A multicomponent coupling sequence for direct access to substituted quinolines

Article abstract of DOI:10.1021/ol901855b

A titanium-catalyzed three-component coupling reaction can be used to generate tautomers of Af-aryl-1,3-dllmlnes. Simple treatment of these products with acetic acid leads to cyclization forming quinoline derivatives In a one-pot procedure. The primary am

Full text of DOI:10.1021/ol901855b

ORGANIC
LETTERS
2009
Vol. 11, No. 20
4720-4723
A Multicomponent Coupling Sequence for
Direct Access to Substituted Quinolines
Supriyo Majumder, Kevin R. Gipson, and Aaron L. Odom*
Michigan State UniVersity, Department of Chemistry, East Lansing, Michigan 48823
odom@chemistry.msu.edu
Received August 10, 2009
ABSTRACT
A titanium-catalyzed three-component coupling reaction can be used to generate tautomers of N-aryl-1,3-diimines. Simple treatment of these
products with acetic acid leads to cyclization forming quinoline derivatives in a one-pot procedure. The primary amines employed can be
substituted anilines, aminonaphthalenes, or even heterocyclic amines, which leads to a variety of fused-ring heterocyclic frameworks. The
one-pot yields varied from 25-71% for the 18 examples presented in this study.
New synthetic protocols1 for quinolines, due to the ubiquity
of these heterocycles, are of great interest as these hetero-
cycles2 have utility in diverse areas such as pharmaceuticals,3
photonic materials,4 and redox switches.5
when prepared using aromatic amines, can be used as direct
precursors for quinolines and related heterocycles in a one-
pot procedure simply by adding acetic acid to the multi-
component coupling product.
We have been investigating a titanium-catalyzed three-
component coupling (3CC) reaction that generates tautomers
of 1,3-diimines.6 Here we report that these 3CC products,
The proposed catalytic cycle involved in the synthesis of
the 3CC product is shown in Scheme 1 and is based on the
mechanism for catalytic hydroamination.7 It is proposed that
the titanium precatalyst, bis(dimethylamido), generates a
titanium imido on reaction with a primary amine. The
titanium imido undergoes a [2 + 2]-cycloaddition reaction
(1) For some recent developments and examples, see: (a) Li, L.; Jones,
W. D. J. Am. Chem. Soc. 2007, 129, 10707. (b) Zhang, Z. H.; Tan, J. J.;
Wang, Z. Y. Org. Lett. 2008, 10, 173. (c) Kouznetsov, V. V.; Romero
Boho´rquiez, A. R.; Stashenko, E. E. Tetrahedron Lett. 2007, 48, 8855.
(2) For some selected recent references on transition-metal-catalyzed
synthesis of nitrogen heterocycles with emphasis on multicomponent
couplings, see: (a) Ackermann, L.; Sandmann, R.; Kaspar, L. T. Org. Lett.
2009, 2031. (b) Krenske, E. H.; Houk, K. N.; Arndtsen, B. A.; St. Cyr,
D. J. J. Am. Chem. Soc. 2008, 120, 5510. (c) Lu, Y.; Arndtsen, B. A. Angew.
Chem. 2008, 47, 5430. (d) Kalisiak, J.; Sharpless, K. B.; Fokin, V. V. Org.
Lett. 2008, 10, 3171. (e) Isamber, N.; Lavilla, R. Chem.sEur. J. 2008, 14,
8444.
(5) Das, D.; Dai, Z.; Holmes, A.; Canary, J. W. Chirality 2008, 20, 585.
(6) (a) Cao, C.; Shi, Y.; Odom, A. L J. Am. Chem. Soc. 2003, 125,
2880. (b) Majumder, S.; Gipson, K. R.; Staples, R. J.; Odom, A. L. AdV.
Synth. Catal. 2009, 351, 2013. (c) Banerjee, S.; Shi, Y.; Cao, C.; Odom,
A. L. J. Organomet. Chem. 2005, 690, 5066. (d) For a recent study on a
potential side reaction to this 3CC that can occur with some substrates, see:
Barnea, E.; Majumder, S.; Staples, R. J.; Odom, A. L. Organometallics
2009, 3876.
(3) For a review, see: Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
(4) Zhang, X.; Shetty, A. S.; Jeneckhe, S. A. Macromolecules 1999,
32, 7422.
(7) For a recent review on hydroamination, see: Mu¨ller, T. E.; Hultzsch,
K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. ReV. 2008, 108, 3795.
10.1021/ol901855b CCC: $40.75
Published on Web 09/14/2009
 2009 American Chemical Society

