A novel three-component reaction of anilines, formaldehyde and β-diketones: Simple synthesis of 3-spirosubstituted 1,2,3,4- tetrahydroquinolines

Article abstract of DOI:10.1055/s-2006-956450

A new three-component reaction of cyclic β-diketones, formaldehyde and substituted anilines is described. The reaction provides a simple synthetic method for the one-pot preparation of 3-spirosubstituted 1,2,3,4- tetrahydroquinolines containing different substituents at the N-atom. This reaction also gives the opportunity to unite in one molecule the 1,2,3,4-tetrahydroquinoline, cyclic β-dicarbonyl, 2-azaspiro and some other (e.g., benzylic, bicyclic, adamantyl) fragments. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956450

LETTER
3349
A Novel Three-Component Reaction of Anilines, Formaldehyde and b-Dike-
tones: Simple Synthesis of 3-Spirosubstituted 1,2,3,4-Tetrahydroquinolines
S
imple Synthesis o
l
f
3-Sp
i
a
tituted 1, 2,3
k
, 4-Tetrahyd
s
roquinolin
e
es i P. Kadutskii,* Nikolas G. Kozlov
Laboratory of Organic Catalysis, Institute of Physical Organic Chemistry, The National Academy of Sciences of Belarus, 13 Surganov st.,
Minsk 220072, Belarus
Fax +375(17)2841679; E-mail: kadutskii@gmail.com
Received 31 August 2006
mixture in a nearly pure state with a good yield.4 The
Abstract: A new three-component reaction of cyclic b-diketones,
results are summarised in Table 1, entries 1–8.
formaldehyde and substituted anilines is described. The reaction
provides a simple synthetic method for the one-pot preparation of 3-
spirosubstituted 1,2,3,4-tetrahydroquinolines containing different
substituents at the N-atom. This reaction also gives the opportunity
to unite in one molecule the 1,2,3,4-tetrahydroquinoline, cyclic b-
dicarbonyl, 2-azaspiro and some other (e.g., benzylic, bicyclic, ad-
amantyl) fragments.
As it is known various N-monosubstituted anilines can
easily be obtained via reductive amination of ketones or
aldehydes.5
Table 1 One-Pot Condensation of Substituted Anilines, Formalde-
hyde and Cyclic b-Diketones – Synthesis of 1¢,4¢-Dihydro-
2H,2¢H,6H-spiro[cyclohexane-1,3¢-quinoline]-2,6-diones 4a–k7
Key words: b-diketones, multicomponent reaction, Mannich reac-
tion, azaspiro compounds, 1,2,3,4-tetrahydroquinolines
Entry
R
R1
R2
Prod- Yield
uct
(%)
Various natural products and pharmaceutical agents con-
tain the tetrahydroquinoline moiety that exhibits a broad
range of biological activities.1 Many new methods for the
synthesis of 1,2,3,4-tetrahydroquinoline derivatives have
been developed.2 Most of these reactions lead to the for-
mation of 2- and 4-substituted tetrahydroquinoline deriv-
atives. However, only a few methods are currently
available for obtaining the tetrahydroquinoline ring sys-
tem with substituents at position 3.3
1
OMe
H
4a
75
OMe
OMe
O
2
3
OMe
OMe
H
4b
4c
78
74
O
Me
Br
4
5
Me
Me
Me
Me
4d
4e
77
81
Herein, we wish to report a new simple method for the
synthesis of 3-substituted 1,2,3,4-tetrahydroquinoline de-
rivatives via a one-pot condensation of N-monosubstitut-
ed anilines, formaldehyde and cyclic b-diketones
(Scheme 1).
F
OMe
OMe
O
6
7
OMe
OMe
Me
Me
4f
77
85
R1
R2
R2
HN
R2 R2
O
O
R
O
4g
OMe
O
O
N
R1
4
O
H
H
R
OMe
O
1
2
3
8
9
Me
Me
H
4h
4i
78
79
Scheme 1
O
OMe
In a general experimental procedure a solution of substi-
tuted aniline 1, formaldehyde (2, as paraformaldehyde)
and 1,3-cyclohexanedione 3 in EtOH was refluxed for
five minutes. On cooling to room temperature a spirotet-
rahydroquinoline derivative 4 precipitated out from the
10
11
Me
Me
H
4j
87
91
Me
4k
SYNLETT 2006, No. 19, pp 3349–3351
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-956450; Art ID: G24606ST
© Georg Thieme Verlag Stuttgart · New York

3350
A. P. Kadutskii, N. G. Kozlov
LETTER
Thereby, the reaction reported here represents a conve-
nient way to introduce different radicals into the 1,2,3,4-
tetrahydroquinoline moiety as the N-substituent starting
from the corresponding ketones or aldehydes.
