Synthesis of 3,4-disubstituted 2(1H)-quinolinones via intramolecular Friedel-Crafts reaction of N-arylamides of Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2009.01.018

3,4-Disubstituted 2(1H)-quinolinones were synthesized starting from the Baylis-Hillman adducts via the following sequential processes: (i) hydrolysis of the Baylis-Hillman adduct to acid, (ii) EDC coupling with anilines, (iii) H₂SO₄-

Full text of DOI:10.1016/j.tetlet.2009.01.018

Tetrahedron Letters 50 (2009) 1249–1251
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Synthesis of 3,4-disubstituted 2(1H)-quinolinones via intramolecular
Friedel–Crafts reaction of N-arylamides of Baylis–Hillman adducts
*
Ko Hoon Kim, Hyun Seung Lee, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
3,4-Disubstituted 2(1H)-quinolinones were synthesized starting from the Baylis–Hillman adducts via the
following sequential processes: (i) hydrolysis of the Baylis–Hillman adduct to acid, (ii) EDC coupling with
anilines, (iii) H2SO4-assisted intramolecular Friedel–Crafts cyclization, and the final (iv) DBU-mediated
isomerization.
Received 11 December 2008
Revised 6 January 2009
Accepted 9 January 2009
Available online 13 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
2(1H)-Quinolinones
Baylis–Hillman adducts
Friedel–Crafts reaction
N-Arylamides
Recently, Baylis–Hillman adducts have been used for the syn-
thesis of many heterocyclic compounds.1–3 Among them, the syn-
thesis of quinolone derivatives has received much attention due
to the importance of these compounds.2,3 Most of the reported
syntheses of quinolone and its derivatives used the Baylis–Hillman
adducts of 2-nitrobenzaldehydes as starting materials.2b–e The con-
struction of quinolone ring was finally carried out by the conden-
sation reaction between the carbonyl group and amino group,
made by in situ reduction of the nitro group.2b–e
Modified Baylis–Hillman adducts with anilines, aza-Baylis–Hill-
man adducts, have also been used for the synthesis of quinolone
derivatives.2a,3a–c As an example, N-phenyl aza-Baylis–Hillman ad-
duct (I) produced 2(1H)-quinolinone (II) via the first aza-Claisen
rearrangement and the following cyclization with PPA (polyphos-
phoric acid)3a or TFA (Scheme 1).2a We and others did not observe
the formation of 4(1H)-quinolinone (III), which could be formed
via the Friedel–Crafts type cyclization of (I) and the following dou-
ble bond isomerization process (Scheme 1).
(i) via DABCO salt
(ii) Friedel-Crafts
H2N
OH
(ii)
(i)
H
N
O
H
N
O
O
Ph
Ph
Ph
OMe
(III)
not formed
)
i
i
(
(i)
O
COOMe
aza-Claisen
rearrangement
Ph
H
H
Ph
N
N
COOMe
Ref. 2a,3a
Ph
H2N
(II)
(I)
Scheme 1.
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.018

1250
K. H. Kim et al. / Tetrahedron Letters 50 (2009) 1249–1251
O
New protocol
H
H
O
Ph
N
N
compound (II)
(i) EDC coupling
(ii) Friedel-Crafts
4a
NH2
OH
(ii)
Ph
N
O
H
Ph
(i)
OH
O
this work
Ph
4a
1a
Figure 1.
Ph
N
DBU
CH3CN, rt
H2SO4
PhNH2 (2a)
OH
O
OH
O
ClCH2CH2Cl
EDC.HCl
4a
Ph
OH
Ph
N
H
(ii)
(i)
(58%)
O
this class of compounds. Aza-Claisen rearrangement of (I) oc-
curred more preferentially than the intramolecular Friedel–Crafts
cyclization,2a,3a thus we changed our protocol as in Scheme 2:
first amide C–N bond formation via EDC [N-ethyl-N-(3-dimethyl-
aminopropyl)carbodiimide] coupling between the Baylis–Hillman
acid 1a and aniline (path i), and the following H2SO4-catalyzed
intramolecular Friedel–Crafts reaction (path ii). We expected that
the intramolecular Friedel–Crafts type cyclization could be suc-
1a
3a (74%)
H
5a (88%)
Scheme 2.
