Rearrangement of 2-bromo-N-quinoline-8-yl-acetamide leading to new heterocycle

Article abstract of DOI:10.1002/jhet.320

(Chemical Equation Presented) A four fused rings containing heterocyclic compound is formed in the reaction between 2-bromo-N-quinoline-8-yl-acetamide, 2-(4-methoxyphenyl)ethylamine, and acetone in the presence of potassium carbonate; the heterocycle undergoes further reaction with perchloric acid to form a perchlorate salt of a quinoxaline derivative.

Full text of DOI:10.1002/jhet.320

March 2010
Rearrangement of 2-Bromo-N-quinoline-8-yl-acetamide Leading
to New Heterocycle
459
Dipjyoti Kalita and Jubaraj B. Baruah*
Department of Chemistry, Indian Institute of Technology, Guwahati, India
*E-mail: juba@iitg.ernet.in
Additional Supporting Information may be found in the online version of this article.
Received July 29, 2009
DOI 10.1002/jhet.320
Published online 2 March 2010 in Wiley InterScience (www.interscience.wiley.com).
A four fused rings containing heterocyclic compound is formed in the reaction between 2-bromo-N-
quinoline-8-yl-acetamide, 2-(4-methoxyphenyl)ethylamine, and acetone in the presence of potassium
carbonate; the heterocycle undergoes further reaction with perchloric acid to form a perchlorate salt of
a quinoxaline derivative.
J. Heterocyclic Chem., 47, 459 (2010).
INTRODUCTION
gives a fused ring heterocyclic compound I as illustrated
in Scheme 1. However, analogous multicomponent reac-
tion between 2-bromo-N-quinoline-8-yl-acetamide, 2-(2-
methoxyphenyl)ethylamine, and acetone in the presence
of potassium carbonate gives a fused ring heterocyclic
carbonyl compound III, not the imine that was obtained
while 2-(4-methoxyphenyl)ethylamine was used. This
compound transforms to perchlorate salt II of another
heterocycle on reaction with perchloric acid. The com-
pound III also undergoes rearrangement reaction with
perchloric acid to form perchlorate salt II. The use of
excess acetone in these reactions serves dual purposes
of reactant as well as solvent.
Intramolecular cyclization processes are very useful in
heterocycle synthesis [1–6] and they are used for synthesis
of variety of natural products and drugs. Among them, N-
acylinium ion cyclization reactions are very attractive [7–
10]. Such intramolecular reactions are carried out under
catalytic conditions [11–18]. Several of these reactions
require multiple steps [1]. Multicomponent reactions to
prepare heterocycles help to reduce the inconvenience
caused by the extra work involved in product purification
[19–24] in each step and also to reduce the reaction time.
We have serendipitously observed formation of a hetero-
cycle from a reaction of 2-bromo-N-quinoline-8-yl-aceta-
mide, 2-(4-methoxyphenyl)ethylamine and acetone. The
characterization of the fused four-member heterocyle
along with its subsequent rearrangement to a quinoxaline
derivative is described here. Some quinoxaline derivatives
[1] have medicinal value, so new method of synthesis for
such compounds are desirable.
All these compounds were characterized from their
spectroscopic properties. The compound I has IR
absorptions at 1676 cmꢀ1 and at 1635 cmꢀ1 due to car-
bonyl and C¼¼N stretching, respectively. The high reso-
lution mass spectrum of the compound shows the mass
for the Mþ peak at 415.2688, that supports the composi-
tion. The 1H NMR and 13C NMR of the compounds
have the desirable numbers of peaks to support the
structure (for assignments of peaks please refer to sup-
porting figures). The compound I is further characterized
by X-ray crystallography and the structure of the com-
pound is shown in Figure 1(a).
RESULTS AND DISCUSSION
A multicomponent reaction between 2-bromo-N-quin-
oline-8-yl-acetamide, 2-(4-methoxyphenyl)ethylamine,
and acetone in the presence of potassium carbonate
C
V
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460
D. Kalita and J. B. Baruah
Vol 47
Scheme 1. Reaction leading to product I and III, which react with
perchloric acid to form salt II.