References and Notes
(1) (a) Perry, N. B.; Blunt, J. W.; Munro, M. H. G.; Sakai, R. J.
Org. Chem. 1988, 53, 4127. (b) Konishi, M.; Zercher, C. K.;
Bechkam, S.; Haubold, E.-M. J. Am. Chem. Soc. 1990, 112,
3715. (c) Wender, P. A.; Zercher, C. K.; Bechkam, S.;
Haubold, E.-M. J. Org. Chem. 1993, 58, 5867. (d) Uchida,
M.; Chihiro, M.; Morita, S.; Kanbe, T.; Yamashita, H.;
Yamasakai, K.; Yabuuchi, Y.; Nakagawa, K. Chem. Pharm.
Bull. 1989, 37, 2109. (e) Carling, R. W.; Leeson, P. D.;
Mosely, A. M.; Smith, J. D.; Saywell, K.; Tricklebank, M.
D.; Kemp, J. A.; Marshal, G. R.; Foster, A. C.; Grimwood,
S. Bioorg. Med. Chem. Lett. 1993, 3, 65. (f) Kam, T.-S.;
Subramaniam, G. Tetrahedron Lett. 2004, 45, 3521.
(2) (a) Weinreb, S. M. In Comprehensive Organic Synthesis,
Vol. 5; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
1991, 401. (b) Bunce, R. A.; Herron, D. M.; Johnson, L. B.;
Kotturi, S. J. Org. Chem. 2001, 66, 2822. (c) Jia, X.; Lin,
H.; Huo, C.; Zhang, W.; Lu, J.; Yang, L.; Zhao, G.; Liu, Z.-
L. Synlett 2003, 1707. (d) Nagarajan, R.; Magesh, C. J.;
Perumal, P. T. Synthesis 2004, 69. (e) Yadav, J. S.; Reddy,
B. V. S.; Padmavani, B. Synthesis 2004, 405. (f) Ding, K.;
Flippen-Anderson, J.; Deschamps, J. R.; Wang, S.
To illustrate the methodology we synthesised tetrahydro-
quinolines containing cyclic (cyclododecyl, entry 9), bi-
cyclic (5,6,6-trimethylbicyclo[2.2.1]hept-2-yl, entry 10)
and tricyclic (2-adamantyl, entry 11) fragments at the N-
atom.6
A possible mechanism for the reported condensation is
outlined in Scheme 2. Accordingly, the b-diketone 3 re-
acts with the amine 1 and formaldehyde (2) via the Man-
nich reaction to give a Mannich base 5. The last one
undergoes a Hofmann–Martius-type rearrangement8 lead-
ing to the formation of an aminodiketone 6 which, in turn,
cyclises to the final product 4 via the second intramolecu-
lar Mannich reaction.
1 + 2 + 3
Tetrahedron Lett. 2004, 45, 1027. (g) Fadel, F.; Titouani, S.
L.; Soufiaoui, M.; Ajamay, H.; Mazzah, A. Tetrahedron
Lett. 2004, 45, 5905. (h) Ori, M.; Toda, N.; Takami, K.;
Tago, K.; Kogen, H. Tetrahedron 2005, 61, 2075.
Mannich
(i) Zhang, W.; Guo, Y.; Liu, Z.; Jin, X.; Yang, L.; Liu, Z.-L.
Tetrahedron 2005, 61, 1325.
R
R
(3) (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031. (b) Baraznenok, I. L.; Nenajdenko, V. G.;
Churakov, A. V.; Nesterenko, P. N.; Balenkova, E. S. Synlett
2000, 514. (c) De, D.; Seth, M.; Bhadori, A. P. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1990, 29, 70.
