Efficient construction of 1,2-dihydroquinoline and 1,2,3,4- tetrahydroquinoline rings using tandem Michael-aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2003.10.011

1,2-Dihydroquinolines and a 1,2,3,4-tetrahydroquinoline were efficiently constructed using tandem Michael-aldol reaction starting from N-protected o-aminobenzaldehydes and α,β-unsaturated carbonyl compounds in good yield.

Full text of DOI:10.1016/j.tetlet.2003.10.011

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8925–8929
Efficient construction of 1,2-dihydroquinoline and
1,2,3,4-tetrahydroquinoline rings using tandem Michael-aldol
reaction
Kazuishi Makino,a Osamu Hara,b Yuko Takiguchi,a Takayuki Katano,a Yumiko Asakawa,a
Keiichiro Hatanoc and Yasumasa Hamadaa,*
aGraduate School of Pharmaceutical Sciences, Chiba University, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 460-8503, Japan
cGraduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 30 August 2003; revised 30 September 2003; accepted 6 October 2003
Abstract—1,2-Dihydroquinolines and a 1,2,3,4-tetrahydroquinoline were efficiently constructed using tandem Michael-aldol
reaction starting from N-protected o-aminobenzaldehydes and a,b-unsaturated carbonyl compounds in good yield.
© 2003 Elsevier Ltd. All rights reserved.
1,2,3,4-Tetrahydroquinolines have shown a variety of
biologically activities such as antiarrhythmic, antitu-
mor, and immunosuppressant effects, and attract atten-
tion for their potential as medicines.1 Recently,
martinelline and martinellic acid bearing a synthetically
interesting heterocyclic ring, a pyrroloquinoline skele-
ton, were isolated from the roots of the tropical plant,
Martinella iquitosensis, as the first natural occurring
nonpeptide bradykinin receptor antagonists (Fig. 1).2
Their intriguing structures as well as biological activi-
ties have prompted us to investigate the synthesis of the
pyrroloquinoline ring.3,4 As a preliminary study we first
investigated development of a new method for con-
struction of the 1,2,3,4-tetrahydroquinoline ring.
Although extensive synthetic work has been done to
prepare the tetrahydroquinolines so far,1 there is still a
need for facile construction of the tetrahydroquinoline
skeleton. We describe here a new method for one-step
construction of the 1,2,3,4-tetrahydroquinoline and 1,2-
dihydroquinoline rings using tandem Michael-aldol
Figure 1.
Keywords: 1,2-dihydroquinoline; 1,2,3,4-tetrahydroquinoline; tandem Michael-aldol reaction.
* Corresponding author. Tel.: +81-43-290-2987; fax: +81-43-290-2987; e-mail: hamada@p.chiba-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.011

8926
K. Makino et al. / Tetrahedron Letters 44 (2003) 8925–8929
Table 1.
Condition
Base
Solvent
Yield (%)
5
6
A
B
4 M K2CO3
NaHCO3
CHCl3
THF
84
0
0
81
cyclization reaction5,6 between N-protected o-amino-
benzaldehydes7 and a,b-unsaturated carbonyl com-
pounds in the presence of a quaternary ammonium
salt.8 In this reaction shown in Figure 1, we expected
that the anion of the sulfonamide would attack the
b-position of the a,b-unsaturated carbonyl compound
to generate the corresponding enolate which would be
able to react intramolecularly with the aldehyde to
produce the 1,2,3,4-terahydroquinoline.9
ing the pyrrolidine ring, a possible side reaction, was
not observed but the desired intermolecular reaction
proceeded in a quantitative yield. The ketone conju-
gated with an aromatic ring needed longer reaction
time and higher temperature but the yield was excellent
(entry 2). Unfortunately, cyclohexenone and b,b-disub-
stituted a,b-unsaturated carbonyl compounds did not
react under the conditions. Next, under condition B the
generality was examined. However, the reactions with
Michael acceptors other than 3-penten-2-one were
found to give the tetrahydroquinolines along with a
considerable amount of the 1,2-dihydroquinolines. It
was found that there was no reliability in the biphasic
liquid–solid reaction under condition B due to base-sen-
sitivity of the terahydroquinolines.