formaldehyde, and methylamine hydrochloride in ethanol/
water (Scheme 2).
Scheme 1
.
Proposed Catalytic Cycles for Hydroamination and
Iminoamination
Scheme 2. Generation of Titanium Catalysts
with an alkyne to obtain an azatitanacyclobutene. Isonitrile
traps this Ti-C containing intermediate to form a 5-mem-
bered metallacycle,8 which is then protolytically cleaved from
the metal for catalyst turnover. The overall reaction is the
addition of iminyl and amine groups across the C-C triple
bond of the alkyne, iminoamination.
This new quinoline synthesis can be viewed as an alternative
to some well-known quinoline syntheses that use anilines and
1,3-dicarbonyls or related compounds, such as the Combes
synthesis.9 These reactions are very effective but require
somewhat difficult to access unsymmetrical 1,3-dicarbonyls if
their quinolines are to be produced.10 One of the benefits of
this class of transformations is that it takes advantage of the
large number of commercially available aniline derviatives.
The titanium catalysts employed here use readily prepared
pyrrolyl ligands. Both of ligands can be made in a single
step from pyrrole. The most commonly employed catalyst
was Ti(dpm)(NMe2)2 (1);11 H2dpm is available from con-
densation of pyrrole and acetone (Scheme 2) in the presence
of trifluoroacetic acid (TFA).12
Both catalysts can either be isolated or can be generated
in near-quantitative yield by in situ reaction of commercially
available Ti(NMe2)4 with the protonated form of the ligand.
The results for 3CC of some arylamines followed by acid
treatment with a few alkynes are shown in Table 1. The
yields are modest, but the reactions are readily run on
multigram scales and provide the products from a single pot.
In these reactions, a small excess of the tert-butyl isonitrile
was added.
The cyclizations of the 3-CC product involve Bro¨nsted
acid-catalyzed15 intramolecular electrophilic attack on the
pendant aromatic ring. Then, tert-butyl amine is lost in the
aromatization of the nitrogen heterocycle.
Using this methodology, the 4-position of the quinoline
product will be unsubstituted. In addition, the route takes
advantage of the abundance of arylamines available com-
mercially to make substituted quinolines.
The regioselectivity of the reaction would be set by the
[2 + 2]-cycloaddition reaction in conjunction with the
relative trapping rates by isonitrile under this scheme. It has
been proposed that the regioselectivity of the addition is
electronically controlled when an arene is found in the alkyne
by stabilization of a partial anionic charge adjacent to the
metal in the azametallacyclobutene intermediate.16 This
An alternative catalyst advantageous for some substrates
was Ti(dpma)(NMe2)2 (2).13 The H2dpma ligand was pre-
pared14 in a single step by Mannich condensation of pyrrole,
(8) For a recently characterized example of the proposed 5-membered
metallacyclic intermediates prepared by isonitrile insertion, see: Vujkovic,
N.; Fillol, J. L.; Ward, B. D.; Wadepohl, H.; Mountford, P.; Gade, L. H.
Organometallics 2008, 27, 2518.
(9) Kouznetsov, V. V.; Vargas Me´ndez, L. Y.; Mele´ndez Go´mez, C. M.
Curr. Org. Chem. 2005, 9, 141.
(10) For a recent quinoline synthesis involving rhodium catalysis, see:
Horn, J.; Marsden, S. P.; Nelson, A.; House, D.; Weingarten, G. G. Org.
Lett. 2008, 10, 4117.
(14) Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem.
2002, 41, 6298.
(15) A related acid-catalyzed cyclization of 1,3-diimine tautomers has been
used previously to generate quinolines in a multistep synthesis. Their 1,3-diimine
tautomers were prepared from enolizable arylimine condensation with nitriles.
The cyclization was accomplished by addition of the Lewis acid AlCl3.
Barluenga, J. Cuervo, H. Fustero, S. Gotor, V. Synthesis 1987, 82. Attempts
to use AlCl3 with the derivatives listed here resulted in very low yields.
(16) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc.
1993, 115, 2753.
(11) (a) Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem.
Commun. 2003, 586. (b) Novak, A.; Blake, A. J.; Wilson, C.; Love, J. B.
Chem. Commun. 2002, 2796.
(12) Littler, B. J.; Miller, M. A.; Hung, C.-H.; Wagner, R. W.; O’Shea,
D. F.; Boyle, P. D.; Lindsey, J. S. J. Org. Chem. 1999, 64, 1391.
(13) Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001,
40, 1987.
Org. Lett., Vol. 11, No. 20, 2009
4721

