Synthesis of 3-Ethoxycarbonyl-4-hydroxyquinoline W-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

Article abstract of DOI:10.1021/ol9903741

(Matrix presented) The reaction of the Baylis-Hillman adducts 1a-e of o-nitrobenzaldehydes and trifluoroacetic acid at 60-70 °C gave 3-ethoxycarbonyl-4-hydroxyquinoline N-oxide derivatives 3a-e in good to moderate yields.

Full text of DOI:10.1021/ol9903741

ORGANIC
LETTERS
2000
Vol. 2, No. 3
343-345
Synthesis of
3-Ethoxycarbonyl-4-hydroxyquinoline
N-Oxides from the Baylis−Hillman
Adducts of o-Nitrobenzaldehydes
Jae Nyoung Kim,* Ka Young Lee, Hyoung Shik Kim, and Tae Yi Kim
Department of Chemistry, Chonnam National UniVersity, Kwangju 500-757, Korea
kimjn@chonnam.chonnam.ac.kr
Received December 1, 1999
ABSTRACT
The reaction of the Baylis−Hillman adducts 1a−e of o-nitrobenzaldehydes and trifluoroacetic acid at 60−70 °C gave 3-ethoxycarbonyl-4-
hydroxyquinoline N-oxide derivatives 3a−e in good to moderate yields.
The Baylis-Hillman reaction is one of the most powerful
carbon-carbon bond-forming methods in organic synthesis.1
The Baylis-Hillman adducts, which are allylic alcohol
derivatives, can be formed most often by the reaction of
activated vinyls and carbonyl compounds.1 Besides the
usefulness of these Baylis-Hillman adducts themselves,
further derivatization with various nucleophilic reagents
toward synthetically useful compounds has been studied in
depth by us and other groups.2
rearranged allylic alcohols 2, we were able to develop a facile
method using trifluoroacetic acid (method v in Scheme 1).4
Scheme 1
The Baylis-Hillman adducts 1 have secondary allylic
alcohol functionality, which can be rearranged to the
thermodynamically more stable primary allylic alcohols 2
via direct3,4 or more frequently indirect three-step methods.5
In the course of our attempts for the one-pot preparation of
Our method works well for the Baylis-Hillman adducts
derived from benzaldehyde, 2-chlorobenzaldehyde, 2-fluo-
robenzaldehyde, and 4-methylbenzaldehyde.4
(1) (a) Ciganek, E. Organic Reactions; John Wiley & Sons: New York,
1997; Vol. 51, pp 201-350. (b) Drewes, S. E.; Roos, G. H. P. Tetrahedron
1988, 44, 4653. (c) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001. (d) Brezezinski, L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem.
Soc. 1997, 119, 4317. (e) Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62,
1521.
(2) (a) Lee, H. J.; Seong, M. R.; Kim, J. N. Tetrahedron Lett. 1998, 39,
6223. (b) Lee, H. J.; Kim, H. S.; Kim, J. N. Tetrahedron Lett. 1999, 40,
4363. (c) Basavaiah, D.; Sarma, P. K. S. J. Chem. Soc., Chem. Commun.
1992, 955. (d) Charette, A. B.; Cote, B.; Monroc, S.; Prescott, S. J. Org.
Chem. 1995, 60, 6888. (e) Basavaiah, D.; Krishnamacharyulu, M.; Hyma,
R. S.; Pandiaraju, S. Tetrahedron Lett. 1997, 38, 2141. (f) Chavan, S. P.;
Ethiraj, K. S.; Kamat, S. K. Tetrahedron Lett. 1997, 38, 7415. (g) Perlmutter,
P.; Tabone, M. Tetrahedron Lett. 1988, 29, 949. (h) Lawrence, R. M.;
Perlmutter, P. Chem. Lett. 1992, 305. (i) Foucaud, A.; El Guemmout, F.
Bull. Soc. Chim. Fr. 1989, 403.
(3) An aqueous sulfuric acid mediated one-pot conversion has been
reported quite recently by Basavaiah et al.: Basavaiah, D.; Kumaragurubaran,
N.; Padmaja, K. Synlett 1999, 1630.
(4) The manuscript for the transformation of secondary allylic alcohols
1 to the corresponding primary allylic alcohols 2 was submitted: Kim, H.
S.; Kim, T. Y.; Lee, K. Y.; Chung, Y. M.; Lee, H. J.; Kim, J. N. Facile
Synthesis of Stereochemically Defined Allylic Alcohol Derivatives from
the Easily Available Baylis-Hillman Adducts.
(5) (a) Hbaieb, S.; Ayed, T. B.; Amri, H. Synth. Commun. 1997, 27,
2825. (b) Beltaief, I.; Hbaieb, S.; Besbes, R.; Amri, H.; Villieras, M.;
Villieras, J. Synthesis 1998, 1765. (c) Charette, A. B.; Cote, B.; Monroc,
S.; Prescott, S. J. Org. Chem. 1995, 60, 6888.
10.1021/ol9903741 CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/11/2000