As mentioned the compound I undergoes hydrolysis
followed by ring opening reactions to give a quinoxaline
derivative in the form of a perchlorate salt II. The salt
II is characterized by conventional spectroscopic techni-
ques as well as by X-ray crystallography [Fig. 1(b)].
The IR spectra of the salt II have characteristic sharp
perchlorate absorption at 1100 cmꢀ1 and its carbonyl
absorption appears at 1705 cmꢀ1
.
Figure 1. Crystal structure of (a) I and (b) II (ORTEP drawn with
50% thermal ellipsoid). [Color figure can be viewed in the online
issue, which is available at www.interscience.wiley.com.]
Plausible reaction paths (Scheme 2) for the formation
of the compound I may be through an initial condensa-
tion reaction of two molecules of acetone to form aldol
type intermediate. The carbonyl group of the aldol gets
condensed with 2-(4-methoxyphenyl)ethylamine to form
an imine derivative as an intermediate species. This
imine containing molecule has a hydroxy group, which
is attached to a tertiary carbon and it would like to form
CAC bond with the quinoiline ring through elimination
of a water molecule. Presumably, this intermediate com-
pound forms a bromide salt through cyclization reaction.
The cyclized product thus formed, undergo a hydride
shift to form a derivative that is suitable for further
nucleophilic attack of an anion generated next to the
C¼¼N group. It forms the desired product I. Thus, by
these reaction steps, two additional rings over the quino-
line rings are constructed. The added advantage of this
reaction is that it does not stop at the stage of formation
of one ring, but continues to form multiple rings; that
generally does not happen in intramolecular cyclization
reactions [2–6].
pound. The enolic cation thus formed, on aromatization
leads to concomitant cleavage of a CAC bond along
with the formation of a new CAC bond at a tertiary
Scheme 2. Plausible paths for formation of I and II.
The formation of the salt II can be explained by a
three steps mechanistic path as illustrated in Scheme 2.
The first step could be the generation of ketone from a
hydrolytic reaction of perchloric acid by the conversion
of imine to keto group. The keto group containing com-
pound thus formed gets protonated under acidic condi-
tion to form enolised form of a cationic species with
perchlorate as a counter anion. This process leads to
opening of the five-member ring of the parent com-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Rearrangement of 2-Bromo-N-quinoline-8-yl-acetamide Leading to New Heterocycle
461
Scheme 3. Formation of product IV in ethyl methylketone.
EXPERIMENTAL
Synthesis and characterization of compounds
Compound I. 2-Bromo-N-quinoline-8-yl-acetamide (1.4 g, 5
mmol), 2-(4-methoxyphenyl)ethylamine (0.735 mL, 5 mmol)
and anhydrous potassium carbonate (1.03 g, 7.5 mmol) were
added to dry acetone (20 mL), and the reaction mixture was
stirred at 70ꢁC for 12 h (progress of the reaction was moni-
tored at regular intervals by using TLC). The reaction mixture
was filtered to remove the residue and the solvent was
removed under reduced pressure. The product obtained was
purified by preparative thin layer chromatography using silica
gel with 30% ethylacetate in petroleum ether as eluant. Yield:
41%. IR (KBr, cmꢀ1): 3125 (w), 3059 (m), 3008 (m), 2960
(m), 2923 (m), 1676 (s), 1658 (w), 1635 (m), 1613 (m), 1584
(m), 1511 (s), 1482 (s), 1387 (s), 1369 (w), 1270 (m), 1246
1
(s), 1172 (m), 1028 (m), 798 (m), 724 (m). H NMR (CDCl3):
8.4 (s, 1H), 7.1(d, J ¼ 8.4 Hz, 2H), 6.8 (d, J ¼ 6.4 Hz, 2H),
6.5 (m, 3H), 6.3 (d, J ¼ 10 Hz, 1H), 5.7 (dd, J ¼ 5.2, 10 Hz,
1H), 4.5 (dd, J ¼ 5.2, 10 Hz, 1H), 3.7 (s, 3H), 3.53 (s,1H),
3.50 (t, J ¼ 7.2 Hz, 2H), 2.8 (t, J ¼ 7.2 Hz, 2H), 2.5 (d, J ¼
10.4 Hz,1H), 1.7 (s, 3H), 1.1 (s, 3H), 1.0 (s, 3H). 13C NMR
(CDCl3): 20.3, 24.7, 27.1, 36.6, 44.6, 53.2, 55.5, 59.5, 66.4,
71.5, 109.9, 113.9, 114.6, 118.7, 120.3, 121.8, 123.5, 124.8,
125.2, 129.0, 130.0, 132.9, 158.1, 166.5. LC-MS [Mþ] calcd
for C26H29N3O2, 415.2260; found 415.2688.