(d) Lombardo, L. J.; Camuso, A.; Clark, J.; Fager, K.; Gullo-
Brown, J.; Hunt, J. T.; Inigo, I.; Kan, D.; Koplowitz, B.; Lee,
F.; McGlinchey, K.; Qian, L.; Ricca, C.; Rovnyak, G.;
Traeger, S.; Tokarski, J.; Williams, D. K.; Wu, L. I.; Zhao,
Y.; Manne, V.; Bhide, R. S. Bioorg. Med. Chem. Lett. 2005,
15, 1895. (e) Santangelo, F.; Casagrande, C.; Miragoli, G.;
Vecchietti, V. Eur. J. Med. Chem. 1994, 29, 877. (f) Lewis,
R. J.; Francis, Ch. A.; Lehr, R. E.; Blank, C. L.-R.
O
O
Hofmann–Martius-type
rearrangement
N
NH
R1
R1
R2
R2
R2
R2
O
O
5
6
+ 2
Mannich
4
Tetrahedron 2000, 56, 5345.
(4) General Procedure for Preparation of 1¢,4¢-dihydro-
2H,2¢H,6H-spiro[cyclohexane-1,3¢-quinoline]-2,6-diones
(4a–i).
Scheme 2
It is remarkable that the 1,2,3,4-tetrahydroquinolines 4a–
k contain the intact cyclic b-dicarbonyl system that can be
utilised for further chemical modification of the substanc-
es. Moreover, these compounds, possessing the 2-aza-
spiro ring system, are structurally similar to the Nitraria
alkaloids.9 Thus, the reported condensation gives an inter-
esting opportunity to unite four unique fragments in one
molecule by means of a simple synthetic procedure. For
example, the product 4k simultaneously contains 1,2,3,4-
A solution of amine 1 (2 mmol) and paraformaldehyde (8
mmol) in EtOH (25 mL) was prepared by gentle warming
(2–3 min). Diketone 3 (2 mmol) was added to this solution
in one portion and the mixture was heated under reflux for
5 min. After cooling to r.t. the colourless precipitate was
filtered off, washed with EtOH (2 × 5 mL) and dried to give
4. The yields reported in Table 1 are unoptimised and
additional crops of 4 could be obtained upon concentration
of the mother liquors.
(5) (a) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.;
Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
3849. (b) Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K.
G. Tetrahedron Lett. 1990, 31, 5595. (c) Salvatore, R. N.;
Yoon, Ch. H.; Jung, K. W. Tetrahedron 2001, 57, 7785.
(6) The N-monosubstituted anilines were prepared by reductive
amination of the desired ketones with the corresponding
primary anilines. Sodium triacetoxyborohydride was used as
a reducing agent in the reaction as reported in ref. 5a.
tetrahydroquinoline,
spiro[5.5]undecane and 2-adamantyl fragments in its
structure.
cyclic
b-dicarbonyl,
2-aza-
In conclusion, we have demonstrated that 3-substituted
1,2,3,4-tetrahydroquinoline derivatives are easily pre-
pared from readily accessible anilines, formaldehyde and
cyclic b-diketones in a simple one-pot procedure. Also
this method allows for the simple introduction of different
substituents at the 1-position of the 1,2,3,4-tetrahydro-
quinoline ring system.
Synlett 2006, No. 19, 3349–3351 © Thieme Stuttgart · New York

LETTER
Simple Synthesis of 3-Spirosubstituted 1,2,3,4-Tetrahydroquinolines
3351
(7) All new compounds gave satisfactory 500 MHz 1H NMR
and 100 MHz 13C NMR and IR spectral data.
Selected Physical Data.
1¢-(5,5,6-Trimethylbicyclo[2.2.1]hept-2-yl)-6¢-methyl-
1¢,4¢-dihydro-2H,2¢H,6H-spiro[cyclohexane-1,3¢-
quinoline]-2,6-dione (4j).
1¢-(1,3-Benzodioxol-5-ylmethyl)-6¢-methoxy-1¢,4¢-
dihydro-2H,2¢H,6H-spiro[cyclohexane-1,3¢-quinoline]-
2,6-dione (4b).
Mp 156 °C. IR (KBr): 3407, 2964, 2893, 2865, 2833, 1728,
1702, 1619, 1505, 1416, 1265, 1170, 1019, 819, 812 cm–1.
