2004, 6, 125–127. (b) Kaval, N.; Halasz-Dajka, B.; Vo-Thanh, G.;
Dehaen, W.; Van der Eycken, J.; Matyus, P.; Loupy, A.; Van der Eycken,
E. Tetrahedron 2005, 61, 9052–9057.
Scandium triflate readily catalyzes this transformation.12b,c
Albeit less efficiently, several main group and transition
metals also catalyze this rearrangement. Remarkably, gado-
linium triflate showed a striking rate acceleration as compared
to scandium triflate. The use of 5 mol % of scandium triflate
in acetonitrile required 22 h for full conversion of 1a to 2a,
whereas the identical reaction with gadolinium triflate was
completed in 15 min (entries 13 and 16). Ultimately,
gadolinium triflate was selected as the optimum catalyst for
(10) (a) Noguchi, M.; Yamada, H.; Sunagawa, T. J. Chem. Soc., Perkin
Trans. 1 1998, 3327–3329. (b) Prajapati, D.; Borah, K. J. Beilstein J. Org.
Chem. 2007, 3, No. 43.
(11) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc.
2008, 130, 416–417. (b) Zhang, C.; Murarka, S.; Seidel, D. J. Org. Chem.
2009, 74, 419–422.
(12) Lewis acid catalysis has been applied to other intramolecular redox
reactions: (a) Woelfling, J.; Frank, E.; Schneider, G.; Tietze, L. F. Eur. J.
Org. Chem. 2004, 90–100. (b) Pastine, S. J.; McQuaid, K. M.; Sames, D.
J. Am. Chem. Soc. 2005, 127, 12180–12181. (c) Pastine, S. J.; Sames, D.
Org. Lett. 2005, 7, 5429–5431.
130
Org. Lett., Vol. 11, No. 1, 2009

this study. Acetonitrile was found to be superior to a number
of other solvents such as toluene, ethyl acetate, tetrahydrofuran
and methanol (results not shown). The use of acetonitrile in
combination with a concentration of 0.1 M was found to provide
the best results in terms of reaction rate and yield.
Table 3. Evaluation of Different Amine Donor Groupsa
The scope of the reaction with regard to the acceptor
moiety is summarized in Table 2. Different malonate esters
participate in this reaction, giving rise to products in good
yields after relatively short reaction times (entries 1-4). An
Table 2. Evaluation of Different Acceptor Groupsa
a Reactions were performed at room temperature on a 1 mmol scale in
MeCN (0.1 M) and were run to full conversion as judged by TLC analysis.
b Reaction was performed at 40 °C.
exception is the benzylester 1e, which rearranged to product
2e in lower yield, while requiring a longer reaction time
(entry 5). The ꢀ-ketoester derived starting material 1f (E/Z
ratio ) 53:47) rearranged to product 2f, which was isolated
as a 64:36 mixture of diastereomers (entry 6). Diketones 1g
and 1h also rearranged efficiently to products 2g and 2h,
respectively (entries 7 and 8). These substrates required
slightly longer reaction times as compared to the correspond-
ing malonate compounds. As anticipated, due to the limited
propensity of the dinitrile substrate 1i to engage into chelating
interactions with the catalyst, no rearrangement of this
a Reactions were performed at room temperature on a 1 mmol scale in
MeCN (0.1 M) and were run to full conversion as judged by TLC analysis.
b dr ) 64:36, major diastereomer not determined. c No reaction.
Org. Lett., Vol. 11, No. 1, 2009
131

compound was observed after 24 h under standard conditions
(entry 9). Further heating of the reaction mixture at 40 °C
for an additional 24 h gave only trace quantities of product
2i.
Scheme 3. Catalytic Enantioselective Variant
The scope of this rearrangement was explored further by
evaluating a number of different amine donors (Table 3).
The piperidine derived compound 1j required a longer
reaction time as compared to the pyrrolidine compound 1a
(entry 1). The related morpholine compound 1k did not
efficiently rearrange at room temperature but reaction at 40
°C for 12 h led to full consumption of 1k, with product 2k
being isolated in 78% yield (entry 2). The corresponding
seven- and eight-membered amine starting materials 1l and
1m rearranged readily to the corresponding products (entries
3 and 4). Presumably due to the enhanced hydride donor
capabilities of benzylic C-H bonds, the tetrahydroisoquino-
line 1n rapidly rearranged to 2n upon exposure to gadolinium
triflate (entry 5). The 2-methylpyrrolidine-derived starting
material 1o gave rise to a single regioisomer (2o) upon
rearrangement (entry 6). This finding likely reflects the
increased hydride donor capability of a tertiary over a
secondary C-H bond. Starting materials that incorporate
noncyclic amines also rearranged to the expected products
(entries 7 and 8). Although structurally closely related, 1p
required heating at 40 °C for 24 h to reach full conversion
to form 2p, while 1q completely rearranged into 2q after
just 2 h at room temperature. This significant rate difference
is likely due to unfavorable steric interactions in the course
of the reaction. Only a single regioisomer of 2q was isolated,
which can be attributed to the superior hydride donor
capability of benzylic over primary C-H bonds.
* Absolute configuration not established.
cantly accelerated by gadolinium triflate catalysis, providing
efficient access to polycyclic tetrahydroquinolines. Current
efforts are focused on identifying more highly enantioselec-
tive variants of this and related reactions.
Acknowledgment. Is made to the donors of the American
Chemical Society Petroleum Research Fund for support of
this research. Financial support from Rutgers, The State
University of New Jersey is gratefully acknowledged. We
thank Dr. Jacob M. Janey (Merck & Co.) for a generous
donation of 1,2-cis-aminoindanol. Dr. Tom Emge (Rutgers
University) is acknowledged for crystallographic analysis.
M.D.K. acknowledges fellowship support from the Aresty
Research Center for Undergraduates.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds
including the X-ray structure of 2p. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802519R
In preliminary experiments, we have found that the use
of various chiral ligands in combination with scandium or
gadolinium triflate does not lead to significant enantioen-
richment in product 2a. Gratifyingly, a chiral magnesium
bisoxazoline catalyst is effective in catalyzing the rearrange-
ment of 1a to 2a (Scheme 3).13 In this instance, product 2a
was isolated in 74% yield and 30% ee, illustrating for the
first time that such a reaction is amendable to enantioselective
catalysis.
(13) For selected examples of chiral magnesium complexes in asym-
metric catalysis, see: (a) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992,
33, 6807–6810. (b) Sibi, M. P.; Ji, J.; Wu, J. H.; Guertler, S.; Porter, N. A.
J. Am. Chem. Soc. 1996, 118, 9200–9201. (c) Evans, D. A.; Nelson, S. G.
J. Am. Chem. Soc. 1997, 119, 6452–6453. (d) Kanemasa, S.; Kanai, T.
J. Am. Chem. Soc. 2000, 122, 10710–10711. (e) Yoon, T. P.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2001, 123, 2911–2912. (f) Barnes, D. M.; Ji,
J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge,
F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am.
Chem. Soc. 2002, 124, 13097–13105. (g) Trost, B. M.; Hisaindee, S. Org.
Lett. 2006, 8, 6003–6005. (h) Cutting, G. A.; Stainforth, N. E.; John, M. P.;
Kociok-Koehn, G.; Willis, M. C. J. Am. Chem. Soc. 2007, 129, 10632–
10633.
In summary, we have demonstrated that intramolecular,
redox neutral C-H bond functionalizations can be signifi-
132
Org. Lett., Vol. 11, No. 1, 2009