2-aryl-4-quinolone synthesis using the thermal rearrangement of iminocyclobutenones

Article abstract of DOI:10.3987/COM-14-S(K)13

2-Aryl-4-quinolone synthesis is developed using the thermal rearrangement of iminocyclobutenones formed by a conjugate addition reaction of ketene silyl acetals to alkynyl imines.

Full text of DOI:10.3987/COM-14-S(K)13

HETEROCYCLES, Vol. 90, No. 1, 2015
97
HETEROCYCLES, Vol. 90, No. 1, 2015, pp. 97 - 103. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 27th February, 2014, Accepted, 19th March, 2014, Published online, 2nd April, 2014
DOI: 10.3987/COM-14-S(K)13
2-ARYL-4-QUINOLONE SYNTHESIS USING THE THERMAL
REARRANGEMENT OF IMINOCYCLOBUTENONES
Iwao Hachiya, Keiichi Yokoyama, Akinori Ito, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering, Mie
University, Tsu, Mie 514-8507, Japan. E-mail: mshimizu@chem.mie-u.ac.jp
Abstract – 2-Aryl-4-quinolone synthesis is developed using the thermal
rearrangement of iminocyclobutenones formed by a conjugate addition reaction of
ketene silyl acetals to alkynyl imines.
Since the discovery of nalidixic acid as an antimicrobial agent in 1962, several 4-quinolone derivatives
have been investigated as a chemotherapeutic agent. While 4-quinolone derivatives possessing a
3-carboxy group such as norfloxacin, ciprofloxacin, and levofloxacin have been introduced (Scheme 1),1
2-aryl-4-quinolones are also significant biologically active compounds because of antimitotic, antiplatelet,
and antiviral activities. Therefore, numerous methods for the synthesis of 2-aryl-4-quinolone derivatives
have been reported.2
OH
O
OH
O
OH
O
OH
O
F
F
F
O
O
O
O
N
N
N
N
N
N
N
N
NH
O
N
NH
Ciprofloxacin
Nalidixic Acid
Norfloxacin
Levofloxacin
Scheme 1. 4-Quinolone Antimicrobial Agents
Alkynyl imines are some of the most useful nitrogen-containing starting materials and extensively used in
the synthesis of nitrogen-containing compounds including heterocycles.3 We have been interested in the
reactivity at the !-position of alkynyl imines as a Michael acceptor and developed efficient synthetic
methods for several nitrogen containing heterocycles such as 2-pyridones,4 bicyclo-pyridones,5
iminopyridines,6 and aminopyridines.6 During these investigations, we have found that aluminum
chloride promoted conjugate addition reactions of alkynyl imines 1 with ketene silyl acetals 2 proceed to
give the iminocyclobutenones 3 in good yields. Furthermore, it has been also developed that
This paper is dedicated to Professor Isao Kuwajima on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 90, No. 1, 2015
chemoselective reduction of iminocyclobutenones 3 proceeds to give the aminocyclobutenones 4 in high
yields, and the subsequent thermal rearrangement of aminocyclobutenone 4 in the presence of an
appropriate amine affords either cis- or trans-!-lactams 7 in good yields and with high
diastereoselectivities (Scheme 2).7 We propose a plausible reaction mechanism of the thermal
rearrangement of aminocyclobutenones 4 via aminoketene 5, which is considered to be one of the
intermediates in the Kinugasa reaction.8 Aminoketene 5 would be generated by ring opening reaction of
aminocyclobutenone 4 and undergoes a cyclization to give the enol 6. Protonation of the enol 6 and/or
concomitant epimerization would occur in the presence of an appropriate amine to afford either cis- or
trans-!-lactams 7 with high diastereoselectivities.
Scheme 2. Diastereoselective Synthesis of !-Lactams 7 Using the Thermal Rearrangement of
Aminocyclobutenones 4
Scheme 3. 2-Aryl-4-quinolone 10 Synthesis Using the Thermal Rearrangement of Iminocyclobutenones 3

