Gas-phase pyrolysis in organic synthesis: Rapid green synthesis of 4-quinolinones

Article abstract of DOI:10.1055/s-2007-985573

Gas-phase pyrolysis of aminomethylene Meldrum's acid derivatives gave quinolinones and/or amines depending on the nature of arylamino moiety. Effect of substituent on reaction rate and nature of pyrolysis products supports the suggested intramolecular nucleophilic substitution reaction via initially formed keteneamine intermediate. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-985573

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LETTER
2205
Gas-Phase Pyrolysis in Organic Synthesis: Rapid Green Synthesis of
4-Quinolinones
S
ynthesis of 4-Qui
o
nolinones uria A. Al-Awadi,*a Ismail Abdelshafy Abdelhamid,a Alya M. Al-Etaibi,b Mohamed Hilmy Elnagdia
a
Chemistry Department, Faculty of Science, Kuwait University, PO Box 5969, Safat 13060, Kuwait
E-mail: nouria@kuc01.kuniv.edu.kw
b
Natural Science Department, College of Health Sciences, Public Authority for Applied Education and Training, Kuwait
Received 16 May 2007
Abstract: Gas-phase pyrolysis of aminomethylene Meldrum’s acid
derivatives gave quinolinones and/or amines depending on the
nature of arylamino moiety. Effect of substituent on reaction rate
and nature of pyrolysis products supports the suggested intramolec-
ular nucleophilic substitution reaction via initially formed ketene-
amine intermediate.
O
O
O
O
O
O
O2N
O2N
HN
Et
N
Et
N
H
Et
H
Key words: Meldrum’s acid, pyrolysis, 4-quinolinones
NO2
5
3
4
The rapid rise in bacterial resistance to traditional anti-
biotic such as b-lactams has encouraged continuous
search for new classes of antibiotics, which led to intro-
duction of nalidixic acid (1) in 1962. Ciprofloxacin (2,
Figure 1) was marketed in 1980; however, recently there
has been a rapid development of resistance to cipro-
floxacin. These searches for new quinolin-4-ones1,2 were
initiated by synthesis of either via cyclization b-amino-
acrylates,3 high-temperature condensation of b-ketoesters
with amines,4 or via reaction of diethyl ethoxymethylene-
malonates with aromatic amines.5 These are multistage
routes and are of limited scope.
Scheme 1
Ten Meldrum’s acid derivatives were synthesized utiliz-
ing the reported synthetic approach11 via condensing
Meldrum’s acid 6 with triethylorthoformate and aromatic
amines 7 to produce 8a–j (Scheme 2).11 Static gas-phase
pyrolysis12 of 8a–j at 300 °C for 900 s resulted in the for-
mation of aromatic amines in addition to quinolinones 11
and acetone, however, in flash vacuum pyrolysis (FVP)13
at 600 °C and 10–2 Torr only quinolinones, acetone, and
trace amount of aromatic amines are produced. The yield
of each product was found to depend on the nature of the
substituent on the benzene ring as well as pyrolysis condi-
tions (cf. Table 1). Pyrolysis of 8a–c either by FVP at 600
°C13 or by static pyrolysis at 300 °C afforded quinolinones
11a–c, acetone, and trace amount of aromatic amines. The
analyses of the product 11b as an example are in
agreement with the proposed structure.14 Pyrolyzing 8d
afforded, in addition to quinolinone 11d and amine 7d,
quinolinone 11a which results most likely via ipso sub-
stitution. On the other hand, pyrolysis of 8e–h under the
same conditions offered in addition to acetone a 1:1
mixture of quinolinones 11e–h and 11i–l. The structure of
11e and 11i was established based on spectral data.15,16
O
O
F
COOH
COOH
N
N
Me
N
N
HN
1
2
Figure 1
Chen and Wang have reported the formation of 4-
quinolinones6 upon heating 3 in diphenyl ether at 250
°C.6,7 It was suggested6 that the reaction does not involve
electrophilic attack on the benzene ring but rather an elec-
trocyclization of 3-(paranitrophenylamino)penta-1,2-
dien-1-one (4,7 cf. Scheme 1).
