ortho-substituted anilines in the synthesis of quinolines.

Another way of preparing quinoline derivatives consist in the use of anilines o-substituted
and two carbon unit usually carbonyl compounds containing a reactive a-methylene group to
complete cyclization process. The Friedländer reaction allows to obtain 2- and 3-substituted
quinolines uses 2-aminobenzaldehyde with a carbonyl component, whereas the Pfitzinger
reaction combines isatin with a carbonyl compound under basic conditions to give 2- and 3-
substituted quinoline-4-carboxylic acids. Diverse methods use anilides derivatives, as the
Knorr quinoline synthesis use a β-ketoanilide to obtain a 2-hydroxyquinoline using sulfuric
acid in a intramolecular electrophilic aromatic substitution, the Meth-Cohn synthesis that
uses acylanilides in DMF/POCl3 and Camps quinoline synthesis from an o-
acylaminoacetophenone and hydroxide. The Niementowski reaction correspond to the
synthesis of 4-hydroxyquinoline derivatives from anthranilic
acids and ketones (or aldehydes).
Figure 6.12.

Pfitzinger reaction

The Pfitzinger reaction (also known as the Pfitzinger-Borsche reaction) correspond to the
divergent approach to the synthesis of substituted quinoline-4-carboxilic acids by the reaction
of isatin with carbonyl compounds in the presence of a strong base (usually hydroxide).
Although the yields are good (over 80 %), the harsh conditions and hampering in purification
are the more recurrent problems in this methodology (Shvekhgeimer, 2004, p. 257). Recent
reports show modifications in the reaction conditions and substitution on the quinoline
core.(El-Feky, Thabet, & Ubeid, 2014, p. 87) Microwave radiation (190-200 °C) has been Commented [C1]: Poomathi, N.; Mayakrishnan, S.;
Muralidharan, D.; Srinivasan, R.; Perumal, P.T. Reaction of
used in a Pfitzinger-decarbocilation process to synthesize quinoline-4-carboxylic acids 47, isatins with 6-amino uracils and isoxazoles: Isatin ring-
opening vs. annulations and regioselective synthesis of
reacting isatin 45 and sodium pyruvate 46 in basic media (NaOH aq). (Zhu, Yang, Yun, & isoxazole fused quinoline scaffolds in water. Green Chem.
2015, 17, 3362–3372.
Li, 2010, p. 35) Unusual annulation agents as enantiomeric enaminones 48 has been used
1,3-dicarbonyls in the Pfitzinger reaction, using isatin 45 was heated at reflux with diverse
enaminones in the presence of an aqueous solution of KOH or NaOH, followed by
acidification (HCl aq) to give the quinoline-4-carboxylic 49 acids in good to excellent yields
(Elghamry and Al-Faiyz, 2016). (Figure 6.13)

Figure 6.13.
Multicomponent reactions has been used in the synthesis of functionalized quinaldines via a
three component cascade cyclization-esterification reaction between diverse isatins 45 and
1,3-dicarbonyl compounds (acetylacetone or ethyl acetoacetate) 50 in the presence of
alcohols 51 catalyzed by trimethylchlorosilane (TMSCl), leading to the synthesis of C-4
carboxilate quinaldine substituted 52 (Lu et al., 2017, p. 3658). (Figure 6.13)

Friedlander

The Friedländer synthesis correspond to the reaction of 2-aminobenzaldehyde and ketones to

