An efficient synthesis of new 1-H-4′-methyl-3′,4′-dihydrospiro[piperidine-4,2′(1′H)quinoline] scaffolds

Article abstract of DOI:10.1016/j.tetlet.2007.02.037

Efficient synthesis of new 3′,4′-dihydrospiro[piperidine-4,2′(1′H)quinolines] by a four step synthetic route based on 1-benzyl-4-piperidone reactivity is reported.

Full text of DOI:10.1016/j.tetlet.2007.02.037

Tetrahedron Letters 48 (2007) 2509–2512
An efficient synthesis of new 1-H-40-methyl-30,40-
dihydrospiro[piperidine-4,20(10H)quinoline] scaffolds
*
´
Leonor Y. Vargas Mendez and Vladimir V. Kouznetsov
Laboratorio de Quı´mica Orga´nica y Biomolecular, Escuela de Quı´mica, Universidad Industrial de Santander,
A.A. 678, Bucaramanga, Colombia
Received 18 January 2007; revised 6 February 2007; accepted 7 February 2007
Available online 13 February 2007
Abstract—Efficient synthesis of new 30,40-dihydrospiro[piperidine-4,20(10H)quinolines] by a four step synthetic route based on
1-benzyl-4-piperidone reactivity is reported.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Because the piperidine ring is the most common hetero-
cyclic unit of many alkaloids, and is a key part of
numerous drug candidates, a research in piperidine
chemistry and synthesis continues to be prominent.1,2
Watson et al. affirmed that in a decade (1988–1998)
there were over 12.000 piperidine compounds mentioned
in clinical and preclinical studies.3 Thus, it is not surpris-
ing that the chemical literature reveals a much more
increasing number of these derivatives with varied bio-
logical activities. Spiropiperidinyl compounds have at-
tracted an increasing interest as the synthetic targets
due to their important activity as pharmacophores in
several biologically active compounds, mainly alka-
loids.4 The synthetic compounds with a 4-spiropiper-
idine motif (types A–E) possess interesting activities as
well5–9 (Fig. 1). The spiro system of 1-H-30,40-dihydro-
spiro[piperidine-4,20(10H)quinoline] F also shows inter-
esting features that make it attractive for synthetic and
pharmacological use. However, its chemistry is little
studied. This is associated primarily with the lack of
general and reliable procedures for the preparation of
such spiropiperidinoquinoline derivatives.10 All cited
syntheses start from N-Boc-4-piperidone and have some
difficulties in the synthesis of the key intermediates—4,4-
disubstituted piperidines. Moreover, the final intramole-
cular cyclizations are not efficient.
With these facts in mind and as a continuation of our
efforts on the synthetic potential of 4-N-aryl(benz-
yl)aminopiperidines to prepare a wide variety of nitro-
gen heterocycles, associated with various biological
activities, we were particularly interested in N-unpro-
O
F
S
O
N
N
N
A
B
C
N
O
O
O
CH3
F
C6H4F-p
NH
R
R
N
H
N
H
N
N
R
E
D
NH
F
O
Figure 1. Compounds with 4-spiro piperidine skeleton as pharmaceuticals.
Keywords: Spiro-4-piperidines; Intramolecular alkene Friedel–Crafts alkylation; 30,40-Dihydrospiro[piperidine-4,20(10H)quinolines].
*
Corresponding author. Tel.: +57 76 349069; fax: +57 76 349069/358210; e-mail: kouznet@uis.edu.co
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.037