Contradicting with reported formation of 2-methyl quino-
linones upon pyrolyzing 3 in diphenyl ether,6 in our hands
pyrolysis of 8i afforded only traces of quinolinones 11m
in addition to acetone. The major pyrolysis product, in
fact, was 4-nitroaniline. This confirms that the electron
density at the cyclization reaction site plays a significant
role in the course of the cyclization reaction. Thus sub-
stituents in 8a–c generally enrich the p-electronic cloud in
the benzene ring, while a nitro substituent in 8i is known
to decrease the p-cloud density in the ring, thus reducing
the nucleophilicity of the ring carbons. We thus believe
that the initially formed 9 either cyclizes into 10 that then
In conjunction with our research interest in the utility of
gas-phase pyrolytic reactions as green benign approaches
in organic synthesis8–10 we describe in this article an effi-
cient synthesis of quinolin-4-one from Meldrum’s acid
derivatives.
SYNLETT 2007, No. 14, pp 2205–2208
0
3
.0
9
.2
0
0
7
Advanced online publication: 13.08.2007
DOI: 10.1055/s-2007-985573; Art ID: G14807ST
© Georg Thieme Verlag Stuttgart · New York

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2206
N. A. Al-Awadi et al.
LETTER
O
+
acetone
NH2
O
O
600 °C, 10–2 Torr
R
CH(OEt)3
O
O
+
O
O
R
O
O
N
R
H
N
H
9
6
7
8
O–
O
H
7,8
R
R
R
a
b
c
d
e
f
g
h
i
N
H
10
H
p-Me
p-OMe
o-OMe
m-Br
+
N
H
11
11
R
a
b
c
d
e
f
H
Me (6)
OMe (6)
OMe (8)
Br (7)
m-Cl
m-OMe
m-NO2
p-NO2
o-NO2
j
Cl (7)
g
h
i
OMe (7)
NO2 (7)
Br (5)
j
Cl (5)
k
l
m
OMe (5)
NO2 (5)
NO2 (6)
NO2 (8)
n
Scheme 2
Table 1 Pyrolysis of Compounds 8
Reactant
Product yield (%)
Flash vacuum pyrolysis
Static pyrolysis
8a
8b
8c
11a (83.5%)
11a (35.6%)
11b (65.2%) + 7b (1%)
11c (14.5%) + 7c (5%)
11b (53%) + 7b (36%)
11c (51.3%) + 7c (17.7%)
8d
8e
11d (20. 1%) + 11a (5.6%) + 7d (2.3%)
11e (14.9%) + 11i (18%)
11f (14.3%) + 11j (15.2%)
11g (17%) + 11k (18.8%)
11h (11.4%) + 11l (21.6%) + 7h (33%)
11m (2.9%) + 7i (9.9%)
11d (15.8%) + 11a (18%) + 7d (26.1%)
11e (14.1%) + 11i (27.7%)
11f (34%) + 11j (20%)
11g (10.1%) + 11k (11.7%)
11h (1.7%) + 11l (2.5%) + 7h (28.2%)
11m (1%) + 7i (12%)
8f
8g
8h
8i
8j
11a (9.6%) + 11n (21%) + 7j (3.5%)
16 (17.8%) + 12(2%)
11a (%) + 11n (%) + 7j (%)
16 (9%) + 12(23%)
15a
15b
15c
Did not sublime
17 (16.5%)
19 (84.8%)
19 (21.6%)
affords 11, or is decomposed prior to cyclization when the here that the attack at ipso position is well known for nitro
cyclization site is not sufficiently nucleophilic. Similar to substituents but we believe that it is quite unusual with
compound 8c, compound 8j undergoes ipso substitution methoxy substituents.17 Our conclusion is that formation
to give a mixture of 11n and 11a. It is worth mentioning of quinolinones via pyrolysis of 8a–j proceeds via an
Synlett 2007, No. 14, 2205–2208 © Thieme Stuttgart · New York

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LETTER
Synthesis of 4-Quinolinones
2207
intramolecular nucleophilic displacement. Although the
fact that 8h is formed in better yield than 8i seems at first
sight contradictory to this assumption, closer inspection
reveals that this is not exactly the case, as substitution in
para-position would contribute to the ease of N–N cleav-
age and this contributes to the observed low yield of 8i.
References and Notes
(1) Hiari, Y. M.; Khanfar, M. A.; Qaisi, A. M.; Abu Shuheil, M.
Y.; El-Abadelah, M. M.; Boese, R. Heterocycles 2006, 68,
1163.
(2) Mann, J.; Crabbe, M. J. C. Bacteria and Antibacterial
Agents; Biochemical & Medicinal Chemistry Series, Oxford
University Press: USA, 1996, 64.