has been tried, the yield from the reaction was not affected.
For example, the substrate combination in Table 1, entry 3,
was used in a reaction sequence using toluene as solvent
with the titanium catalyst, followed by addition of acetic acid
to the reaction mixture (eq 1). In other words, the solvent
system for the cyclization step was 1:1 toluene/acetic acid.
The calibrated GC yield was essentially the same as running
the reaction in acetic acid only.
Table 1. Examples of Quinoline Syntheses
Both R- and ꢀ-aminonaphthalenes were also explored,
which provide various benzoquinolines (Table 2). From this
sampling, the reaction appears equally amenable to having
the amine in either of these two positions (entries 2 and 3).
Table 2. Examples of Benzoquinoline Syntheses
a Most reactions carried out with arylamine, alkyne, and tert-butyl
isonitrile in a 1:1:1.5 ratio with 10 mol % catalyst at 100 °C for 24-48 h.
Once the 3CC is complete, product was heated at 150 °C in HOAc. b Used
20 mol % of Ti(dpm)(NMe2)2 at 140 °C.
a Most reactions carried out with arylamine, alkyne, and tert-butyl
isonitrile in a 1:1:1.5 ratio with 10 mol % of catalyst at 100 °C for 24-48
h. b Used 20 mol % 1 at 140 °C. c Total yield for two regioisomers; isomer
shown favored 10:1. d Total yield for two regioisomers; isomer shown
favored 2.5:1.
results in 3-aryl substitution being electronically favored for
aryl-substituted alkynes. For 1-hexyne, the favored product
was generally the 2-substituted quinoline derivative.
For the majority of the reactions done here, the 3CC
reaction was run in toluene, and this solvent was removed
before the acid was added. However, if the solvent removal
is inconvenient, the acid can be added without removal of
volatiles at this intermediate stage. For substrates where this
The reaction can also be generalized to include various
amine-substituted heterocycles. The results of a short study
using 1-phenylpropyne are shown in Table 3 and illustrate
the variety of heterocyclic frameworks available.
Using 2-aminothiophene as a substrate generated a thienopy-
ridine (entry 1). In addition, 3-aminobenzothiophene provided
4722
Org. Lett., Vol. 11, No. 20, 2009

As shown in Table 1, relatively electron-rich aromatic
amine derivatives can be readily converted to quinolines
using this methodology. We propose an iminium intermediate
that undergoes intramolecular electrophilic aromatic substitu-
tion as the cyclization step. This is supported by observations
with the electron-deficient 4-cyano-aniline as substrate. The
reaction of 4-cyanoaniline, 1-phenylpropyne, and tert-bu-
tylisonitrile in the presence of 1 produced the expected 3CC
product by GC-FID and GC-MS. However, treatment with
acetic acid in an attempt to cyclize produced only a trace of
the quinoline derivative. Instead, large amounts of N-(4-
cyanophenyl)acetamide were observed as the 3CC product
was consumed. This side reaction of acetamide formation
from acetic acid solvent was observed with other substrates
as well but was qualitatively more prevalent in systems with
sluggish cyclizations.17
Table 3. Examples of Products Prepared from Amino
Heterocycles
Inexpensive titanium catalysis can be used to access a
variety of pyridine-related fused heterocyles in a single step
from commercially available amines, alkynes, and isonitriles.
Further applications of some of these heterocycles and this
methodology are under development.
Acknowledgment. We thank the National Science Foun-
dation and the Petroleum Research Fund administered by
the American Chemical Society for financial support. K.R.G.
thanks the Ronald E. McNair program at Michigan State
University for support.
a Most reactions carried out with arylamine, alkyne, and tert-butyl
isonitrile in a 1:1:1.5 ratio with 10 mol % of catalyst at 100 °C for 24-48
h. b Converts directly to the product without external acid.
Supporting Information Available: Experimental and
1
characterization details for quinolines. H and 13C NMR
the benzothienopyridine (entry 2). The methodology is also
applicable to pyrrolo- and indolopyridazines.
spectra for the quinolines. This material is available free of
charge via the Internet at http://pubs.acs.org.
Again for these heteroarmatic amines, unsymmetrical
alkynes containing an aromatic group generally result in
products with the alkyne-derived aryl ꢀ to the pyridine
nitrogen in the product. Alkyl groups R to the pyridine
nitrogen in the product can be favored with the use of catalyst
2.
OL901855B
(17) For examples of related observations in a similar cylization see
Tom, N. J.; Ruel, E. M. Synthesis 2001, 1351.
Org. Lett., Vol. 11, No. 20, 2009
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