We investigated a model reaction using the N-protected
o-aminobenzaldehyde and 3-penten-2-one as shown in
Table 1. The reaction of 4-methoxybenzenesulfonamide
3 with the acceptor (3 equiv.) was carried out under
biphasic liquid–liquid conditions using chloroform and
4 M aqueous potassium carbonate in the presence of
benzyltriethylammonium chloride (BTEACl, 0.2 equiv.)
(condition A). After stirring the mixture at 23°C for 64
h, 1,2-dihydroquinoline 5 was unexpectedly obtained in
84% yield.10 Apparently under these reaction conditions
base-catalyzed dehydration took place. In the absence
of BTEACl, no reaction was observed. Our efforts for
obtaining the tetrahydroquinolines found an alternative
condition using sodium hydrogen carbonate as a base
in tetrahydrofuran in the presence of BTEACl (condi-
tion B).11 The biphasic liquid–solid reaction at 23°C
proceeded to give after 72 h the tetrahydroquinoline 6
in 81% yield. Under 50% potassium hydroxide as a base
desired reaction did not take place but the enone 4 was
completely consumed. Use of a tosyl group as N-pro-
tection gave somewhat low yield due to incomplete
conversion. The relative stereochemistry of 6 was eluci-
dated by the value of coupling constants between Ha
and Hb, and Hb and Hc, respectively (Fig. 2).
A diastereoselective Michael-aldol reaction using a chi-
ral Michael acceptor was also investigated. The reac-
tion of 3 with the chiral acceptor 912 in chloroform at
23°C for 14 h smoothly proceeded to afford a
diastereomeric mixture of the cycloadducts (10a and
10b) in a quantitative yield and in a ratio of 76:24
(Table 3). Stereochemical elucidation of the products
by spectroscopic means was difficult. However, the
esters (11a and 11b) derived from the adducts in two
steps were separable by column chromatography and
the major 11a was fortunately a nice crystalline.13,14
Single-crystal X-ray analysis15 of 11a unambiguously
disclosed the R-configuration of the newly formed
stereocenter, the 2-position of the 1,2-dihydroquinoline
(Fig. 3). The effect of the arenyl group at the sulfon-
amide was briefly investigated. Interestingly, the 2-
naphthyl derivative 14 also gave the cycloadducts in a
quantitative yield and was found to improve somewhat
the diastereoselectivity to a ratio of 83:17.
We next examined a new Michael-aldol reaction of the
N-protected o-aminobenzaldehydes with some Michael
acceptors to clarify the generality of these reaction
conditions. The results are summarized in Table 2.
First, under condition A several reactions were exam-
ined. The a,b-unsaturated aldehyde easily reacted with
arylsulfonamide 3 (entries 4 and 5). The elongation of
the alkyl chain and introduction of a functional group
as a nitrile and urethane function were compatible with
the reaction under the conditions (entries 3 and 5). In
the case of entry 5, the intramolecular cyclization form-
Figure 2.

K. Makino et al. / Tetrahedron Letters 44 (2003) 8925–8929
8927
Table 2.
Entrya
R1
R2
Conditions
Yield (%)
1
2
3
4
5
Me
Me
Me
Ph
Me
H
rt, 64 h
rt–45°C, 7 days
rt, 68 h
rt, 27 h
rt, 68 h
84
88 (94)b
92 (97)b
73
-(CH2)2-CN
Me
-(CH2)3-NHBoc
H
82 (98)b
a All reactions were performed using 3 (0.24 mmol) and acceptor 7 (0.72 mmol, 3 equiv.).
b The yields in parentheses are based on consumed starting materials.
Table 3.
Entry
Sulfonamide
Conditions
Yield
Ratio
1
2
3
4
3
rt, 14 h
rt, 15 h
rt, 16.5 h; 50°C, 21 h
rt, 16.5 h; 50°C, 21 h
Quant.
Quant.
Quant.
Quant.
76:24
60:40
77:23
83:17
12
13
14
Figure 3.
In summary, a new efficient method for the synthesis of
1,2-dihydroquinolines and 1,2,3,4-tetrahydroquinoline
from N-protected o-aminobenzaldehydes and a,b-
unsaturated carbonyl compounds by tandem Michael-
aldol reaction has been developed. It is demonstrated
that the method can be also used for diastereo-
selective construction of 1,2-dihydroquinolines. Further
investigation directed towards total synthesis of
martinelline is now ongoing according to this proce-
dure.