Based on the importance of quinolone derivatives2–4 and the
synthetic potential of the Friedel–Crafts reaction in Baylis–Hill-
man chemistry,5 we decided to develop a new methodology for
Table 1
Synthesis of 3-methylene dihydroquinolones 4 and 3-methylquinolones 5
Entry
Acid 1
Amine 2
B–H amide 3a (%)
Product 4b (%)
Product 5c (%)
OH O
Ph
Ph
OH O
Ph
OH
1
Aniline (2a)
Ph
Ph
Ph
N
H
1a
N
H
O
O
O
N
H
O
O
O
3a (74)
4a (58)
4b (54)
5a (88)
5b (83)
Me
Ph
Ph
OH O
OH O
OH O
2
1a
4-Methylaniline (2b)
Me
Me
N
H
N
H
N
H
3b (70)
OMe
Ph
Ph
MeO
MeO
3
4
1a
1a
4-Methoxtaniline (2c)
N-Methylaniline (2d)
N
H
N
H
N
H
3c (60)
4c (57)
4d (91)
5c (80)
5d (99)
Ph
Ph
Ph
N
Me
N
Me
O
N
Me
O
3d (71)
Cl
Ph
Ph
OH O
OH O
5
6
1a
1a
4-Chloroaniline (2a)
1-Napthylamine (2f)
Cl
Cl
Ph
Ph
N
H
N
H
O
O
N
H
O
3e (59)
3f (63)
4e (43)
4f (60)
5e (85)
5f (87)
Ph
Ph
N
H
N
H
N
H
O
Cl
Cl
OH O
OH O
OH
7
2a
N
H
3g (75)
Cl
1b
N
H
O
N
H
O
Cl
4g (69)
5g (80)
Cl
O
Cl
O
Cl OH O
Cl OH O
N
H
OH
8
2a
N
H
N
H
3h (61)
4h (44)
5h (82)
1c
a
Conditions: acid 1 (1.5 mmol), amine 2 (1.8 mmol), EDCÁHCl (1.8 mmol), DMF, rt, 12 h.
Conditions: amine 3 (1.0 mmol), H2SO4 (3.0 equiv), CH2Cl2, reflux, 20 min.
Conditions: compound 4 (0.5 mmol), DBU (1.0 equiv), CH3CN, rt, 30 min.
b
c

K. H. Kim et al. / Tetrahedron Letters 50 (2009) 1249–1251
1251
3. For the synthesis of quinolone derivatives from Baylis–Hillman adducts in our
group, see: (a) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005, 61, 1493–
1499; (b) Lee, C. G.; Gowrisankar, S.; Kim, J. N. Tetrahedron Lett. 2004, 45, 7409–
7413; (c) Kim, S. C.; Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005, 26,
1001–1004; (d) Kim, S. C.; Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean
Chem. Soc. 2006, 27, 1133–1139; (e) Kim, S. C.; Gowrisankar, S.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 3463–3466. and further references cited therein.
4. For the synthesis and biological activities of quinolinone and related
compounds, see: (a) Park, K. K.; Lee, J. J. Tetrahedron 2004, 60, 2993–2999; (b)
Kadnikov, D. V.; Larock, R. C. J. Org. Chem. 2004, 69, 6772–6780; (c) Battistuzzi,
G.; Bernini, R.; Cacchi, S.; Salve, I. D.; Fabrizi, G. Adv. Synth. Catal. 2007, 349, 297–
302; (d) Bernini, R.; Cacchi, S.; Salve, I. D.; Fabrizi, G. Synlett 2006, 2947–2952;
(e) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Eur. J. Org. Chem. 2004, 4039–
4047; (f) Koltunov, K. Y.; Walspurger, S.; Sommer, J. Chem. Commun. 2004, 1754–
1755; (g) Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo, S.-C. Bioorg. Med.
Chem. 1998, 6, 1657–1662; (h) Sai, K. K. S.; Gilbert, T. M.; Klumpp, D. A. J. Org.
Chem. 2007, 72, 9761–9764.
5. For the Friedel–Crafts reaction with modified Baylis–Hillman adducts, see: (a)
Lim, H. N.; Ji, S.-H.; Lee, K.-J. Synthesis 2007, 2454–2460; (b) Jeon, K. J.; Lee, K.-J. J.
Heterocycl. Chem. 2008, 45, 615–619; (c) Basavaiah, D.; Bakthadoss, M.; Reddy,
G. J. Synthesis 2001, 919–923; (d) Basavaiah, D.; Reddy, R. M. Tetrahedron Lett.
2001, 42, 3025–3027; (e) Gowrisankar, S.; Lee, K. Y.; Lee, C. G.; Kim, J. N.
Tetrahedron Lett. 2004, 45, 6141–6146.
6. Typical experimental procedure for the synthesis of compounds 3a, 4a, and 5a: To a
stirred solution of 1a (267 mg, 1.5 mmol) and aniline (2a, 167 mg, 1.8 mmol) in
DMF (3 mL) was added EDC hydrochloride (343 mg, 1.8 mmol). After stirring at
room temperature for 12 h, the reaction mixture was poured into water and
extracted with EtOAc. Column chromatographic purification process (hexanes/
EtOAc, 4:1) afforded pure amide 3a (281 mg, 74%). To a stirred solution of
cessful due to the formation of stable benzylic carbocation
although the aryl group of amide is not an electron-rich aryl
moiety. Fortunately, intramolecular Friedel–Crafts reaction of
amide 3a produced expected methylene compound 4a in moder-
ate yield (58%) as shown in Scheme 2 in short time (20 min).6 In
the reaction, we did not observe the formation of compound (II),
which could be formed via the Friedel–Crafts reaction of rela-
tively unstable primary carbocation intermediate as demon-
strated in Figure 1.
N-Arylamides of Baylis–Hillman adducts 3a–h were synthe-
sized from the reaction of acid 1a–c and aniline derivatives 2a–f
by using EDC in good to moderate yields (59–75%).6,7 The next Fri-
edel–Crafts reaction was carried out in the presence of H2SO4
(3.0 equiv) in CH2Cl2 at refluxing temperature in short time (20
min). The yields of methylene compounds 4a–h were moderate
to good (43–91%).6 This is the first successful result on the Fri-
edel–Crafts cyclization involving the aryl moiety of N-arylamides
of Baylis–Hillman adducts. Conversion of these exo-methylene
compounds 4a–h into their endo-isomers 5a–h was carried out un-
der the influence of DBU in CH3CN in high yields (80–99%).6 The re-
sults are summarized in Table 1.
As shown in entry 5, the yield of product 4e was low (43%), pre-
sumably due to the presence of an electron-withdrawing chloro
substituent as compared with entries 1–4. The reaction was influ-
enced also by the steric crowdedness around the benzylic carbo-
cation. When the aryl group of Baylis–Hillman adduct was para-
chloro (entry 7), the yield of 4 g was moderate (69%), while it
was low (44%) with ortho-chloro derivative (entry 8).
In summary, we disclosed the synthesis of 3,4-disubstituted
2(1H)-quinolinones starting from the Baylis–Hillman adducts via
the H2SO4-assisted intramolecular Friedel–Crafts cyclization as
the key step. Friedel–Crafts cyclization involving the aryl moiety
of N-arylamides of Baylis–Hillman adducts is unprecedented in
Baylis–Hillman chemistry, and further studies are currently
underway.
compound 3a (253 mg, 1.0 mmol) in CH2
Cl2 (5 mL) was added H2SO4 (294 mg,
3.0 mmol), and the reaction mixture was heated to reflux for 20 min. After the
usual aqueous extractive workup and chromatographic purification process,
(hexanes/EtOAc, 5:1) compound 4a was isolated, 136 mg (58%). Compound 4a
(117 mg, 0.5 mmol) was dissolved in CH3CN (3 mL) and was treated with DBU
(76 mg, 0.5 mmol) at room temperature for 30 min. After the usual aqueous
extractive workup and chromatographic purification process (hexanes/EtOAc,
2:1), compound 5a was isolated, 103 mg (88%).4a Other compounds were
synthesized similarly, and the representative spectroscopic data of 3a, 4a, 5a,
5b, and 5f are as follows.
Compound 3a: 74%; white solid; mp 133–135 °C; IR (KBr) 3315, 1658, 1531,
1442 cmÀ1 1H NMR (CDCl3, 300 MHz) d 3.54 (d, J = 4.5 Hz, 1H), 5.55 (s, 1H), 5.66
;
(d, J = 4.5 Hz, 1H), 6.11 (s, 1H), 7.06–7.12 (m, 1H), 7.26-7.48 (m, 9H), 8.34 (br s,
1H); 13C NMR (CDCl3, 75 MHz) d 74.73, 120.20, 123.04, 124.57, 126.03, 127.97,
128.61, 128.97, 137.44, 140.38, 145.36, 165.21; ESIMS m/z 254 (M++1). Anal.
Calcd for C16H15NO2: C, 75.87; H, 5.97; N, 5.53. Found: C, 75.96; H, 5.72.; N, 5.29.
Compound 4a: 58%; white solid; mp 163–165 °C; IR (KBr) 1678, 1360, 1242
cmÀ1 1H NMR (CDCl3, 300 MHz) d 4.96 (s, 1H), 5.46 (dd, J = 2.4 and 1.2 Hz, 1H),
;
6.38 (t, J = 1.2 Hz, 1H), 6.83 (dd, J = 7.8 and 0.9 Hz, 1H), 6.96–7.01 (m, 1H), 7.06–
7.08 (m, 1H), 7.13–7.33 (m, 6H), 8.09 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d
49.63, 115.46, 123.30, 125.59, 125.61, 127.16, 127.91, 128.06, 128.84, 128.97,
136.11, 139.92, 141.71, 164.38; ESIMS m/z 236 (M++1). Anal. Calcd for
C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.55; H, 5.79; N, 5.76.
Acknowledgments
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD, KRF-2008-
313-C00487). Spectroscopic data were obtained from the Korea Ba-
sic Science Institute, Gwangju branch.
Compound 5a:4a,4b 88%; white solid; mp 226–227 °C; IR (KBr) 1651, 1431 cmÀ1
;
1H NMR (CDCl3, 300 MHz) d 2.10 (s, 3H), 7.03–7.09 (m, 2H), 7.23–7.27 (m, 2H),
7.41–7.56 (m, 5H), 12.57 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 14.28, 115.92,
121.07, 122.12, 126.68, 127.42, 127.92, 128.62, 128.76, 129.23, 136.98, 137.10,
148.78, 164.60; ESIMS m/z 236 (M++1).
Compound 5b: 83%; white solid; mp 210–212 °C; IR (KBr) 1653 cmÀ1 1H NMR
;
References and notes
(CDCl3, 300 MHz) d 2.07 (s, 3H), 2.26 (s, 3H), 6.83 (s, 1H), 7.22–7.28 (m, 3H), 7.39
(d, J = 8.1 Hz, 1H) 7.44–7.56 (m, 3H), 12.28 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d
14.33, 21.08, 115.74, 120.99, 126.25, 127.36, 127.86, 128.63, 128.76, 130.62,
131.62, 135.06, 137.14, 148.56, 164.28; ESIMS m/z 250 (M++1). Anal. Calcd for
C17H15NO: C, 81.90; H, 6.06; N, 5.62. Found: C, 82.07; H, 6.24; N, 5.37.
1. For the general review on Baylis–Hillman chemistry, see: (a) Basavaiah, D.; Rao,
A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811–891; (b) Kim, J. N.; Lee, K. Y.
Curr. Org. Chem. 2002, 6, 627–645; (c) Lee, K. Y.; Gowrisankar, S.; Kim, J. N. Bull.
Korean Chem. Soc. 2005, 26, 1481–1490; (d) Singh, V.; Batra, S. Tetrahedron 2008,
64, 4511–4574. and further references cited therein.
2. For the synthesis of quinolone derivatives from Baylis–Hillman adducts by other
groups, see: (a) Pathak, R.; Madapa, S.; Batra, S. Tetrahedron 2007, 63, 451–460;
(b) Benakki, H.; Colacino, E.; Andre, C.; Guenoun, F.; Martinez, J.; Lamaty, F.
Tetrahedron 2008, 64, 5949–5955; (c) Familoni, O. B.; Klaas, P. J.; Lobb, K. A.;
Pakade, V. E.; Kaye, P. T. Org. Biomol. Chem. 2006, 4, 3960–3965; (d) Basavaiah,
D.; Reddy, R. M.; Kumaragurubaran, N.; Sharada, D. S. Tetrahedron 2002, 58,
3693–3697; (e) Madapa, S.; Singh, V.; Batra, S. Tetrahedron 2006, 62, 8740–8747;
(f) Hong, W. P.; Lee, K.-J. Synthesis 2006, 963–968; (g) Familoni, O. B.; Kaye, P. T.;
Klaas, P. J. Chem. Commun. 1998, 2563–2564.
Compound 5f: 87%; pale yellow solid; mp 275–277 °C; IR (KBr) 1633 cmÀ1 1H
;
NMR (CDCl3, 300 MHz) d 2.18 (s, 3H), 7.10 (d, J = 8.7 Hz, 1H), 7.27–7.31 (m, 2H),
7.43–7.72 (m, 6H), 7.84 (dd, J = 8.1 and 1.2 Hz, 1H), 8.95 (d, J = 8.4 Hz, 1H), 12.38
(br s, 1H); 13C NMR (CDCl3, 75 MHz) d 14.31, 116.96, 121.68, 122.03, 122.44,
123.90, 126.70, 127.39, 127.56, 127.97, 128.41, 128.73, 128.78, 133.40, 133.62,
137.38, 149.85, 164.21; ESIMS m/z 286 (M++1). Anal. Calcd for C20H15NO: C,
84.19; H, 5.30; N, 4.91. Found: C, 84.28; H, 5.52; N, 4.63.
7. For the coupling reaction with EDC, see: (a) Adam, W.; Groer, P.; Humpf, H.-U.;
Saha-Moller, C. R. J. Org. Chem. 2000, 65, 4919–4922; (b) Holmes, C. P. J. Org.
Chem. 1997, 62, 2370–2380; (c) Sheehan, J. C.; Cruickshank, P. A.; Boshart, G. L. J.
Org. Chem. 1961, 26, 2525–2528.