Modified procedure for the synthesis of 2-chloroquinoline-3-carbaldehydes using phosphorus pentachloride

Article abstract of DOI:10.1080/00397911.2015.1135956

An alternative, convenient, and efficient procedure for the synthesis of 2-chloroquinoline-3-carbaldehyde was carried out by the action of Vilsmeiers reagent on acetanilides using phosphorus pentachloride as chlorinating agent in place of phosphoryl chloride, obtaining good yields for activated acetanilides. The optimal conditions for this reaction requires only 4.5 equivalents of phosphorus pentachloride, 3 equivalents of N,N-dimethylformamide, and 1 equivalent of the corresponding acetanilide at 100 °C for approximately 4 h.

Full text of DOI:10.1080/00397911.2015.1135956

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A Modified Procedure for the Synthesis of
2-Chloroquinoline-3-Carbaldehydes Using
Phosphorus Pentachloride
Angel H. Romero
To cite this article: Angel H. Romero (2016): A Modified Procedure for the Synthesis
of 2-Chloroquinoline-3-Carbaldehydes Using Phosphorus Pentachloride, Synthetic
Communications, DOI: 10.1080/00397911.2015.1135956
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1135956
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Date: 01 February 2016, At: 07:36

A modified Procedure for the synthesis of 2-chloroquinoline-3-carbaldehydes using
phosphorus pentachloride
Angel H. Romero1
1Laboratorio de Química Medicinal y Heterociclos, Departamento de Química,
Universidad Simón Bolívar, Valle de Sartenejas, Apartado, Venezuela
Corresponding author Angel H. Romero E-mail: angel.ucv.usb@gmail.com
Abstract
An alternative, convenient and efficient procedure for the synthesis of 2-chloroquinoline-
3-carbaldehyde was carried out by the action of Vilsmeier´s reagent on acetanilides using
phosphorus pentachloride as chlorinating agent in place of phosphoryl chloride, obtaining
good yields for activated acetanilides. The optimal conditions for this reaction requires
only 4.5 equivalent of phosphorus pentachloride, 3 equivalent of N,N-dimethylformamide
and 1 equivalent of the corresponding acetanilide at 100ºC for approximately 4 hours.
KEYWORDS: 2-chloroquinoline-3-carbaldehydes, Vilsmeier´s reagent, phosphorus
pentachloride, acetanilides, cyclization
1
INTRODUCTION
2-chloroquinoline-3-carbaldehydes (1) are compounds considerable interesting in the
chemistry due to their importance as synthetic intermediates for the preparation of large
numbers of heterocyclic systems,[1] stereoselective ligands,[2] and compounds with
diverse kind of biological activities.[3] These quinolines (1) are prepared practically by
1

two important procedures such as: (i) Vilsmeier-Haack reaction of acetanilides, and (ii)
oxidation of the corresponding alcohol (2-chloroquinolin-3-yl)methanol to aldehyde.[1f, 4,
5] However, the first method above mentioned (i) is the most convenient and traditional
for the synthesis of 2-chloroquinoline-3-carbaldehydes (1); this strategy consists in a
multicomponent reaction that involves processes of chloration, formylation and
cyclization of acetanilides by the action of the Vilsmeier´s reagent (DMF/POCl3) in
POCl3 solution (Scheme 1).[4]
In this reaction, Vilsmeier´s reagent is generated in situ and derived of the reaction
between N,N-disubstituted formamides and phosphoryl chloride,[4,6] although this reagent
also can be to obtain using chlorinating agent such as phosphorus pentachloride (PCl5),[7]
and tionyl chloride (SOCl2).[8] Particularly, the Vilsmeier´s reagent from PCl5 produces in
situ POCl3 (Scheme 2),[7] which could be interesting for reducing the amount of
chlorinating agent necessary in the synthesis of 2-chloroquinoline-3-carbaldehydes (1)
reported by Meth-Cohn,[4] due to that his method requires a large excess of POCl3.
Furthermore, another important advantage of the PCl5 is that it does not require an
additional purification.
In addition, the phosphorus pentachloride have been widely used in the chloration of
different organic compounds such as N-vinylazoles,[9] dialkylcyanamides,[10]
triethylamine[11,12], sucrose-6-acetate or sucrose-6-benzoate.[13] Then, considering the
above mentioned and well known chlorinating properties of the PCl5, this work was
focused in demonstrating that the PCl5 can replace to POCl3 in the reaction reported by
2

Meth-Cohn[4] (Scheme 1) for the synthesis of the 2-chloroquinoline-3-carbaldehydes (1).
The synthesis of these kind of compounds using PCl5 have not been reported previously
in the literature and represents a novel, modified and alternative procedure.
2 RESULTS AND DISCUSSION
The first step in this work was optimized the reaction conditions searching the optimal
amount of PCl5, working under the same conditions reported in the literature.[4] The
results of optimization using the acetanilide as substrate (Table 1) showed that 4.5
equivalent of PCl5 are enough for obtaining the best yield in this reaction (72%), while
amount of PCl5 below four equivalents provided a decreasing in the yield (42-68%). In
addition, it should be noted that when further raising of four equivalent of PCl5 no
significant effect in the yield (62-70%) was observed. However, in this sense, is
important to explain that when were used seven equivalent of PCl5 during the formation
of Vilsmeier´s reagent, the reaction solution was turned over saturated due to that PCl5 is
a solid compound, and probably it characteristic could have a small negative effect in the
yield of this reaction. In conclusion, these results of optimization were expected due to
that in theory this reaction only need three equivalent of chlorinating agent, where an
equivalent is involved in the chloration of the corresponding acetanilide and other two
equivalents react with DMF, generating two equivalents of Vilsmeier´s reagent.
Simultaneously, when PCl5 reacts with the acetanilide and DMF, there are generated
three equivanlent of POCl3 (Scheme 2), which act as solvent in the reaction.
3