We have then investigated the possible utility of this reac-
tion for synthesis of condensed azines, by condensing 6
with heterocyclic amines 12–14. The reaction produced
15a–c in good yields. The FVP of 15a,b at 600 °C
afforded the condensed azines 16 and 17. On the other
hand, FVP of 15c gave a product that can in theory be
formulated as pyrido[2,3-b]pyrazine (18), or pyr-
azino[1,2-a]pyrimidine (19). The structure of 19 was
established based on the absence of D2O exchangeable
NH signal18 (cf. Scheme 3).
(3) Heindel, N. D.; Brodof, T. A.; Kogelschatz, J. E.
J. Heterocycl. Chem. 1966, 3, 222.
(4) (a) Lauer, W. M.; Kaslow, C. E. Org. Synth., Coll. Vol. III;
Wiley and Sons: New York, 1955, 580. (b) Reynolds, G.
A.; Hauser, C. R. Org. Synth., Coll. Vol. III; Wiley and Sons:
New York, 1955, 593.
(5) Price, C. C.; Roberts, R. M. Org. Synth., Coll. Vol. III; Wiley
and Sons: New York, 1955, 272.
(6) Chen, B.; Huang, X.; Wang, J. Synthesis 1987, 482.
(7) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Publishers: London, 2000, 133.
(8) Al-Awadi, H.; Ibrahim, M. R.; Dib, H. H.; Al-Awadi, N. A.;
Ibrahim, A. I. Tetrahedron 2005, 61, 10507.
NH2
(9) Al-Awadi, N. A.; George, B. J.; Dib, H. H.; Ibrahim, M. R.;
Ibrahim, Y. A.; El-Dusouqui, O. M. Tetrahedron 2005, 61,
8257.
(10) Al-Awadi, N. A.; Elnagdi, M. H.; Ibrahim, Y. A.; Kaul, K.;
Kumar, A. Tetrahedron 2001, 57, 1609.
N
N
NH2
N
NH2
N
H
N
12
13
14
(11) Hickson, C. L.; Keith, E. M.; Martin, J. C.; McNab, H.;
Monahan, L. C.; Walkinshaw, M. D. J. Chem. Soc., Perkin
Trans. 1 1986, 1465.
NH
N
R = pyridyl
O
6
(12) Static Pyrolysis of 8–j
The substrate (0.2 g) was introduced in the Pyrex reaction
tube (12 cm length and 1.5 cm internal diameter). The tube
was sealed under vacuum (0.02 m bar) and placed in the
pyrolyzer for 900 s at 300 °C. The content of the tube was
then separated by preparative high-performance liquid
16
O
O
N
R = benzimidazolyl
O
O
NH
N
R
chromatography (HPLC) and was analyzed by 1H NMR, 13
NMR, IR and GC-MS. Relative and percent yields were
determined from NMR.
C
N
H
O
17
15a–c
R = pyrazinyl
X
15
O
R
(13) Flash Vacuum Pyrolysis of 8a–j
N
N
The sample was volatilized from a tube in a Buchi Kugelrohr
oven through a 30 × 2.5 cm horizontal-fused quartz tube and
was heated externally by a cabolite Eurotherm tube furnace
MTF-12/38A to 600 °C. The products were collected in a U-
shaped trap cooled in liquid nitrogen. The whole system was
maintained at a pressure of 10–2 Torr by an Edwards Model
E2M5 high-capacity rotary oil pump, the pressure being
measured by a Pirani gauge situated between the cold trap
and pump. Under these condition the contact time in the hot
zone was estimated to be 10 ms. Products collected in the U-
shaped trap were analyzed by 1H NMR, 13C NMR, IR and
GC-MS. Relative and percent yields were determined from
NMR.
a
b
c
pyrid-4-yl
benzimidazol-2-yl
pyrazin-2-yl
N
H
N
18
N
N
O
19
Scheme 3
A simple, green approach for synthesis of quinolinones,
azoloazines, and pyrimidoazines is now available. More-
over we were able provide evidence that the conversion of
8 into 11 processes via an intramolecular nucleophilic
substitution reaction for which substituents on the aryl
moiety play an important role.
Compounds 11a,c,d,f–h,j–n, 16, and 17 has been reported
earlier and proved to be identical with products obtained
here.19–27
(14) 6-Methyl-1H-quinolin-4-one (11b)
Mp 240–242 °C. IR (KBr): 3050 (NH), 1625 (CO) cm–1.