Compound II. Compound I (0.41 g, 1 mmol) was dissolved
in dilute perchloric acid (3M) and heated for 10 min. The solu-
tion was kept undisturbed, yellow colored crystal of compound
II appeared after 6 days. Yield: 46%. IR (KBr, cmꢀ1): 3258
(m), 3110 (w), 3083 (m), 2962 (m), 1705 (s), 1608 (w), 1587
(m), 1541 (s), 1471 (m), 1427 (s), 1384 (m), 1361(m), 1239
(w), 1177 (m), 1100 (s), 927 (m), 839 (s), 764 (m), 623 (s).
1H NMR (CDCl3/DMSO-d6): 12.0 (s,1H), 9.4 (d, J ¼ 6 Hz,
1H), 9.2 (d, J ¼ 8.4 Hz, 1H), 8.2 (m, 1H), 8.0 (d, J ¼ 8.4 Hz,
1H), 7.9 (t, J ¼ 8.0 Hz, 1H), 7.6 (d, J ¼ 7.6 Hz, 1H), 6.0 (s,
1H), 2.9 (d, J ¼ 18.4 Hz, 1H), 2.6 (d, J ¼ 19.2 Hz, 1H), 2.1
(s, 3H), 1.0 (s, 3H), 0.7 (s, 3H). 13C NMR (DMSO-d6): 24.0,
24.7, 31.5, 51.2, 72.9, 118.9, 122.9, 123.2, 127.3, 129.8, 131.0,
131.5, 148.3, 149.8, 162.1, 206.9. LC-MS [Mþ] calcd for
C17H19N2O2ClO4, 283.1441; found 283.1651.
carbon. This new CAC bond formation along with enol
to keto transformation as illustrated in Scheme 2 gives
the final product II.
Furthermore, we did not observe any aldol condensa-
tion and cyclization reactions from the reaction between
2-bromo-N-quinoline-8-yl-acetamide and acetone in the
presence of potassium carbonate without using an
amine. When 2-(4-methoxyphenyl)ethylamine was
reacted with acetone in the presence of potassium car-
bonate, it led to the corresponding imine. However, this
imine did not react with 2-bromo-N-quinoline-8-yl-acet-
amide to give product I. This suggests that the aldol
condensation and the formation of imine took place con-
comitantly in the presence of 2-bromo-N-quinoline-8-yl-
acetamide. When the same reaction was carried out with
2-(2-methoxyphenyl)ethylamine, we obtained the prod-
uct III. The formation of product, product II on treat-
ment of III with perchloric acid, shows that formation
of II does not depend on the amine used. The formation
of a ketone instead of imine as the final product while
using 2-(2-methoxyphenyl)ethylamine may be due to the
hydrolysis of the corresponding imine. We also carried
out similar reactions of 2-bromo-N-quinoline-8-yl-aceta-
mide with other amines such as benzylamine, picolyl-
amine, and no reaction was observed under analogous
reaction conditions. However, aromatic amines such as
8-aminoquinoline replaced the bromide of 2-bromo-N-
quinoline-8-yl-acetamide to form CAN bonded deriva-
tive. Use of ethylmethyl ketone as solvent did not lead to
the aldol condensation reaction; instead, 2-(4-methoxy-
phynelamino)-N-(quinoline-8-yl)acetamide (IV) was
formed by substitution of bromine by 2-(4-methoxy-
phenyl)ethylamine (Scheme 3).