form quinoline derivatives, this is a very versatile reaction due diverse functional groups are
well tolerated on both the arylamine and ketone components. Several Brønsted acids such as
hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, phosphoric acid, dodecylphosphonic
acid, PEG-supported sulfonic acid, sulfonic acid functionalized ionic liquids, and o-
benzenedisulfonimide as well as Lewis acids have been reported as effective catalyst to this
transformation; however, many of these procedures often suffer from strong acidic con- Commented [C2]: (a) Thummel, R. P. Synlett 1992,1; (b)
Eckert, H. Angew. Chem., Int. Ed. 1981, 20, 208; (c) Gladiali,
ditions, unsatisfactory yields and harsh conditions. Therefore, new catalytic systems are S.; Chelucci, G.; Mudadu, M. S.; Gastaut, M. A.; Thummel, R.
P. J. Org. Chem. 2001, 66, 400.
sought seeking to improve the efficiency of the reaction. (Maleki, Seresht, & Ebrahimi, 2015, 14. (a) Cheng, C. C.; Yan, S. J. Org. React. 1982, 28,37; (b)
Akbari, J.; Heydari, A.; Kalhor, H. R.; Kohan, S. A. J. Comb.
p. 149) Chem. 2010, 12, 137.
15. (a) Sterkowski, L.; Czamy, A. J. Fluorine Chem. 2000, 104,
281; (b) Ghassamipour, S.; Sardarian, A. R. Tetrahedron Lett.
Brønsted acid-mediated the Friedländer quinoline synthesis, the acid organocatalyst o- 2009, 50, 514.
16. (a) Hu, Y.-Z.; Zang, G.; Thummel, R. P. Org. Lett. 2003, 5,
benzenedisulfonimide 53 has been used in a solvent-free Friedländer reaction using 2- 2251; (b) Hasaninejad, A.; Zare, A.; Shekouhy, M.; Ameri-
Rad, J. Green Chem. 2011, 13, 958.
aminoarylketones 54 and diverse carbonyl compounds 55 obtained several 2,3-disubstituted
quinolines 56 . (Barbero, Bazzi, Cadamuro, & Dughera, 2010, p. 2342) (Figure 6.14)
Chitosan-SO3H and efficient, friendly and biodegradable acid catalyze the Friedländer
condensation/annulation reaction of 2-aminoaryl ketones 54 with α-methyleneketones 57 and
cyclopentanone/cyclohexanone 58 to produce the corresponding substituted quinoline 59, 60
(Reddy, Venkateswarlu, Reddy, & Reddy, 2013, p. 5767). (Figure 6.14)
Figure 6.14.

Lewis acids have proven to be effective catalysts in the Friedländer reaction, several
examples show efficient catalyst of prepared catalyst as SiO2/ZnCl2 in the synthesis of
quinoline compounds (Soleimani, Naderi Namivandi, & Sepahvand, 2017, p. e3566). The
synthesis of benzazepine-fused quinoline 64 catalyzed by BF3.OEt2 in acetonitrile from 2-
aminobenzaldehydes derivative 61, 2-methylindole 62 and diverse aromatic aldehydes 63
obtaining the fused quinoline compounds in good to excellent yield (Min, Pan, & Gu, 2016,
p. 364). (Figure 6.15)

Figure 6.15.

Electrophylic cyclization as efficient route in the synthesis of quinoline core

The synthetic strategy of electrophilic cyclization corresponds to a process in which an
internal unsatured reactant can participate as nucleophiles, while the electrophilic reagents
frequently bring about cyclizations, diverse groups can act as internal nucleophiles: carboxy,
carboxylate, hydroxy, amino and amido. The electrophilic cyclization process applied to
substituted quinoline synthesis can be carried out using two routes: a) route i: from
arylamines generating intramolecular additions process or b) route ii using o-aryl(alkyl)-(1-
ehtyn-1-yl) arylamines via intramolecular addition reactions (Figure 6.16).

Figure 6.16.