However, to our surprise the expected allylic alcohol 2a
was not obtained from the o-nitro derivative 1a as in Scheme
2. Instead we obtained a very polar compound which was
alkoxy substituents (entries 4 and 5) are shown in Table 1.
Starting materials 1a-e were prepared from the correspond-
ing o-nitrobenzaldehydes and ethyl acrylate in the presence
of 1,4-diazabicyclo[2.2.2]octane in 83-97% yields.8
Scheme 2
Table 1
identified as 3-ethoxycarbonyl-4-hydroxyquinoline N-oxide
(3a, 82%). The structure of 3a was confirmed unequivocally
by various spectroscopic data including NOE experiments
(Figure 1)6 and chemical transformation (Scheme 3). Deoxy-
Figure 1. NOE results of 3a.
genation of 3a with triphenylphosphine in refluxing THF
gave 4, which was identical in all respects with the authentic
sample prepared by the well-known Gould-Jacobs reaction7
as shown in Scheme 3.
The reaction mechanism could be proposed as shown in
Scheme 4 as Woodrell et al. have reported recently in
mechanistically similar systems.9a Proton abstraction at the
benzylic position by nitro group generates unstable aci-nitro
Scheme 3
Scheme 4
Representative examples including electron-withdrawing
chloro substituents (entries 2 and 3) or electron-donating
(6) A stirred solution of 1a (251 mg, 1 mmol) in trifluoroacetic acid (2
mL) was heated to 60-70 °C during 20 h. After cooling to room
temperature, the reaction mixture was poured into water and extracted with
chloroform (2 × 30 mL). The organic layers were dried (MgSO4) and
evaporated to give crude 3a. Column chromatography on silica gel (CH2-
Cl2/MeOH, 14:1) afforded analytically pure 3a as a white solid, 192 mg
(82%): mp 182-183 °C; IR (KBr) 3463, 2547, 1716, 1617, 1552, 1487,
intermediate I. Cyclization followed by rearomatization gave
N-hydroxy oxazolidine derivative II. Trifluoroacetic acid-
catalyzed dehydration of II produced nitroso intermediate
1349, 1231, 773 cm-1 1H NMR (CDCl3 + few drops of DMSO-d6) δ
;
1.39 (t, J ) 7.2 Hz, 3H), 4.5 (br s, 1H), 4.36 (q, J ) 7.2 Hz, 2H), 7.47 (t,
J ) 8.1 Hz, 1H), 7.74 (t, J ) 8.1 Hz, 1H), 7.95 (d, J ) 8.1 Hz, 1H), 8.38
(d, J ) 8.1 Hz, 1H), 8.73 (s, 1H); 13C NMR (CDCl3) δ 13.78, 60.13, 106.74,
115.02, 125.16, 125.91, 126.68, 132.23, 139.05, 143.52, 164.44, 171.58;
irradiation of the peak of H-2 (s, δ ) 8.73 ppm) produced no NOE of any
protons. Irradiation of the hydroxyl proton (br s, δ ) 4.5 ppm) showed
1.3% enhancement of the intensity of H-2 (s, δ ) 8.73 ppm) and 1.1% of
H-8 (d, δ ) 7.95 ppm); CIMS m/z (rel intensity) 89 (12), 114 (16), 115
(12), 143 (14), 170 (89), 171 (73), 200 (12), 216 (55), 218 (100), 233 (7),
234 (MH+, 1). Anal. Calcd for C12H11NO4: C, 61.80; H, 4.75; N, 6.01.
Found: C, 61.65; H, 4.91; N, 6.00.
344
Org. Lett., Vol. 2, No. 3, 2000