8928
K. Makino et al. / Tetrahedron Letters 44 (2003) 8925–8929
Ohnishi, M.; Taniguchi, N.; Fukumoto, K.; Kabuto, C.
References
J. Am. Chem. Soc. 1993, 115, 8107–8115; (k) Ogiku, T.;
Yoshida, S.; Takahashi, M.; Kuroda, T.; Ohmizu, H.;
Iwasaki, T. Tetrahedron Lett. 1992, 33, 4473–4476; (l)
Ihara, M.; Ohnishi, M.; Takano, M.; Makita, K.;
Taniguchi, N.; Fukumoto, K. J. Am. Soc. Chem. 1992,
114, 4408–4410; (m) Xia, Y.; Kozikowski, A. P. J. Am.
Chem. Soc. 1989, 111, 4116–4117; (n) Kobayashi, S.;
Mukaiyama, T. Chem. Lett. 1986, 221–224.
1. Katrizky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031–15070.
2. Witherup, K. M.; Ransom, R. W.; Graham, A. C.;
Bernard, A. M.; Salvatore, M. J.; Lumma, W. C.; Ander-
son, P. S.; Pitzenberger, S. M.; Verga, S. L. J. Am. Chem.
Soc. 1995, 117, 6682–6685.
3. (a) Batey, R. A.; Powell, D. A. Chem. Commun. 2001,
2362–2363; (b) He, Y.; Mahmud, H.; Wayland, B. R.;
Dias, H. V. R.; Lovely, C. J. Tetrahedron Lett. 2002, 43,
1171–1174; (c) Malassene, R.; Sanchez-Bajo, L.; Toupet,
L.; Hurvois, J. P.; Moinet, C. Synlett 2002, 1500–1504;
(d) Nyerges, M.; Fejes, I.; Toke, L. Synthesis 2002,
1823–1828; (e) Mahmud, H.; Lovely, C. J.; Dias, H. V.
R. Tetrahedron 2001, 57, 4095–4105; (f) Hadden, M.;
Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.; Thomp-
son, N. Tetrahedron 2001, 57, 5615–5624; (g) Frank, K.
E.; Aube, J. J. Org. Chem. 2000, 65, 655–666; (h)
Nieman, J. A.; Ennis, M. D. Org. Lett. 2000, 2, 1395–
1397; (i) Nyerges, M.; Fejes, I.; Toke, L. Tetrahedron
Lett. 2000, 41, 7951–7954; (j) Snider, B. B.; Ahn, Y.;
Foxman, B. M. Tetrahedron Lett. 1999, 40, 3339–3342;
(k) Hadden, M.; Stevenson, P. J. Tetrahedron Lett. 1999,
40, 1215–1218; (l) Batey, R. A.; Simoncic, P. D.; Lin, D.;
Smyj, R. P.; Lough, A. J. Chem. Commun. 1999, 651–652;
(m) Lovely, C. J.; Mahmud, H. Tetrahedron Lett. 1999,
40, 2079–2082; (n) Kim, S. S.; Cheon, H. G.; Kang, S.
K.; Yum, E. K.; Choi, J. K. Heterocycles 1998, 48,
221–226; (o) Gurjar, M. K.; Pal, S.; Rao, A. V. R.
Heterocycles 1997, 45, 231–234; (p) Ho, T. C. T.; Jones,
K. Tetrahedron 1997, 53, 8287–8294.
7. Yavari, I.; Esmaili, A. A.; Ramazani, A.; Bolbol-Amiri,
A. R. Monatsh. Chem. 1997, 128, 927–931.
8. Shioiri, T.; Arai, S. In Stimulated Concepts in Chemistry;
Vogtle, F.; Stoddart, J. F.; Shibasaki, M., Eds.; New
York: Wiley-VCH, 2000; pp. 123–143.
