A novel three-component reaction of anilines, formaldehyde and dimedone: simple synthesis of spirosubstituted piperidines

Article abstract of DOI:10.1016/j.tetlet.2008.04.160

A three-component condensation of anilines with dimedone and formaldehyde leads to the formation of 3,5-dispirosubstituted piperidines. This simple reaction can serve as a convenient source of 3,5-disubstituted piperidines as well as polyfunctional 3-spir

Full text of DOI:10.1016/j.tetlet.2008.04.160

Tetrahedron Letters 49 (2008) 4560–4562
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Tetrahedron Letters
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A novel three-component reaction of anilines, formaldehyde and
dimedone: simple synthesis of spirosubstituted piperidines
*
Nikolas G. Kozlov, Aliaksei P. Kadutskii
Laboratory of Organic Catalysis, Institute of Physical Organic Chemistry, The National Academy of Sciences of Belarus, 13 Surganov Street, Minsk 220072, Belarus
a r t i c l e i n f o
a b s t r a c t
Article history:
A three-component condensation of anilines with dimedone and formaldehyde leads to the formation of
3,5-dispirosubstituted piperidines. This simple reaction can serve as a convenient source of 3,5-disubsti-
tuted piperidines as well as polyfunctional 3-spirofused piperidines.
Received 3 April 2008
Revised 24 April 2008
Accepted 30 April 2008
Available online 4 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
b-Diketones
Multicomponent reaction
Mannich reaction
Azaspiro compounds
Piperidines
The piperidine ring system is one of the most common motifs
found in numerous natural products, drugs and drug candidates.
The important bioactivities of piperidines have stimulated the
development of new synthetic approaches, and considerable syn-
thetic effort has been devoted to the preparation of these
compounds.1
Spirofused piperidines have attracted particular attention due
to their miscellaneous interesting physiological activities.2 In addi-
tion, spiropiperidinyl ring systems have been isolated from various
plant alkaloids and animal toxins. For example, some neurotoxic 2-
spirofused piperidines were isolated from the neotropical poison-
ous frog Dendrobates histrionicus3 and their 3-spirofused analogues,
the alkaloids sibirine, nitramine, isonitramine and nitrabirine, were
isolated from plants of the genus Nitraria.4 The Nitraria alkaloids
without any substituents on the N-atom. Surprisingly, the products
were neither the desired tetrahydroquinolines 4 nor probable acri-
dones 57 or Hantzsch dihydropyridines 68 (the expected products
of the three-component condensation of anilines, formaldehyde
and dimedone are shown in Scheme 1).
We have found that the condensation of anilines 1 with dime-
done (5,5-dimethyl-1,3-cyclohexanedione, 2) and formaldehyde 3
leads to the formation of 3,5-dispirosubstituted piperidines 7
(Scheme 2).
O
R
Ref.6
incorporating
a
2-azaspiro[5.5]undecane moiety have long
N
H
O
O
attracted the interest of synthetic chemists, and many syntheses
of such compounds have been published in the literature in recent
years.5
4
NH2
R
H
H
Ref.7
Ref.8
In this Letter, we report a simple reaction leading to the forma-
tion of polysubstituted piperidine derivatives containing the 2-aza-
spiro[5.5]undecane unit. In our recent work, we described a three-
component reaction of mono-N-substituted anilines, formalde-
hyde and cyclic b-diketones as a novel synthetic route to N-substi-
tuted 3-spirofused 1,2,3,4-tetrahydroquinolines.6a Following this
procedure, we tested several N-unsubstituted anilines in the reac-
tion in order to obtain the same spiro-tetrahydroquinolines but
O
N
H
5
O
O
R
O
O
1
2
3
N
Ar
6
* Corresponding author. Tel.: +375 17 2455904; fax: +375 17 2841679.
E-mail address: kadutskii@gmail.com (A. P. Kadutskii).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.160

N. G. Kozlov, A. P. Kadutskii / Tetrahedron Letters 49 (2008) 4560–4562
4561
2+3
NH2
Knoevenagel
H
H
O
O
O
O
N
O
O
O
O
O
+ 2
Michael
O
R
R
1
2
3
7
O
O
O
Scheme 2.