HETEROCYCLES, Vol. 90, No. 1, 2015
99
We next envisioned that a ring opening reaction of iminocyclobutenone 3 followed by a cyclization of
iminoketene 8’ would give 4-quinolone 10 via an intermediate 9 (Scheme 3). Although several
4-quinolone syntheses via iminoketene intermediates have already been reported, there still remain some
drawbacks such as a limited substrate scope and/or forcing cyclization conditions at high temperatures.9
Herein, this paper describes the 2-aryl-4-quinolone synthesis using the thermal rearrangement of
iminocyclobutenones.10
Table 1. Synthesis of 4-Quinolones 10 Using the Thermal Rearrangement of Iminocyclobutenones 3
Entry
1
3
R1
R2
R3
10
Time (h)
3.0
Yield (%)a
3a
3a
3a
3a
3b
3c
3d
3e
3f
Ph
2-thienyl
2-thienyl
2-thienyl
2-thienyl
Ph
Me
Me
Me
Me
Me
Me
10a
10a
10a
10a
10b
10c
10d
10e
10f
10g
10h
10h
94
2
Ph
2.0
84
3
Ph
1.0
74
4
Ph
0.5
17
5
Ph
3.0
95
6
Ph
2-furyl
3.0
91
7
Ph
2-naphthyl Me
2-naphthyl Me
3.0
81
8
2-thienyl
3.0
76
9
2-naphthyl Ph
Me
Me
Et
3.0
87
10
11
12c
3g
3h
3h
2-thienyl
Ph
Ph
Ph
Ph
3.0
91
68 (29)b
5.0
Ph
Et
5.0
86
aIsolated yield. bYield of the recovered 3h in parenthesis. cReaction performed in xylenes.
We first examined reaction time in the thermal rearrangement of iminocyclobutenone 3a in toluene at
reflux. When the reaction was carried out for 3 h, the desired 4-quinolone 4a was obtained in 94% yield
(Table 1, entries 1-4).11 Several iminocyclobutenones 3b-h were subjected to the thermal rearrangement
conditions. The reaction of diphenylated iminocyclobutenone 3b gave the 4-quinolone 10b in 95% yield
(entry 5). The reaction of iminocyclobutenone 3c having a 2-furyl group as a hetero aromatic group also

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HETEROCYCLES, Vol. 90, No. 1, 2015
afforded 4-quinolone 10c in 91% yield (entry 6). When iminocyclobutenones 3d and 3e possessing a
2-naphthyl group at the R2 moiety were used, both yields slightly decreased probably due to the steric
bulkiness (entries 7 and 8). The reactions of the iminocyclobutenones 3f and 3g possessing a 2-thienyl or
a 2-naphthyl group at the R1 moiety gave 4-quinolones 10e and 10f in high yields, respectively (entries 9
and 10). When the iminocyclobutenone 3h having an ethyl group at the R3 moiety was carried out in
toluene at reflux for 5 h, 4-quinolone 10h was obtained in 68% yield along with the recovered
iminocyclobutenone 3h in 29% yield (entry 11). The reaction of 3h was next carried out in xylenes at
reflux for 5 h to consume the remaining iminocyclobutenone 3h. The reaction proceeded to reach
completion to afford 4-quinolone 10h in 86% yield (entry 12).
We next examined the effects of the substituents on a phenyl group at the nitrogen atom, and Table 2
summarizes the results. The reactions of N-phenylated iminocyclobutenones 11a and 11b gave
4-quinolones 12a and 12b in 93% and 98% yields, respectively (entries 1 and 2). When
para-halophenylated iminocyclobutenones 11c-e were used, 4-quinolones 12c-e were obtained in high
yields irrespective of the kind of the halogen (entries 3-5). The reaction of ortho-methoxyphenylated
iminocyclobutenone 11f gave 4-quinolone 12f in quantitatively yield (entry 6), whereas use of
2,4-disubstituted iminocyclobutenone 11g decreased the yield (entry 7).
Table 2. Effects of ortho, para-Substituents of Phenyl Groups at the Nitrogen Atom
O
O
R3
R2
Ph
N
Ph
R1
toluene, reflux, 3 h
R1
N
H
R2
R3
11
12
Entry
11
R1
R2
H
R3
H
12
Yield (%)a
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
Ph
12a
12b
12c
12d
12e
12f
93
2-thienyl
2-thienyl
2-thienyl
2-thienyl
Ph
H
H
98
H
F
98
H
Br
Cl
H
89
H
87
OMe
Cl
quant
77
11g
2-thienyl
OMe
12g
aIsolated yield.