9. For similar cyclization using N-alkyl o-aminophenyl-
ketones and N-methyl o-aminobenzaldehyde, see (a)
Kobayashi, K.; Nakanishi, R.; Shimizu, A.; Kitamura,
T.; Morikawa, O,; Konishi, H. J. Chem. Soc., Perkin
Trans. 1 1999, 1547–1551; (b) Apple, I. A.; Meth-Cohn,
O. ARKIVOC 2002, 4–14.
10. Typical procedure for condition A: To a mixture of 2-(4-
methoxybenzenesulfonylamino)benzaldehyde 3 (70 mg,
0.24 mmol), enone 4 (0.72 mmol), and BnEt3NCl (10 mg,
0.04 mmol) in CHCl3 (1 mL) was added 4 M aq. K2CO3
(1 mL) at 23°C under an argon atmosphere. After stirring
the mixture for 64 h at 23°C, the mixture was diluted
with EtOAc. The organic layer was washed with H2O and
saturated aqueous NaCl, and dried over Na2SO4. After
removal of the solvent, the residue was purified with
column chromatography. The product was eluted with
EtOAc–n-hexane (1:2) to give the 1,2-dihydroquinoline as
solids in 84% yield: mp 142–143°C (EtOAc–n-hexane); IR
1
(KBr) 2969, 2928, 1660, 1595 1260, 1163 cm−1; H NMR
4. For total synthesis of martinellic acid and martinelline,
see: (a) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J.
Org. Chem. 2003, 68, 442–451; (b) Powell, D. A.; Batey,
R. A. Org. Lett. 2002, 4, 2913–2916; (c) Xia, C.; Heng,
L.; Ma, D. Tetrahedron Lett. 2002, 43, 9405–9409; (d)
Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3,
2189–2191; (e) Hadden, M.; Nieuwenhuyzen, M.;
Osborne, D.; Stevenson P. J.; Thompson, N. Tetrahedron
Lett. 2001, 42, 6417–6419; (f) Snider, B. B.; Ahn, Y.;
O’Hare, S. M. Org. Lett. 2001, 3, 4217–4220.
(CDCl3) l 1.09 (d, 3H, J=7 Hz), 2.12 (s, 3H), 3.79 (s,
3H), 5.50 (q, 1H, J=6.9 Hz), 6.71 (d, 2H, J=9.2 Hz),
6.82 (s, 1H), 7.1 (dd, 1H, J=7.6 Hz, 1.5 Hz), 7.23 (d, 2H,
J=9.0 Hz) 7.30 (dt, 1H, J=7.5Hz, 1.1 Hz), 7.46 (dd, 1H,
J=8.1 Hz, 1.6 Hz), 7.79 (d, 1H, J=8.1 Hz); 13C NMR
(CDCl3) l 19.0, 24.9, 48.8, 55.5, 113.5, 126.7, 127.1,
128.4, 128.5, 128.9, 130.4, 130.9, 131.9, 134.2, 138.5,
162.9, 195.2; MS (FAB, NBA) 358 (M+H+). Anal. calcd
for C19H19NO4S: C, 63.85; H, 5.36; N, 3.92. Found: C,
63.9; H, 5.24; N, 3.86.
5. For a review of tandem reactions and Michael-aldol
reaction, see: (a) Tietze, L. F. Chem. Rev. 1996, 96,
115–136; (b) Takasu, K. Yakugaku Zasshi 2001, 121,
887–898.
11. Typical procedure for condition B: The reaction was car-
ried out by using sodium hydrogen carbonate as a base
and tetrahydrofuran as a solvent instead of 4 M K2CO3
and CHCl3 according to condition A. Chromatography
of the crude material using EtOAc–n-hexane (1:1) as an
eluant gave the tetrahydroquinoline in 81% yield: IR
6. (a) Kataoka, T.; Kinoshita, S.; Kinoshita, H.; Fujita, M.;
Iwamura, T.; Watanabe, S. Chem. Commun. 2001, 1958–
1959; (b) Richards, E. L.; Murphy, P. J.; Dinon, F.;
Fratucello, S.; Brown, P. M.; Gelbrich, T.; Hursthouse,
M. B. Tetrahedron 2001, 57, 7771–7784; (c) Yang, X.-F.;
Hou, X.-L.; Dai, L.-X. Tetrahedron Lett. 2000, 41, 4431–
4434; (d) Schneider, C.; Reese, O. Angew. Chem., Int. Ed.