8
For example, treatment of p-anisidine (1, R = OMe) with 1 equiv
of 2 in the presence of a large excess of formaldehyde gave spirane
7a in 41% yield relative to the amine (82% relative to dimedone). The
use of stoichiometric quantities of p-anisidine and dimedone
improved the yield to 86%. p-Toluidine, p-phenethidine, p-phenoxy-
aniline and 4-aminobiphenyl behaved in the same manner. The
reaction took place at room temperature for 12 h, during which
time the spiroproducts crystallized from the reaction mixture in a
nearly pure state and in very good yields.9 The results are summa-
rized in Table 1.
+ 1, + 3
Mannich
+ 3
Mannich
O
O
O
7
H
N
O
A possible mechanism for the spiropiperidine ring formation is
outlined in Scheme 3.
R
Scheme 3.
The spirocyclization seems to proceed as a domino sequence of
Knoevenagel, Michael and double Mannich reactions. The well-
known reaction of dimedone with formaldehyde leads to the for-
mation of the standard dimedone–formaldehyde adduct 8. In turn,
this undergoes two consecutive Mannich reactions with a suitable
aniline 1 to produce the spiro-piperidine 7.
Unfortunately, the chemistry worked well only for a limited
number of electron-rich para-substituted anilines. Aniline itself
(1, R = H) as well as para-unsubstituted anilines containing an
ortho- or meta-substituent gave resinous products (entry 7).10
Anilines bearing electron-withdrawing groups (e.g., NO2, COOCH3,
entries 8 and 9) did not give any spiro-products, and the di-
medone–formaldehyde adduct 8 was the only isolated product.11
Nevertheless, p-bromoaniline (1, R = Br) led to the desired spirane
in an excellent yield (entry 6) although a prolonged reaction time
(up to two weeks) was required. The low reactivity of anilines
containing electron-withdrawing groups can be attributed to their
relatively weak nucleophilicity and therefore decreased activity in
the Mannich steps of the reaction.
benzo[a]acridin-11-one 10 and spirobenzo[f]quinoline 11 (Scheme
4).12
The piperidine derivatives 7a–f and 9 obtained incorporate a
polysubstituted 2-azaspiro[5.5]undecane unit and also contain
highly reactive cyclic b-dicarbonyl systems that could be utilised
for further chemical modification of the substances. In addition,
these compounds are examples of 3,5-disubstituted piperidines,
compounds which have a range of important pharmaceutical prop-
erties.13 Thus, the reported reaction could serve as a convenient
source of 3,5-disubstituted piperidines as well as polyfunctional
3-spirofused piperidines. Further studies on this reaction are in
progress in our laboratory.
In conclusion, a novel three-component reaction of anilines,
dimedone and formaldehyde is shown to provide a simple syn-
thetic route to unusual 3,5-dispirosubstituted piperidines. The
reaction is mild, operationally simple and offers high yields. The
It is noteworthy that p-phenylenediamine (1, R = NH2) reacted
very quickly (the reaction time was less than 5 min) with 2 and
3 in refluxing ethanol to form the interesting product 9 containing
two spiropiperidine ring systems (entry 10). It should also be noted
that 2-naphthalenamine (entry 11) did not give the corresponding
spiropiperidine but instead a mixture of two products, namely
R = EWG
8
O
N
O
O
N
O
Table 1
R = NH2
1 + 2 + 3
O
O
O
O
The reaction of anilines 1 with dimedone 2 and formaldehyde 3
Entry
R
Producta
Yieldb (%)
1
2
3
4
5
OMe
Me
OEt
OPh
Ph
Br
7a
7b
7c
7d
7e
7f
86
84
83
97
90
84
9
O
6
7
8
9
10
11
H
NO2
COOMe
NH2
—
8
8
9
—
62
57
37
O
O
1 = 2-naphth
+
alenamine
NH
N
3,4-(–CH@CH–CH@CH–)
10+11
52+27
OEt
a
All new compounds gave satisfactory 500 MHz 1H and 100 MHz 13C NMR and IR
10
11
spectral data.
b
Yield refers to pure isolated products.
Scheme 4.