HETEROCYCLES, Vol. 90, No. 1, 2015
101
We next examined the thermal rearrangement of iminocyclobutenones 13 having meta-substituents on a
phenyl group at the nitrogen atom. These iminocyclobutenones have two reaction sites on the phenyl
moiety to form 4-quinolones 14 or 15 (Scheme 4).
Table 3 summarizes the results. The reaction of iminocyclobutenones 13a and 13b having an
electron-withdrawing group such as fluoro or bromo group afforded a mixture of 4-quinolones 14 and 15
in high yields and with a moderate preference of 7-substituted-4-quinolone 14 (entries 1 and 2). On the
other hand, use of iminocyclobutenone 13c having an electron-donating group such as a methyl group
gave a mixture of 4-quinolones 14c and 15c in high yields and with a slight 5-substituted-4-quinolone 15
selectivity (entry 3). The reason of the reversal of the selectivity is not yet clear at the present stage.
O
O
Ph
Ph
O
Ph
N
H
R
Ph
N
R
ring-
opening
N
14
Ph
or
R
Ph
O
R
R
13
O
Ph
Ph
Ph
N
H
Ph
N
iminoketene intermediate
15
Scheme 4. Thermal Rearrangement of Iminocyclobutenones 13
Table 3. Effects of meta-Substituents of Phenyl Groups at the Nitrogen Atom
O
O
O
R
Ph
Ph
+
N
Ph
toluene, reflux, 3 h
R
Ph
Ph
N
H
R
Ph
N
H
13
14
15
Yield (%)a
entry
13
R
14
15
1
2
3
13a
13b
13c
F
74 (14a)
69 (14b)
38 (14c)
24 (15a)
29 (15b)
57 (15c)
Br
Me
aIsolated yield.

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HETEROCYCLES, Vol. 90, No. 1, 2015
In conclusion, we have developed a 2-aryl-4-quinolone synthesis using the thermal rearrangement of
iminocyclobutenones. The present 2-aryl-4-quinolone synthesis is an attractive alternative method
because iminocyclobutenones are readily available using a conjugate addition reaction of ketene silyl
acetals to alkynyl imines and thermal rearrangements occur under mild reaction conditions to afford the
corresponding 2-aryl-4-quinolones in high yields.
ACKNOWLEDGEMENTS
This work was supported by Grants-in Aid for Scientific Research (B), (C) and Innovative Areas
“Organic Synthesis Based on Reaction Integration. Development of New Methods and Creation of New
Substances” from JSPS and MEXT.
REFERENCES AND NOTES
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Chem., 2007, 72, 7968; (j) C. P. Jones, K. W. Anderson, and S. L. Buchwald, J. Org. Chem., 2007,
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HETEROCYCLES, Vol. 90, No. 1, 2015
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7. I. Hachiya, T. Yoshitomi, Y. Yamguchi, and M. Shimizu, Org. Lett., 2009, 11, 3266.
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10. Iminocyclobutenones were prepared using conjugate addition reactions of alkynyl imines with
ketene silyl acetals according to the literature method in reference 7.
11. Typical procedure (Table 1, entry 1): A solution of iminocyclobutenone 3a (38.7 mg, 0.0999
mmol) in toluene (1.0 mL) was stirred at reflux for 3 h. After cooling to room temperature, the
solvent was removed in vacuo and then the residue was purified by preparative TLC on silica gel
(CH2Cl2/MeOH = 19/1 as an eluent) to give 4-quinolone 10a (36.2 mg, 94%). Yellow white solid;
o
1
Mp 279-280 C; H NMR (500 MHz, CDCl3-(CD3)2SO (9:1)) ! 1.72 (s, 3H), 1.80 (s, 3H), 3.86 (s,
3H), 6.99-7.07 (m, 5H), 7.11 (dd, J = 3.1, 5.5 Hz, 1H), 7.19 (dd, J = 3.1, 9.2 Hz, 1H), 7.40 (d, J =
3.1 Hz, 1H), 7.58 (d, J = 5.5 Hz, 1H), 7.62 (d, J = 3.1 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 11.4 (s, 1H);
13C NMR (126 MHz, CDCl3-(CD3)2SO) ! 20.1, 21.1, 53.8, 102.9, 118.7, 120.3, 120.8, 124.0, 124.0,
125.1, 125.6, 127.4, 127.6, 128.0, 133.2, 133.9, 134.2, 139.2, 140.8, 154.2, 173.8; IR (KBr) 3160,
3060, 2997, 2966, 2927, 2848, 1614, 1571, 1540, 1491, 1436, 1369, 1342, 1291, 1258, 1228, 1164,
1113, 1029, 1053, 832, 794, 765, 735, 694 cm-1; HRMS (EI): Calcd for C24H21NO2S (M)+ 387.1293,
found 387.1308.