Then, the optimal conditions were applied for the preparation of the series of 2-
chloroquinoline-3-carbaldehydes (5a-i) using the corresponding acetanilides and the
results are summarized in Table 2. The obtained compounds were confirmed by spectra
data and melting point reported.[4] The results were practically similar to the results
reported by Meth-Cohn,[4] where the activated acetanilides (Entries 1-6) showed better
yields (yield 49-72%) than the strongly deactivated systems (yield 0-30%) (Entries 7-9)
under the same reaction conditions of time and heating. This results is no surprisisng due
to that the mechanism of this reaction should be exactly same to reported by Meth-
Cohn,[4] where the electron-donanting groups in the meta position of the acetanilide
activates the cyclization process for obtaining the corresponding quinoline, while
electron-withdrawing groups decrease the capacity nucleophilic of the arene ring
producing an incomplete process of the cyclization.
In summary, this work demonstrated that the phosphorus pentachloride can be used as
chlorinating agent for the synthesis of 2-chloroquinoline-3-carbaldehydes by the action
the Vilmeier´a reagent on acetanilides following the same procedure reported by Meth-
Cohn[4]; representing an alternative, convenient, practical and efficient procedure.
Furthermore, the present method has an economical implication towards the raw material
cost and becomes highly profitable in the industrial process for the synthesis of these
quinolines, due to that there is required less amount of chlorinating agent.
3 EXPERIMENTAL SECTION
4

General procedure for the synthesis of 2-chloroquinoline-3-carbaldehydes 5a-i:
DMF (12 mmol, 3 equiv.) was cooled at 0ºC in a round flask equipped with a drying tube
and phosphorus pentachloride (18 mmol, 4.5 equiv.) was added slowly and the mixture
was stirred for 15 minutes keeping the temperature below 0 ºC. To this solution was
added in a portion the corresponding acetanilide (4 mmol, 1 equiv.) and the reaction
mixture was heated under reflux and stirring for the appropiate time depending of the
acetanilide. The resulted mixture was cooled to 0ºC and the solution was poured slowly
into ice-water and stirring for ten minutes, obtaining a yellow solid which was filtered,
washed several time with cold water and dried under vacuum. Finally, the 2-
chloroquinoline-3-carbaldehydes were recristalized according to the literature. [4]
2-chloroquinoline-3-carbaldehyde (5a): Recristalization eluent: Ethyl acetate; Yield 552
mg (72%); yellow pale solid, mp 145-146 ºC. IR (KBr): 3043 (st. C-H), 2872 (st. C-H),
1688 (st. C=O), 1615-1553 (st. C=C) cm-1. 1H-NMR (270 MHz, J Hz, CDCl3) δ: 10,55
(s, 1H); 8,76 (s, 1H); 8,07 (d, J=8,6; 1H); 7,98 (d, J=7,9; 1H); 7,89 (dd, J1=8,3; J2=7,7;
1H); 7,64 (dd, J1=8,3; J2= 7,9; 1H). 13C-NMR (100 MHz, CDCl3) δ: 189,4 (d); 150,3 (s);
140,5 (d); 133,7 (d); 130,6 (s); 129,6 (s); 129,1 (d); 127,7(d); 126,6 (d); 121,2. Anal.
Calcd for C10H6ClNO: C, 62,48; H, 3,11; N, 7,23 %. Found: C, 62,68; H, 3,16; N, 7,31
%.
ACKNOWLEDGMENTS
The autor thanks to Decanato de Investigación y Desarrollo (Universidad Simón Bolívar,
Caracas) for its finacial support, as well as to the TSU Noelany Ciguela (Universidad
5

Simón Bolívar, Caracas) and Prof. Jaime Charris (Universidad Central de Venezuela,
Caracas) for the spectroscopic facilities.
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6

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7

Table 1. Optimization studies according proportions of PCl5.
Entrya Equiv. of PCl5 Yield (%)b
1
2
3
4
5
7.0
5.0
4.5
4.0
3.0
63
70
72
68
42
a All reactions were performed used acetanilide (1 mol equiv), DMF (3 mol equiv.) and
PCl5 at 120ºC for 4 h.
bIsolated yields of 2-chloroquinoline-3-carbaldehydes after recristalization with ethyl
acetate.
8

Table 2. Results of synthesis of 2-chloroquinoline-3-carbaldehydesgderivates.
Entry R
t (h) Yield (%)a Yield (%)b mp (ºC)c mp (ºC)d
1
2
3
4
5
6
7
8
9
H (5a)
4
4
4
72
64
71
60
49
74
28
30
0
78
74
66
67
54
65
30
35
0
145-146 146-147
121-123 121-123
142-144 143-144
133-135 135-136
142-144 143-145
189-191 190-192
186-188 189-191
156-157 158-159
6-CH3 (5b)
7-CH3 (5c)
8-CH3 (5d) 16
6-OCH3 (5e) 16
7-OCH3 (5f) 4
6-Br (5g)
7-Cl (5h)
6-NO2 (5i)
4
4
4
____
_____
aYield of reaction conditions: 3 equiv. DMF, 4.5 equiv. PCl5 and 1 equiv. of the
corresponding acetanilide at 120 ºC for 4-16 h.
bYield reported in the literarure using POCl3.[4]
cMeltting point obtained for (5a-h) in this report.
dMelting point reported in the literature.[4]
9

Scheme 1. Method reported by Meth-cohn for the synthesis of 2-chloroquinoline-3-
carbaldehydes (1).[4]
10

Scheme 2. Reaction of N,N-alkylformamide and phosphorus pentachloride (PCl5).
11