4562
N. G. Kozlov, A. P. Kadutskii / Tetrahedron Letters 49 (2008) 4560–4562
Mp 186 °C. IR (KBr): 2958, 2930, 2870, 1729, 1698, 1609, 1519, 1486, 1215,
1065, 769, 702 cmꢁ1 1H NMR (500 MHz, CDCl3): d 0.97 (s, 6H), 0.98 (s, 6H),
starting materials are readily available and the products are easy to
isolate.
.
2.50 (s, 2H), 2.66 (d, J = 13.5 Hz, 4H), 2.81 (d, J = 13.5 Hz, 4H), 3.48 (s, 4H), 7.15
(d, J = 8.5 Hz, 2H), 7.25–7.29 (m, 1H), 7.36–7.39 (m, 2H), 7.48 (d, J = 8.5 Hz, 2H),
7.51–7.53 (m, 2H). 13C NMR (100 MHz, CDCl3): d 18.45, 28.40, 28.70, 30.84,
32.33, 51.27, 54.70, 58.25, 65.71, 118.83, 126.68, 127.81, 128.77, 134.17,
140.76, 150.81, 206.07. Anal. Calcd for C31H35NO4: C, 76.67; H, 7.26; N, 2.88.
Found: C, 76.70; H, 7.25; N, 2.90. 15-(4-Bromophenyl)-3,3,11,11-Tetramethyl-15-
azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrone (7f): Mp 202 °C. IR (KBr): 2959,
2949, 2922, 1732, 1721, 1703, 1689, 1590, 1492, 1250, 1223, 1078, 826,
References and notes
1. (a) Elbein, A. D.; Molyneux, R. In Alkaloids; Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; John Wiley and Sons: New York, 1987; Vol. 57, p 1; (b)
O’Hagan, D. Nat. Prod. Rep. 1997, 14, 637; (c) Felpin, F.-X.; Lebreton, J. Curr. Org.
Synth. 2004, 1, 83; (d) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 23, 3679.
2. (a) Bienayme, H.; Chene, L.; Grisoni, S.; Grondin, A.; Kaloun, B.; Poigny, S.;
Rahali, H.; Tam, E. Bioorg. Med. Chem. Lett. 2006, 16, 4830; (b) Maier, Ch. A.;
Wunsch, B. J. Med. Chem. 2002, 45, 438; (c) Feliu, L.; Martinez, J.; Amblard, M.
QSAR Comb. Sci. 2004, 23, 56; (d) Kouznetsov, V. V.; Diaz, B. P.; Sanabria, C. M.
M.; Vargas, L. Y. M.; Poveda, J. C.; Stashenko, E. E.; Bahsas, A.; Amaro-Luis, J. Lett.
Org. Chem. 2005, 2, 29; (e) Kouznetsov, V. V. Khim.-Farm. Zh. 1991, 25, 61; (f)
Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679; (g) Quaglia, W.;
Gianella, M.; Piergentili, A.; Pigini, M.; Brasili, L.; Di Torso, R.; Rossetti, L.;
Spompiato, S.; Melchiorre, C. J. Med. Chem. 1998, 41, 1557.
3. (a) Daly, J. W. In Progress in the Chemistry of Organic Natural Products; Herz, W.,
Griesebach, H., Kirby, G. W., Eds.; Springer: Berlin, 1982; p 205; (b) Daly, J. W. J.
Toxicol., Toxin Rev. 1982, 1, 33; (c) Daly, J. W.; Garraffo, M.; Spande, T. F.; Decker,
M. W.; Sullivan, J. P.; Williams, M. Nat. Prod. Rep. 2000, 17, 131; (d) Daly, J. W.;
Myers, C. W.; Whittaker, N. Toxicon 1987, 25, 1023.
4. (a) Osmanov, Z.; Ibragimov, A. A.; Yunusov, S. Yu. Khim. Prir. Soedin. 1982, 126;
(b) Ibragimov, A. A.; Osmanov, Z.; Tashkhodzhaev, B.; Adbullaev, N. D.;
Yagudaev, M. R.; Yunusov, S. Yu. Khim. Prir. Soedin. 1981, 623; (c)
Tashkhozhaev, B. Khim. Prir. Soedin. 1982, 75.
516 cmꢁ1 1H NMR (500 MHz, CDCl3): d = 0.96 (s, 6H), 0.97 (s, 6H), 2.46 (s, 2H),
.
2.61 (d, J = 13.5 Hz, 4H), 2.79 (d, J = 13.5 Hz, 4H), 3.38 (s, 4H), 6.95 (d, J = 8.5 Hz,
2H), 7.30 (d, J = 8.5 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d 28.20,28.50, 30.66,
32.01, 51.05, 54.43, 65.36, 113.67, 120.21, 131.80, 150.38, 205.76. Anal. Calcd
for C25H30BrNO4: C, 61.48; H, 6.19; Br, 16.36; N, 2.87. Found: C, 61.51; H, 6.20;
Br, 16.35; N, 2.90. 3,3,11,11-tetramethyl-15-[4-(3,3,11,11-tetramethyl-
1,5,9,13-tetraoxo-15-azadispiro[5.1.5.3]hexadec-15-yl)phenyl]-15-azadispiro-
[5.1.5.3]hexadecane-1,5,9,13-tetrone (9): Mp (acetone) 230 °C (decomp.). IR
(KBr): 2968, 2951, 2928, 2869, 2819, 1731, 1509, 1245, 1218, 1159 cmꢁ1 1H
.
NMR (500 MHz, DMSO-d6): d 0.89 (s, 12H), 0.93 (s, 12H), 2.47 (s, 4H), 2.70 (d,
J = 13.5 Hz, 8H), 2.82 (d, J = 13.5 Hz, 8H), 3.29 (s, 8H), 6.98 (s, 4H). 13C NMR
(100 MHz, DMSO-d6): d 27.61, 28.00, 30.50, 31.47, 50.43, 54.26, 65.07, 119.01,
145.35, 206.50. Anal. Calcd for C44H56N2O8: C, 71.33; H, 7.62; N, 3.78. Found: C,
71.34; H, 7.60; N, 3.80.
10. 2-Methylaniline, 2-methoxyaniline, 3-methylaniline and 3-methoxyaniline
were tested. We suppose that in these cases dimedone works as an acid
catalyst resulting in some kind of aniline–formaldehyde polymerization
involving the para-position and the N-atom of aniline.
11. Reaction of 4-nitroaniline (0.34 g, 2.5 mmol) with paraformaldehyde
and dimedone following the general procedure gave 0.45 g (62%) of 2-[(4,4-
dimethyl-2,6-dioxocyclohexyl)methyl]-5,5-dimethyl-1,3-cyclohexanedione (8).
Mp (EtOH) 190 °C.
5. For the chemistry of 2-azaspiro compounds, see: Alonso, E. R.; Tehrani, K. A.;
Boelens, M.; De Kimpe, N. Synthesis 2005, 1726 and literature cited therein.
6. (a) Kadutskii, A. P.; Kozlov, N. G. Synlett 2006, 3349; (b) Kadutskii, A. P.; Kozlov,
N. G. Russ. J. Org. Chem. 2006, 42, 855.
12. (a) Reaction of 2-naphthalenamine (0.72 g, 5 mmol) with paraformaldehyde
(0.9 g, 30 mmol) and dimedone (1.4 g, 10 mmol) following the general
procedure gave 0.73 g (52%) of 10 (the substance precipitated from the hot
reaction mixture which was filtered off, washed with 10 mL of CHCl3 and
dried) and 0.48 g (27%) of 11 (the substance precipitated from the combined
mother liquors on standing overnight). Analytical data: 9,9-Dimethyl-8,9,10,12-
tetrahydrobenzo[a]acridin-11(7H)-one (10): Mp (DMF) 256 °C. IR (KBr): 3300,
2980, 2945, 2840, 1640, 1625, 1600, 1585, 1520, 1500, 1480, 1400, 1252, 1155,
7. (a) Quiroga, J.; Mejia, D.; Insuasty, B.; Abonia, R.; Nogueras, M.; Sanchez, A.;
Cobo, J.; Low, J. N. Tetrahedron 2001, 57, 6947; (b) Tratrat, C.; Giorgi-Renault, S.;
Husson, H.-Ph. Org. Lett. 2002, 19, 3187; (c) Kadutskii, A. P.; Kozlov, N. G. Russ. J.
Org. Chem. 2006, 42, 1388.
8. This would be a classical example of the Hantzsch pyridine synthesis. For some
examples of such
a reaction with dimedone, see: (a) Dzvinchuk, I. B.;
Tolmacheva, N. A. Chem. Heterocycl. Compd. 2001, 37, 506; (b) Chebanov, V.
