Published on the web June 7, 2013
1073
Synthetic Utility of Propylphosphonic Anhydride-DMSO Media:
An Efficient One-pot Three-component Synthesis of 2-Arylquinolines
Kereyagalahally H. Narasimhamurthy, Siddappa Chandrappa, Kothanahally S. Sharath Kumar,
Toreshettahally R. Swaroop, and Kanchugarakoppal S. Rangappa*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore-570006, India
(Received May 7, 2013; CL-130432; E-mail: rangappaks@chemistry.uni-mysore.ac.in)
Propylphosphonic anhydride (T3Pμ)-DMSO-mediated one-
O
O
O
P
pot three-component synthesis which provides 2-arylquinolines
in a single step from benzyl alcohols, anilines, and ethyl vinyl
ether by the modified Povarov reaction has been demonstrated.
T3Pμ-DMSO is a mild and low-toxic peptide coupling agent
and an easy to handle reagent for bulk reactions at room
temperature.
P
P
n-Pr
n-Pr
O
O
n-Pr
O
Figure 1. Structure of propylphosphonic anhydride (T3Pμ).
Quinolines, as a leading pharmaceutically important com-
pound, are present in many biologically active alkaloids and
exhibit a number of interesting biological activities, such as
antibacterial,1 anti-inflammatory,2 antifungal and analgesic
properties.3 Since the basic skeleton of quinolines is widespread
in natural products, numerous approaches including the Conrad-
Limpach-Knorr synthesis,4 the Skraup-Doebner-Von Miller
synthesis,5 and the Friedlander synthesis,6 have been developed
for the synthesis of quinolines. Recently, reports concerning
transition-metal-mediated synthesis of quinolines have also
appeared,7 and many transition metals like rhodium,7a iron,7b
zinc,7c and iridium,7d are being used.
F3C
T3P®/DMSO
Ethyl acetate
CH2OH
EtO
O
1h
O
O
N
0° to rt, 4-5h
3
4h
CF3
O
NH2
2g
Scheme 1. General approach for the synthesis of 2-arylquino-
lines.
Cyclocondensation and cycloaddition reactions are the most
effective methods for the construction of N-heterocycles. Among
these, the acid-catalyzed imino Diels-Alder Povarov reaction8a
has been widely used to build substituted quinoline core from
anilines, aldehydes, and electron-rich alkenes by asymmetric,8b
enantioselective,8c and diastereoselective8d synthesis by the
Povarov reaction.
Although a variety of methods for the synthesis of these
quinoline frameworks have been developed, most of the
preparations involve stepwise processes, decrease in yield, and
tedious workup and harsh reaction conditions, and to overcome
all these cumbersome processes new synthetic methods are
being explored. From a literature survey it was evident that
quinolines were not synthesized from alcohols through the
Povarov reaction, in this reaction media that utilizes oxidation of
alcohols to carbonyl compounds, and then cyclocondensation
with anilines followed by the Diels-Alder [4 + 2] cycloaddition
with electron-rich alkenes, through the Povarov reaction gave
quinolines in high yields. One-pot synthetic sequences have
been now recognized as more a sustainable approach to target
molecules as they minimize the number of steps as well as the
reaction time and waste. Therefore, development and search for
new procedures with novel substrate scope is continuing and is
in great demand.
tion of a range of functionalized heterocycles.13a,13b T3Pμ has
also been used in the synthesis of quinolines.14a-14c Recently, we
have reported a one-pot tandem approach for the synthesis of
benzimidazoles, benzothiazoles,15 and 4-thiazolidinones,16 from
alcohols using DMSO-propylphosphonic anhydride (T3Pμ)
media as an oxidizing as well as cyclodehydrating agent, in
continuation of our work on the development of new synthetic
methodologies toward pharmaceutically important heterocyclic
compounds.
We attempted T3Pμ-DMSO-mediated one-pot three-com-
ponent synthesis of 2-arylquinolines directly from various
alcohols, involving oxidation, condensation followed by cy-
clization under mild reaction conditions (Scheme 1) and the
results are presented in Table 1. Initially, a model reaction was
conducted between benzyl alcohol (1a) (1.1 mmol), aniline
(1.0 mmol) (2a) and ethyl vinyl ether (1.0 mmol) (3) in the
presence of T3Pμ (1.0 mmol) in a mixture of solvents containing
EtOAc:DMSO in 2:1 ratio at 25 °C for 8 h, which afforded
2-arylquinolines in 20% yield. We then monitored the reaction
by increasing the equivalence of T3Pμ and we observed that
2.0 mmol of T3Pμ gave maximum yield 93% of the desired
2-arylquinoline 4a (Table 1, Entry 3). These results suggested
that the stoichiometry of T3Pμ plays an important role in the
progress of the reaction. Next we studied the effect of solvent on
reaction. Initially the reaction was carried out in DMSO and we
did not get considerable yield of the required compound of
2-arylquinoline. Subsequently we tried various solvent mixtures
like THF, toluene, CH2Cl2, CHCl3, dioxane, and CH3CN with
Propylphosphonic anhydride (Figure 1) is a prevailing
peptide coupling reagent with low toxicity.9 Its versatility as a
reagent in organic synthesis has generated innovative uses
beyond peptide synthesis.10 T3Pμ has been utilized in molecular
rearrangements,11 dehydration chemistry,12 and in the prepara-
Chem. Lett. 2013, 42, 1073-1075
© 2013 The Chemical Society of Japan
Narasimhamurthy, Kereyagalahally H.