1H NMR (CDCl3): d = 0.87 (s, 3 H), 0.91 (s, 3 H), 1.03 (d,
J = 7.5 Hz, 3 H), 1.31 (dd, J = 1.1, 10.3 Hz, 1 H), 1.49 (dt,
J = 3.6, 13.0 Hz, 1 H), 1.70 (d, J = 3.7 Hz, 1 H), 1.75–1.95
(m, 3 H), 2.00 (dq, J = 1.1, 7.4 Hz, 1 H), 2.05–2.13 (m, 1 H),
2.16 (d, J = 2.0 Hz, 1 H), 2.26 (s, 3 H), 2.51 (dt, J = 5.3, 15.5
Hz, 1 H), 2.72 (dt, J = 5.3, 15.5 Hz, 1 H), 2.81–2.97 (m, 2 H),
2.88 (d, J = 11.0 Hz, 1 H), 2.91 (d, J = 13.0 Hz, 1 H), 3.16
(d, J = 13.0 Hz, 1 H), 3.36 (dt, J = 3.9, 9.7 Hz, 1 H), 3.71 (d,
J = 11.0 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.85 (s, 1 H),
6.97 (d, J = 8.0 Hz, 1 H). 13C NMR (CDCl3): d = 15.81,
17.96, 20.50, 24.72, 26.31, 32.46, 34.84, 35.80, 37.03,
37.40, 37.88, 39.67, 48.17, 49.38, 49.93, 60.55, 71.76,
114.87, 125.63, 127.47, 127.86, 128.07, 146.13, 205.77,
206.23. Anal. Calcd for C25H33NO2: C, 79.11; H, 8.76; N,
3.69. Found: C, 79.10; H, 8.74; N, 3.70.
Mp 148 °C. IR (KBr): 3439, 3404, 2931, 2904, 2830, 1726,
1701, 1504, 1489, 1444, 1242, 1151, 1036 cm–1. 1H NMR
(CDCl3): d = 1.82 (m, 1 H), 2.02 (m, 1 H), 2.60–2.75 (m, 4
H), 3.21 (s, 2 H), 3.46 (s, 2 H), 3.75 (s, 3 H), 4.30 (s, 2 H),
5.95 (s, 2 H), 6.55–6.63 (m, 2 H), 6.71–6.80 (m, 4 H). 13
C
NMR (CDCl3): d = 19.05, 30.64, 37.86, 55.21, 56.25, 56.33,
67.07, 101.69, 108.37, 109.03, 113.10, 113.72, 115.39,
120.92, 123.33, 132.85, 139.13, 147.41, 148.70, 152.88,
206.33. MS (70 eV): m/z (%) = 135 (82), 252 (100), 393 (23)
[M+], 394 (5) [M + H+]. Anal. Calcd for C23H23NO5: C,
70.21; H, 5.89; N, 3.56. Found: C, 70.21; H, 5.90; N, 3.57.
1¢-(3,4-Dimethoxybenzyl)-6¢-methoxy-4,4-dimethyl-1¢,4¢-
dihydro-2H,2¢H,6H-spiro[cyclohexane-1,3¢-quinoline]-
2,6-dione (4g).
Mp 159 °C. IR (KBr): 2963, 2916, 2834, 1722, 1691, 1511,
1459, 1259, 1229, 1201, 1160, 1137, 1053, 1026 cm–1. 1H
NMR (CDCl3): d = 0.88 (s, 3 H), 1.05 (s, 3 H), 2.43 (d,
J = 14.0 Hz, 2 H), 2.63 (d, J = 14.0 Hz, 2 H), 3.20 (s, 2 H),
3.41 (s, 2 H), 3.75 (s, 3 H), 3.85 (s, 3 H), 3.89 (s, 3 H), 4.31
(s, 2 H), 6.55–6.63 (m, 2 H), 6.76–6.86 (m, 4 H). 13C NMR
(CDCl3): d = 27.77, 29.99, 30.62, 31.51, 51.65, 55.51, 55.90,
56.24, 56.57, 56.65, 65.89, 66.51, 110.96, 111.83, 112.95,
113.64, 115.37, 119.98, 123.65, 131.53, 139.32, 148.83,
150.04, 152.93, 206.16. MS (70 eV): m/z (%) = 151 (100),
252 (63), 437 (12) [M+], 438 (3) [M + H+]. Anal. Calcd for
C26H31NO5: C, 71.37; H, 7.14; N, 3.20. Found: C, 71.37; H,
7.14; N, 3.21.