A.; Saraev, V. E.; Kobzar’, K. M.; Desenko, S. M.; Orlov, V. D.; Gura, E. A. Chem.
Heterocycl. Compd. 2004, 40, 475.
1040, 810 cmꢁ1 1H NMR (500 MHz, DMSO-d6/Py-d5, 2:1): d 1.06 (s, 6H), 2.30
.
(s, 2H), 2.43 (s, 2H), 4.02 (s, 2H), 7.26 (d, J = 8.6 Hz, 1H), 7.37 (ddd, J = 8.0, 7.1,
0.8 Hz, 1H), 7.52 (ddd, J = 8.3, 7.1, 1.3 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.79 (d,
J = 8.3 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 9.22(br s, 1H). 13C NMR (100 MHz, CDCl3):
d 21.47, 27.52, 31.45, 40.24, 50.08, 102.30, 113.12, 116.56, 121.70, 123.05,
126.16, 126.96, 127.65, 129.66, 131.83, 133.93, 150.93, 193.18. Anal. Calcd for
9. General procedure for the reaction of anilines, formaldehyde and dimedone.
Preparation of 3,3,11,11-tetramethyl-15-aryl-15-azadispiro[5.1.5.3]hexadecane-
1,5,9,13- tetrones (7a–f): A solution of 1 (2.5 mmol) and paraformaldehyde
(0.45 g, 15 mmol) in ethanol (20 mL) was prepared by gentle warming (2–
3 min). Dimedone 2 (0.7 g, 5 mmol) was added to this solution in one portion.
The mixture was heated under reflux for 3–5 min to dissolve all the reactants
and then allowed to stand overnight at room temperature. The resulting
colourless precipitate was filtered off, washed with ethanol (2 ꢀ 5 mL) and
dried to give the desired spirane. Selected analytical data: 3,3,11,11-
Tetramethyl-15-(4-methylphenyl)-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tet-
rone (7b): Mp 199 °C. IR (KBr): 2958, 2921, 2869, 1732, 1721, 1702, 1689, 1613,
C
19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.27; H, 6.68; N, 5.01.
4-Ethoxymethyl-1,4-dihydro-40,40-dimethyl-20H,3H,60H-spiro[benzo(f)quinoline-2,
10-cyclohexane]-20,60-dione (11): Mp (EtOH) 137 °C (lit.6b 137 °C).; (b) The
mechanistic explanations for the formation of similar products were given
earlier. See Refs. 6,7.
13. For the synthesis of some 3,5-disubstituted piperidine derivatives and their
biological activities, see: (a) Olofsson, B.; Bogár, K.; Fransson, A.-B.; Bäckvall, J.-
E. J. Org. Chem. 2006, 71, 8256; (b) Takemiya, A.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 6042; (c) Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A.; Viviani, N.
Tetrahedron 1999, 55, 11871; (d) Amat, M.; Escolano, C.; Lozano, O.; Llor, N.;
Bosch, J. Org. Lett. 2003, 5, 3139; (e) Lee, M. J.; Lee, K. Y.; Kim, J. N. Bull. Korean
Chem. Soc. 2005, 26, 477.
1514, 1249, 1237, 1224, 1069, 808, 523 cmꢁ1
(s, 6H), 0.98 (s, 6H), 2.25 (s, 3H), 2.46 (s, 2H), 2.63 (d, J = 13.5 Hz, 4H), 2.81 (d,
J = 13.5 Hz, 4H), 3.37 (s, 4H), 6.99 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H). 13
.
1H NMR (500 MHz, CDCl3): d 0.97
C
NMR (100 MHz, CDCl3): d 20.78, 28.57, 28.88, 30.98, 32.46, 51.43, 55.83, 66.00,
119.50, 129.84, 131.60, 149.78, 206.13. Anal. Calcd for C26H33NO4: C, 73.73; H,
7.85; N, 3.31. Found: C, 73.78; H, 7.88; N, 3.33. 15-[1,10-Biphenyl]-4-yl-
3,3,11,11-tetramethyl-15-azadispiro[5.1.5.3]hexadecane-1,5,9,13-tetrone
(7e):