The first quinoline synthesis via electrophilic cyclization correspond to the reaction of the 6-
endo-dig electrophilic cyclization of N-(2-alkynyl)anilines 65 by the electrophile ICl, I2, Br2,
PhSeBr, and p-NO2C6H4SCl that improve the electrophilicity of the alkyne, activating it
toward attack by the aromatic ring, followed by aromatization (oxidation by air), giving 3-
halogen, selenium, or sulfur-substituted quinolines 66 (Zhang, Yao, Campo, & Larock, 2010,
p. 1177). (Figure 6.17) The strategy based in the electrophilic cyclization is complemented
by various processed based in sequential propargyl−allenyl isomerization/aza-
electrocyclization of propargyl phenyl imines 67 using DBU (1, 8-diazabicyclo[5.4.0]undec-
7-ene) and DBN (1,5-diazabicyclo[4.3.0]non-5-ene) in MECN to give diverse 2,3-diphenyl
quinolines 68 (Zhou, Liu, & Xu, 2012, p. 9418). A one-pot Ugi four component condensation
Brønsted acid promoted reaction of propiolic acids 69, aldehides/ketones 70, aminoaldehyde
acetals 71 and isocyanides 72 followed by a reaction with anilines 73 in ethanol, permit the
access to structurally diverse substituted fused quinolines 74 (Ghoshal, Yugandhar,
Nanubolu, & Srivastava, 2017, p. 600). (Figure 6.17)
Figure 6.17.
Metal-catalyzed reactions have shown their efficiency in the synthesis of quinoline
derivatives, the alkyltriflate compounds are used as the alkylation reagent to induce
carbon−carbon or carbon−heteroatom bond formation. A domino electrophilic reaction
mediated by alkyltriflate 75 from arylisothiocyanate 76 and alkyne 77 in dichloroethane, via
the formation of alkylthiosubstituted carbenium ion and subsequent coupling with the alkyne
followed by an annulation reaction to give the quinoline compounds 78 (Zhao, Yan, Yin, &
Xi, 2014, p.1120).(Figure 6.17)
Commented [C3]: Matsubara, Y.; Hirakawa, S.;
Yamaguchi, Y.; Yoshida, Z.-I. Angew. Chem., Int. Ed. 2011,
50, 7670. (b) Gao, G.; Niu, Y.; Yan, Z.; Wang, H.; Wang, G.;
Shaukat, A.; Liang, Y. J. Org. Chem. 2010, 75, 1305.
(c) Gabriele, B.; Mancuso, R.; Salerno, G.; Lupinacci, E.;
Ruffolo, G.; Costa, M. J. Org. Chem. 2008, 73, 4971. (d)
Zhang, Z.; Tan, J.; Wang,
Z. Org. Lett. 2008, 2, 173
The route ii corresponds to the synthesis of diverse substituted quinolines based in derivatives
of arylamines o- (1-ehtyn-1-yl) through nucleophic addition annulations reactions(Arcadi,
Marinelli, & Rossi, 1999, p. 13233). A sequential hydration–condensation–double
cyclization reaction catalyzed by Brønsted acid p-toluenesulfonic acid allowed the synthesis
of fused quinolines 81 from pyridine-substituted o-alkynylanilines 79 and β-keto esters 80
(Peng, Wang, Peng, Ding, & Zhu, 2011, p. 1723). (Figure 6.18) Molecular iodine (I2) act as
Lewis acid catalyst in the 6-endo-dig iodocyclization of 2-tosylaminophenylprop-1-yn-3-ols
81 to construct 2,4-alkyl(aryl) 3-iodoquinolines 82 in moderate to excellent yields (up to
99%) under mild conditions (MeOH as solvent) (Ali et al., 2011, p. 2598), intramolecular
cyclization of o-alkynylaryl isocyanides 83 catalyzed by I2 using photoirradiation
condditions isocyanides proceeds to afford the corresponding 2,4-diiodoquinolines 84
(Mitamura & Ogawa, 2011, p. 1163). (Figure 6.18)

DABCO (1,4-diazabicyclo[2.2.2]octane) is a highly nucleophilic amine used as promotor in

the synthesis of 2-alkoxy- and 2-aroxy-3-substituted quinolines 87 starting from o-
alkynylaryl isocyanides 86 and various oxygenated nucleophiles (alcohols/phenol) in mild
reaction conditions. DABCO triggers the reaction via nucleophilic addition to isocyanide and
subsequent cyclization provides the product as a leaving group being replaced by oxygenated
nucleophiles(J. Zhao, Peng, Liu, Wang, & Zhu, 2010, p. 7502). (Figure 6.18)
Figure 6.18.

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