Compound III. 2-Bromo-N-quinoline-8-yl-acetamide (1.4 g,
5 mmol), 2-(2-methoxyphenyl)ethylamine (0.735 mL, 5 mmol)
and anhydrous potassiumcarbonate (1.03 g, 7.5 mmol) were
added to dry acetone (20 mL) and the reaction mixture was
stirred at 70ꢁC for 12 h (progress of the reaction was monitored
at regular intervals using TLC). The reaction mixture was fil-
tered to remove the residue and the solvent was removed under
reduced pressure. The product obtained was purified by prepara-
tive thin layer chromatography using silica gel with 30% ethyla-
cetate in petroleum ether as eluant. Yield: 25%. IR (KBr, cmꢀ1):
3432 (b), 2924 (s), 2853 (m), 1681 (s), 1596 (m), 1527 (s), 1491
(m), 1458 (m), 1384 (m), 1325 (m), 1244 (s), 1174 (w), 1024
1
(m), 827 (m), 792 (m), 753 (s). H NMR (CDCl3): 8.2 (s, 1H),
6.4 (m, 2H), 6.3 (d, J ¼ 7.2 Hz, 1H), 6.1 (d, J ¼ 10 Hz, 1H),
5.5 (m, 1H), 4.1 (m, 1H), 3.3 (s, 1H), 2.6 (d, J ¼ 10 Hz, 1H),
1.9 (s, 3H), 0.9 (s, 6H). 13C NMR (CDCl3): 24.7, 26.9, 33.1,
45.3, 59.8, 68.6, 71.3, 114.8, 116.7, 119.1, 120.7, 122.1, 123.3,
136.3, 148.7, 165.5. LC-MS [Mþ] calcd for C17H18N2O2,
282.1368; found 283.1448 [Mþþ1].
In conclusion, these results demonstrate a new reac-
tion leading to a novel heterocylic quinoxaline deriva-
tive II. The formation of compound I in one pot is ad-
vantageous, as synthesis of this compound by alternative
routes would require multiple steps and less common
reagents.
Compound IV. 2-Bromo-N-quinoline-8-yl-acetamide (1.4 g,
5
mmol), 2-(4-methoxyphenyl)ethylamine (0.735 mL,
5
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D. Kalita and J. B. Baruah
Vol 47
[5] Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991;
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mmol), and anhydrous potassiumcarbonate (1.03 g, 7.5 mmol)
were added to ethyl methylketone (20 mL), and the reaction
mixture was stirred at 70ꢁC for 12 h (progress of the reaction
was monitored at regular intervals using TLC). The reaction
mixture was filtered to remove the residue and the solvent was
removed under reduced pressure. The product obtained was
purified by preparative thin layer chromatography using silica
gel with 30% ethylacetate in petroleum ether as eluant. Yield:
45%. IR (KBr, cmꢀ1): 3315 (m), 2925 (m), 2851 (w), 1655
(s), 1612 (w), 1579 (w), 1530 (s), 1488 (m), 1463 (m), 1424
(w), 1326 (s), 1245 (s), 1175 (m), 1033 (m), 786 (s), 750 (m).
1H NMR (CDCl3): 10.5 (s, 1H), 8.7 (m, 2H), 8.1 (d, J ¼ 6.8
Hz, 1H), 7.5 (m,3H), 7.4 (q, J ¼ 4 Hz, 1H), 7.1 (d, J ¼ 8.4,
1H), 6.8 (d, J ¼ 8.8, 1H), 4.3 (s, 3H), 3.7 (s,2H), 3.5 (s, 1H),
2.9 (t, J ¼ 6.8 Hz, 2H), 2.8 (t, J ¼ 6.0 Hz, 2H). 13C NMR
(DMSO-d6/CDCl3): 28.8, 34.9, 62.0, 85.4, 115.5, 121.1, 121.2,
126.4, 127.3, 129.0, 133.3, 135.6, 137.6, 147.8, 170.6. LC-MS
[Mþ] calcd for [Mþ] C20H21N3O2, 335.1634; found 336.1679
[Mþþ1].
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Acknowledgments. The authors thank Department of Science
and Technology, New-Delhi for financial assistance. The author
DK thanks Council of Scientific and Industrial Research, New
Delhi, India for a junior fellowship.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet