Synthesis of quinolines from the Baylis-Hillman acetates via the oxidative cyclization of sulfonamidyl radical as the key step

Article abstract of DOI:10.1016/S0040-4039(02)01314-X

Ethyl 3-quinolinecarboxylates 5 were synthesized in good to moderate yields from the Baylis-Hillman acetates 1 via the oxidative cyclization reaction of the N-tosylamidyl radical, which was generated from the rearranged tosylamide derivatives 2 by iodoben

Full text of DOI:10.1016/S0040-4039(02)01314-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6209–6211
Synthesis of quinolines from the Baylis–Hillman acetates via the
oxidative cyclization of sulfonamidyl radical as the key step
Jae Nyoung Kim,* Yun Mi Chung and Yang Jin Im
Department of Chemistry and Institute of Basic Science, Chonnam National University, Kwangju 500-757, Republic of Korea
Received 9 May 2002; revised 27 June 2002; accepted 28 June 2002
Abstract—Ethyl 3-quinolinecarboxylates 5 were synthesized in good to moderate yields from the Baylis–Hillman acetates 1 via the
oxidative cyclization reaction of the N-tosylamidyl radical, which was generated from the rearranged tosylamide derivatives 2 by
iodobenzene diacetate and iodine. © 2002 Elsevier Science Ltd. All rights reserved.
Recently, we have reported on the synthesis of quinoli-
nes from the Baylis–Hillman adducts of N-tosylimines
derived from ortho-halobenzaldehydes.1 In the reaction,
there must be an ortho-halogen atom inevitably at the
benzaldehyde portion in order to generate the quinoline
backbone by SNAr mechanism (Scheme 1). Thus, the
usefulness of the reaction was limited. In this regard we
intended to search for another procedure without the
SNAr step. Oxidative coupling reaction of the N-tosyl-
amidyl radical might provide the route for the forma-
tion of the dihydroquinoline backbone.
similar system.2 Togo and Yokoyama have reported
many brilliant papers on the reaction of N-centered-
and O-centered radicals generated by using iodoben-
zene diacetate and related reagents.3 Thus our ratio-
nale, intramolecular oxidative cyclization reaction of
the N-tosylamidyl radical to dihydroquinoline back-
bone, seemed plausible.
The Baylis–Hillman acetate 1 was prepared as previ-
ously from benzaldehydes and ethyl- or methyl acrylate
followed by acetylation with acetic anhydride in the
presence of DMAP.1 The reaction of 1 and tosylamide
in the presence of K2CO3 in DMF gave the rearranged
tosylamide derivatives 2 in moderate yields (48–76%).
In the reaction side product 3, a 2:1 product of 1 and
tosylamide, was generated in variable amounts (Scheme
2).4 Thus, we performed the reaction with excess use of
tosylamide (5.0 equiv.). The reaction of 2 in the pres-
ence of iodobenzene diacetate (1.6 equiv.) and iodine
(1.0 equiv.) in dichloroethane afforded a mixture of
N-tosyl dihydroquinolines 4 and quinolines 5 in vari-
able ratios depending on the substrate. As shown in
Table 1 (entry 1), two components 4a and 5a were
isolated. Dihydroquinoline 4a could be converted into
5a quantitatively in the normal elimination reaction
conditions (K2CO3, DMF, 120–130°C) by the elimina-
tion of p-toluenesulfinic acid.1 Thus, in other cases we
did not isolate the dihydroquinolines 4. Instead, the
next elimination step was performed directly after usual
aqueous workup. The representative results are shown
in Table 1.5
It has been well recognized that radical reactions are
quite useful for organic synthesis. However, study on
the radical cyclization via nitrogen-centered radicals is
somewhat limited. Fortunately, some papers on the
oxidative coupling of aminyl radicals were reported in a
NHTs
COOEt
COOEt
NHTs
TsNH2/K2CO3
DMF, heating
Xn
Xn
Xn
X
X
X, Xn = F, Cl
COOEt
COOEt
Xn
N
N
Ts
Scheme 1.
Keywords: quinolines; Baylis–Hillman acetates; sulfonamidyl radical;
iodobenzene diacetate.
* Corresponding author. Fax: +82-62-530-3389; e-mail: kimjn@
chonnam.chonnam.ac.kr
It is noteworthy to compare that 5,7-dichloro derivative
5e was synthesized in 80% (entry 6), whereas 7-
monochloro derivative was obtained in 70% from the
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01314-X

6210
J. N. Kim et al. / Tetrahedron Letters 43 (2002) 6209–6211
OAc
E E
COOEt
COOEt
NHTs
TsNH2 (5 eqiuv)
+
K2CO3 (5 equiv)
DMF, 40-50 oC
H
H
N
Ts
1
2
3, E = COOEt
PhI(OAc)2 (1.6 equiv)
I2 (1.0 equiv), ClCH2CH2Cl
60-70 oC, 2 h
COOEt
+
COOEt
1. workup
5
N
2. K2CO3 (4.0 equiv)
DMF, 120-130 oC, 4 h
N
Ts
4
5
Scheme 2.
Table 1. Synthesis of quinolines 5
same starting material 1e by adopting the method in
proceeded without irradiation with tungsten lamp. It is
interesting to note the regioselective formation of
product 5f in the case of entry 7. Radical cyclization
toward 6-bromodihydroquinoline, the precursor of 5f,
is easier than the corresponding 8-bromo analog pre-
our previous paper.1
The plausible reaction mechanism is shown in Scheme 3
as reported in a similar case.2,3 In our case, the reaction

J. N. Kim et al. / Tetrahedron Letters 43 (2002) 6209–6211
6211
COOEt
COOEt
PhI(OAc)2
- AcOH
I2
heating
2
Ts
N
Ts
N
H
H
I
I
AcO
Ph
COOEt
Ts
COOEt
- e, -H+
- TsH
4
5
H
N
N
H
Ts
Scheme 3.
sumably due to the unfavorable steric hindrance during
the radical cyclization stage.
Sakurai, H.; Oka, S. J. Am. Chem. Soc. 1994, 116, 3684.
4. Lee, H. J.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 1999,
40, 4363.
In conclusion we disclosed herein the facile synthesis of
ethyl 3-quinolinecarboxylates from the Baylis–Hillman
acetates via the oxidative cyclization reaction of N-
tosylamidyl radical as the key step.
5. The compounds 4a, 5a and 5c were reported in our
previous paper.1 Other products were also easily character-
1
ized by their H and 13C NMR spectrum. As an example,
typical procedure for the synthesis of 5e is as follows. To
a stirred solution of 1e (317 mg, 1.0 mmol) and p-toluene-
sulfomamide (855 mg, 5.0 mmol) in DMF (5 mL) was
added K2CO3 (690 mg, 5.0 mmol) and stirred at 40–50°C
for 3 h. After the usual workup process and column
chromatographic purification (hexanes/ether, 1:2), pure 2e
was obtained as a white solid, 262 mg (61%): mp 94–96°C;
1H NMR (CDCl3) l 1.32 (t, J=7.1 Hz, 3H), 2.43 (s, 3H),
3.78 (d, J=6.7 Hz, 2H), 4.24 (q, J=7.1 Hz, 2H), 5.25 (brs,
1H), 7.26–7.78 (m, 8H); 13C NMR (CDCl3) l 14.16, 21.54,
40.74, 61.67, 127.18, 127.51, 129.03, 129.54, 129.76, 131.01,
131.56, 134.83, 135.95, 136.22, 138.77, 143.66, 166.58. A
stirred mixture of 2e (128 mg, 0.3 mmol), iodobenzene
diacetate (155 mg, 0.48 mmol) and iodine (77 mg, 0.3
mmol) in dichloroethane (5 mL) was heated to 60–70°C
during 2 h. After usual aqueous workup process the
obtained crude mixture of 4e and 5e was dissolved in
DMF. To the solution K2CO3 (166 mg, 1.2 mmol) was
added and the reaction mixture was heated to 120–130°C
for 4 h. After usual workup process and column chro-
matographic purification (hexanes/ether, 1:4) pure 5e was
obtained as a white solid, 65 mg (80%): mp 128–129°C; IR
Acknowledgements
This work was supported by the grant (No. R02-2000-
00074) from the Basic Research Program of the Korea
Science and Engineering Foundation.
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