LC-MS: m/z (%) = 159 (100) [M+]. 1H NMR (400 MHz,
DMSO): d = 2.39 (s, 3 H, CH3), 6.0 (d, 1 H, J = 7.2 Hz,
quinoline-H3), 7.45 (d, 1 H, quinoline-H8), 7.48 (d, 1 H,
quinoline-H7), 7.86 (d, 1 H, J = 7.2 Hz, quinoline-H2), 8.31
(s, 1 H, quinoline-H5), 11.72 (br s, 1 H, D2O exchangeable,
NH). 13C NMR (DMSO, 100 MHz): d = 21.55, 109.09,
119.18, 124.70, 125.96, 134.31, 134.57, 138.67, 140.50,
178.48. DEPT 135: d = 21.55, 109.09, 119.18, 124.70,
125.96, 134.57, 140.50.
Acknowledgment
This work was supported by Kuwait University through research
grant # Sc08/04 and ANALAB and SAF grants # GS01/01 and
GS04/01.
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2208
N. A. Al-Awadi et al.
LETTER
(15) 7-Bromo-1H-quinolin-4-one (11e)
13C NMR (75 MHz, DMSO): d = 109.6, 118.2, 133.0, 145.8,
154.2, 155.9, 156.8. DEPT 135: d = 109.6, 118.2, 133.0,
154.2, 155.9. Anal. Calcd for C7H5N3O (147.14): C, 57.14;
H, 3.43; N, 28.56. Found: C, 57.53; H, 3.62; N, 28.83.
(19) Huang, X.; Liu, Z. J. Org. Chem. 2002, 67, 6731.
(20) Tois, J.; Vahermo, M.; Koskinen, A. Tetrahedron Lett. 2005,
46, 735.
Mp 242–244 °C. LC-MS: m/z = 225 [M + 1]. 1H NMR (400
MHz, DMSO): d = 6.04 (d, 1 H, H3, J = 7.37 Hz), 7.52 (d, 1
H, J = 8.56 Hz), 7.74 (s, 1 H, H-5), 7.82 (d, 1 H, J = 7.37 Hz,
H2), 8 (d, 1 H, J = 8.56 Hz, H6), 11.22 (br, 1 H, NH). 13
NMR (100 MHz, DMSO): d = 111.5, 120.4, 123.2, 126,
128.4, 132.7, 141, 143.4, 177.4.
C
(16) 5-Bromo-1H-quinolin-4-one (11i)
(21) Huang, X.; Liu, Z. Tetrahedron Lett. 2001, 42, 7655.
(22) Griera, R.; Armengol, M.; Reyes, A.; Alvarez, M.; Palomer,
A.; Cabre, F.; Pascual, J.; Garcia, M. L.; Mauleon, D. Eur. J.
Med. Chem. 1997, 547.
(23) Hirano, J.; Hamase, K.; Zaitsu, K. Tetrahedron 2006, 62,
10065.
(24) For 5-OMe: Cassis, R.; Tapia, R.; Valderrama, J. Synth.
Commun. 1995, 15, 125.
(25) Ruchelman, A. L.; Kerrigan, J. E.; Li, T.-K.; Zhou, N.; Liu,
A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. 2004, 12,
3731.
Mp 234–236 °C. IR (KBr): 1645 (CO) cm–1. LC-MS: m/z =
225 [M + 1]. 1H NMR (400 MHz, DMSO): d = 6.06 (d, 1 H,
H3, J = 7.24 Hz), 7.41–7.47 (m, 3 H, ArH), 7.93 (d, 1 H,
J = 7.24 Hz, H-2), 11.18 (br, 1 H, NH). 13C NMR (75 MHz,
DMSO): d = 110.3, 119.5, 121.5, 125.6, 127.2, 130.6, 139.3,
142, 177.
(17) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry: Reaction Mechanisms and Structure, 5th ed.; J.
Wiley and Sons, Inc.: New York, 2001, 68.
(18) Pyrazino[1,2-a]pyrimidin-4-one (19)
Mp 178–180 °C. IR (KBr): 1692 (CO) cm–1. LC-MS: m/z =
148 [M + 1]. 1H NMR (400 MHz, DMSO): d = 6.67 (d, 1 H,
J = 6.44 Hz, pyrimidine-H), 8.19 (d, 1 H, J = 4.64 Hz,
pyrazine-H), 8.41 (d, 1 H, J = 6.44 Hz, pyrimidine-H), 8.73
(d, 1 H, J = 4.64 Hz, pyrazine-H), 9.13 (s, 1 H, pyrazine-H).
(26) Reimlinger, H.; Peiren, M. A.; Merenyi, R. Chem. Ber. 1972,
105, 794.
(27) Czuba, W. C.; Kowalski, P.; Grzegozek, M. Pol. J. Chem.
1980, 54, 1573.
Synlett 2007, No. 14, 2205–2208 © Thieme Stuttgart · New York