2000, 39, 2948–2950; (e) Takasu, K.; Ueno, M.; Ihara, M.
Tetrahedron Lett. 2000, 41, 2145–2148; (f) Mitsudera, H.;
Kakehi, A.; Kamimura, A. Tetrahedron Lett. 1999, 40,
7389–7392; (g) Arai, T.; Sasai, H.; Aoe, K.; Okamura,
K.; Date, T.; Shibasaki, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 104–106; (h) Ihara, M.; Taniguchi, T.; Yamada,
M.; Tokunaga, Y.; Fukumoto, K. Tetrahedron Lett.
1995, 36, 8071–8074; (i) Ye, B.; Qiao, L.-X.; Zhang,
Y.-B.; Wu, Y.-L. Tetrahedron 1994, 50, 9061–9066; (j)
Ihara, M.; Taniguchi, T.; Makita, K.; Takano, M.;
1
(neat) 3492, 2969, 2925, 1712 cm−1; H NMR (CDCl3) l
1.36 (3H, d, J=6.4 Hz), 2.24 (3H, s), 2.55 (1H, dd,
J=8.8, 10.6 Hz), 3.61 (1H, d, J=10.6 Hz), 3.83 (3H, s),
4.42 (1H, dq, J=6.4, 8.8 Hz), 6.85 (2H, d, J=9.0 Hz),
7.28–7.43 (5H, m), 7.66 ( 1H, d, J=7.7 Hz); 13C NMR
(CDCl3) l 24.3, 32.2, 53.2, 55.5, 66.0, 67.8, 114.1, 122.4,
126.8, 127.9, 128.2, 129.0, 130.3, 133.1, 137.1, 163.0;
HRMS (FAB) calcd for C19H22NO5S 376.1219 (M+H+),
found 376.1246.
12. The chiral acceptor was prepared from the known (4S)-3-
(2,2-dimethyl-[1,3]dioxolan-4-yl)acrylic acid ethyl ester in
two steps: (1) reduction of the ester with diisobutylalu-
minum hydride in methylene chloride in 66% yield and
(2) oxidation of the allyl alcohol with activated man-
ganese dioxide in 93% yield.

K. Makino et al. / Tetrahedron Letters 44 (2003) 8925–8929
8929
13. The esters 11a and 11b were prepared from a mixture of
10a and 10b in two steps: (1) oxidation of the aldehyde to
the carboxylic acid using NaClO2 in aqueous t-BuOH in
the presence of KH2PO4 and 2-methyl-2-butene in a
quantitative yield and (2) esterification using iodomethane
in dimethylformamide in the presence of KHCO3 in 77%
yield.
(CDCl3) l 24.3, 25.0, 52.0, 54.5, 55.5, 64.7, 76.7, 109.2,
113.6, 124.7, 126.4, 127.2, 127.6, 128.3, 129.0, 129.9, 130.4,
134.9, 135.9, 163.2, 165.1. Anal. calcd for C23H25NO7S: C,
60.12; H, 5.48; N, 3.05. Found: C, 60.14; H, 5.41; N, 3.01
15. Crystallographic data for 11a: formula C23H25NO7S, FW=
459.5, orthorhombic, space group P212121, a=8.337(1),
3
,
,
b=12.901(1), c=21.389(1) A, V=2300.4(6) A , Z=8,
Nonius Kappa CCD, Mo Ka, R=0.047, Rw=0.046.
CCDC 218556 contains the supplementary crystallographic
data for this paper. These data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
14. 11a: mp 146–147°C [h]D22=+431.3 (c 0.62, CHCl3); IR (KBr)
2979, 1706, 1595, 1312, 1160 cm−1; 1H NMR (CDCl3) l 0.86
(3H, s), 1.14 (3H, s), 3.77 (3H, s), 3.78 (3H, s), 3.94–4.02
(1H, m), 4.18–4.25 (2H, m), 5.34 (1H, d, J=3.1 Hz),
6.68–6.72 (2H, m), 7.11 (1H, dd, J=7.6, 1.5 Hz), 7.16 (3H,
s), 7.20 (1H, dt, J=7.5, 1.1 Hz), 7.24–7.28 (2H, m),
7.36–7.40 (1H, m), 7.81 (1H, d, J=8.1 Hz); 13C NMR