1¢-Cyclododecyl-6¢-methoxy-1¢,4¢-dihydro-2H,2¢H,6H-
spiro[cyclohexane-1,3¢-quinoline]-2,6-dione (4i).
Mp 186 °C. IR (KBr): 3431, 2937, 2925, 2859, 1717, 1692,
1611, 1580, 1505, 1256, 1239, 1052 cm–1. 1H NMR
(CDCl3): d = 1.30–1.50 (m, 20 H), 1.59–1.70 (m, 2 H), 1.74–
1.88 (m, 1 H), 2.06–2.18 (m, 1 H), 2.62–2.67 (m, 2 H), 2.81–
2.87 (m, 2 H), 3.15 (s, 2 H), 3.35 (s, 2 H), 3.74 (s, 3 H), 3.88
(t, J = 5.8 Hz, 1 H), 6.68 (br s, 2 H), 6.37 (s, 1 H). 13C NMR
(CDCl3): d = 18.31, 22.47, 22.60, 23.01, 23.77, 23.97, 26.42,
29.65, 37.22, 48.07, 50.91, 55.42, 65.98, 111.58, 112.12,
115.02, 123.10, 138.75, 151.28, 205.74. Anal. Calcd for
C27H39NO3: C, 76.20; H, 9.24; N, 3.29. Found: C, 76.21; H,
9.22; N, 3.28.
1¢-(2-Adamantyl)-6¢-methyl-4,4-dimethyl-1¢,4¢-dihydro-
2H,2¢H,6H-spiro[cyclohexane-1,3¢-quinoline]-2,6-dione
(4k).
Mp 205 °C. IR (KBr): 3440, 2919, 2900, 2862, 1725, 1695,
1502, 1248, 1155, 819, 519 cm–1. 1H NMR (CDCl3):
d = 0.94 (s, 3 H), 1.07 (s, 3 H), 1.56 (d, J = 12.5 Hz, 2 H),
1.75 (s, 2 H), 1.83–1.96 (m, 6 H), 2.06 (d, J = 12.5 Hz, 2 H),
2.24 (s, 3 H), 2.28 (br s, 2 H), 2.56 (d, J = 14.0 Hz, 2 H), 2.80
(d, J = 14.0 Hz, 2 H), 3.05 (s, 2 H), 3.51 (s, 3 H), 6.56 (d,
J = 8.0 Hz, 1 H), 6.88 (s, 1 H), 6.93 (d, J = 8 Hz, 1 H). 13
C
NMR (CDCl3): d = 20.45, 27.02, 27.51, 28.02, 29.00, 29.77,
30.65, 32.26, 34.37, 37.57, 37.59, 46.18, 51.21, 60.98,
69.57, 114.64, 125.76, 127.58, 127.84, 128.30, 144.59,
206.01. Anal. Calcd for C27H35NO2: C, 79.96; H, 8.70; N,
3.45. Found: C, 80.00; H, 8.73; N, 3.42.
(8) For the original work, see: (a) Hofmann, A. W.; Martius, C.
A. Ber. Dtsch. Chem. Ges. 1871, 4, 742. (b) For
mechanistic considerations, see: Drumm, P. J.; O’Connor,
W. F.; Reilly, J. J. Am. Chem. Soc. 1940, 62, 1241. For
synthetic applications of the rearrangement, see:
(c) Martínez, R.; Cortés, E.; Toscano, R. A.; Linzaga, I. J.
Heterocycl. Chem. 1990, 27, 363. (d) Martínez, R.; Cortés,
E.; Toscano, R. A.; Alfaro, L. J. J. Heterocycl. Chem. 1990,
27, 1273. (e) Martínez, R.; Cortés, E.; Toscano, R. A.;
Alfaro, L. J.; Avila, J. G. J. Heterocycl. Chem. 1991, 28, 589.
(9) For chemistry of 2-azaspiro compounds, see: Alonso, E. R.;
Tehrani, K. A.; Boelens, M.; De Kimpe, N. Synthesis 2005,
1726; and literature cited therein.
Synlett 2006, No. 19, 3349–3351 © Thieme Stuttgart · New York