III. Conjugate addition of nitroso to the unsaturated carbonyl
group would form IV. Finally deprotonation of IV afforded
N-oxide derivative 3a. However, we could not exclude the
mechanisms involving radical species or involving electro-
cyclization of the intermediate I entirely at this point.
The reaction of 1a in acetic acid (60-70 °C, 36 h) did
not produce 3a at all. In formic acid (60-70 °C, 36 h) 3a
was also not obtained; instead the formate of 1a was isolated
in low yield (10%). It is interesting to note that the
corresponding B-H adduct prepared from o-nitrobenzalde-
hyde and acrylonitrile did not form the quinoline ring.
Instead, trace amounts of rearranged allylic alcohol derivative
of type 2 were isolated in low yield (10%).
Further studies on the reaction mechanism are currently
underway. Most of all, we are interested in finding the
photochemical conditions for the same transformation. Pho-
tochemically labile protecting groups are very important in
medicinal chemistry and bioorganic chemistry,9 and our final
aims will also be focused on developing a photolabile
connector for the two biologically active moieties.
(7) (a) Carretero, J. C.; Garcia Ruano, J. L.; Vicioso, M. Tetrahedron
1992, 48, 7373. (b) Anderson, G. L. J. Heterocycl. Chem. 1985, 22, 1469.
(c) Kaminsky, D. Fr. Demande 2,002,888 (Chem. Abstr. 1970, 72, 90322v).
Characterization of 4: mp 265-267 °C (lit. 269-270 °C, see ref 7c); IR
(KBr) 3434, 3169, 2982, 2904, 1706, 1623, 1529, 1476, 1380, 1292, 1202,
1141, 766 cm-1; 1H NMR (DMSO-d6) δ 1.29 (t, J ) 7.1 Hz, 3H), 4.23 (q,
J ) 7.1 Hz, 2H), 7.42 (t, J ) 8.1 Hz, 1H), 7.63 (d, J ) 8.1 Hz, 1H), 7.71
(t, J ) 8.1 Hz, 1H), 8.17 (d, J ) 8.1 Hz, 1H), 8.56 (s, 1H), 12.41 (br s,
1H); 13C NMR (DMSO-d6) δ 14.52, 59.77, 109.94, 118.98, 124.90, 125.82,
127.44, 132.61, 139.15, 145.11, 165.00, 173.68.
(8) To a stirred solution of the corresponding o-nitrobenzaldehydes (2
mmol) and ethyl acrylate (0.6 mL) was added DABCO (225 mg, 0.2 mmol),
and the solution was stirred at room temperature for 3 days. After the usual
workup, pure products 1a-e were obtained by column chromatography on
silica gel (hexane/ether, 7:3).
(9) (a) Woodrell, C. D.; Kehayova, P. D.; Jain, A. Org. Lett. 1999, 1,
619. (b) Pirrung, M. C.; Lee, Y. R.; Park, K.; Springer, J. B. J. Org. Chem.
1999, 64, 5042. (c) Pirrung, M. C.; Shuey, S. W. J. Org. Chem. 1994, 59,
3890. (d) Walker, J. W.; Reid, G. P.; McCray, J. A.; Trentham, D. R. J.
Am. Chem. Soc. 1998, 110, 7170. (e) Givens, R. S.; Matuszewski, B. J.
Am. Chem. Soc. 1984, 106, 6860. (f) Amit, B.; Zehavi, U.; Patchornik, A.
J. Org. Chem. 1974, 39, 192. (g) Givens, R. S.; Athey, P. S.; Kueper, L.
W., III.; Matuszewski, B.; Xue, J.-y. J. Am. Chem. Soc. 1992, 114, 8708.
(h) Givens, R. S.; Athey, P. S.; Matuszewski, B.; Kueper, L. W.; Xue, J.-
y.; Fister, T. J. Am. Chem. Soc. 1993, 115, 6001. (i) Pillai, V. N. R. Synthesis
1980, 1. (j) Givens, R. S.; Kueper, L. W., III. Chem. ReV. 1993, 93, 55.
Acknowledgment. We wish to thank Dr. Hyoung Rae
Kim (Korea Research Institute of Chemical Technology) for
his help with NOE experiments. Financial support from the
Ministry of Education of Korea is greatly acknowledged.
OL9903741
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