2510
L. Y. Vargas Me´ndez, V. V. Kouznetsov / Tetrahedron Letters 48 (2007) 2509–2512
R1
R1
H
N
R2
R3
R2
R3
Ph
N
ii
Ph
N
i
Ph
N
R3
R2
+
72-85%
78-89%
N
H2N
O
1
2a-f
4a-f
3a-f
R1
R1
R2 R3
iii
51-93%
a
H
H
H
H
H
H
Me
MeO H
F
Cl
H
H
H
H
H
N
b
c
d
e
f
HN
Ph
iv
N
N
R3
R2
R3
R2
H
H
Me
78-95%
Me
CH3 R1
CH3 R1
6a-f
5a-f
Scheme 1. Reagents and conditions: (i) Toluene, reflux, 6–8 h, cat. AcOH; (ii) allylmagnesium bromide, Et2O, 4–5 h and then work-up with NH4Cl;
(iii) 85% H2SO4, 80 ꢁC, 4–6 h; (iv) HCOONH4/Pd/C/MeOH, reflux, 10 min.
tected spiro-4-piperidines (type F) that could serve as
useful precursors to many drug-like molecules. To
the best of our knowledge, an efficient N-unpro-
tected spiro-4-piperidines synthesis has not been
described. The results of our quest for an efficient prep-
aration of such spiro-4-piperidines are reported in this
Letter.
with hydrogen gas in the presence of Pd on carbon,13a,b
however an ammonium formate with Pd/C is also con-
sidered as a versatile agent in catalytic hydrogen transfer
reductions.13c Thus, the last step of our synthetic route
was realized with easily handled system HCOONH4/
Pd/C in methanol that allowed to obtain the desired 1-
H-40-methyl-30,40-dihydrospiro[piperidine-4,20(10H)quino-
lines] 6 in excellent yields (78–95%).14 These final spiro
piperidines are stable colorless crystalline substances
with high melting points. Homonuclear and inverse-
detected 2D NMR experiments allowed the assignment
of all the signals and correlations, corroborating the
obtained dihydrospiro[piperidine-4,20(10H)quinoline] core.
Our synthetic route to the desired spirocyclic piperidines
is outlined in Scheme 1. The synthesis of final type mole-
cules F was planned from commercially available 1-
benzyl-4-piperidone 1 in four steps. The condensation
of this c-piperidone with substituted anilines was
achieved in boiling toluene in the presence of AcOH
with azeotropic removal of water. Ketimines 3 were ob-
tained and purified by distillation under reduced pres-
sure in good yields (72–85%).
In conclusion, the synthesis described herein provides an
efficient and original route in four-steps to 1-H-40-
methyl-30,40-dihydrospiro[piperidine-4,20(10H)quinolines]
in excellent yields from commercially available 1-benzyl-
4-piperidinone and anilines. The proposed method con-
sists in mild reaction conditions, excellent yields, and
simplicity. The obtained products should be useful inter-
mediates for the assembly of novel diverse spiro-4-piper-
idine scaffolds. Preliminary results on the inhibitory
activity at acetylcholinesterase enzyme indicated that
some obtained compounds act as potent acetylcholin-
esterase inhibitors and will be reported in the immediate
future.
The new 4-allyl-1-benzyl-4-N-arylaminopiperidines 4
were prepared by addition of allylmagnesium bromide
to the corresponding freshly distilled ketimines 3 using
the Grignard procedure (allylmagnesium bromide has
been prepared from allyl bromide and magnesium in
anhydrous Et2O). These aminopiperidine compounds
were isolated as stable reddish or yellow oils in good
yields (78–89%) following the distillation under reduced
pressure and chromatographic techniques. The simplic-
ity of the Grignard procedure and accessibility of the
starting materials allowed us to prepare these amino-
piperidines in large quantities, which are appropriate
substrates to construct tetrahydroquinoline ring via an
acid catalyzed intramolecular Friedel–Crafts alkyl-
ation—powerful and widely used methodology in the
construction of diverse polycycles.11 Thus, in the next
key step, the treatment of c-allyl-c-N-arylaminopiper-
idines 4 with excess of 85% H2SO4 at 80 ꢁC afforded
effectively the new 1-benzyl-40-methyl-30,40-dihydro-
Acknowledgments
This work was supported by the grant of Instituto
Colombiano para el Desarrollo de la Ciencia y la
´
´
Tecnologıa ‘Francisco Jose de Caldas’ (COLCIEN-
CIAS-CENIVAM, Grant No. 432-2004). L.Y.V.M.
thanks COLCIENCIAS and Universidad Industrial de
Santander for her doctoral fellowship.
spiro[piperidine-4,20(10H)quinolines]
5
in 51–93%
yields12 (Scheme 1).
Supplementary data
Having in our hands diverse N-benzyl substituted spiro-
4-piperidines 5, we have dedicated our effort to find the
best suited debenzylation procedures. This purpose is al-
ways achieved by a common debenzylation reaction
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.tetlet.2007.02.037.

L. Y. Vargas Me´ndez, V. V. Kouznetsov / Tetrahedron Letters 48 (2007) 2509–2512
2511
at 85% (w/v) (6 mL) was added dropwise to a mixture of
aminopiperidine 4b (2.00 g, 6.25 mmol) in CH2Cl2 (5 mL)
0 ꢁC. The mixture was heated at 85 ꢁC for 6 h with
vigorous stirring. The reaction progress was monitored via
TLC. Then the mixture was cooled down to 5 ꢁC and was
basified with NH4OH solution, and extracted with CH2Cl2
(3 · 25 mL). The oily residue after dichloromethane sep-
aration was purified by column chromatography over
alumina with ethyl acetate and heptane (1:15) to give
1.76 g (88%) of 5b as a yellow viscous oil. IR (film): mNH
References and notes
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Kutscher, B., Reichert, D., Eds.; Stuttgart: Thieme, 1999;
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Structure, Preparation, Reactivity and Synthetic Applica-
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1
3406 cmꢀ1; H NMR (400 MHz, CDCl3, d): 1.31 (2H, d,
J = 6.7 Hz, 40-CH3), 1.39 (1H, t, J = 12.5 Hz, 30-Ha),
1.55–1.75 (4H, m, 3(5)-H), 1.84 (1H, dd, J = 12.9, 5.5 Hz,
30-He), 2.22 (3H, s, 60-CH3), 2.27–2.37 (2H, m, 2(6)-Ha),
2.54 (1H, dd, J = 11.8, 6.3 Hz, 2- or 6-He), 2.63 (1H, dd,
J = 11.9, 6.3 Hz, 2 or 6-He), 2.87 (1H, sept, J = 6.5 Hz, 40-
H), 3.52 (2H, s, CH2–Ph), 3.84 (1H, br s, H–N), 6.64 (1H,
d, J = 8.0 Hz, 80-H), 6.79 (1H, d, J = 8.0 Hz, 70-H), 6.95
(1H, s, 50-H), 7.22–7.32 (5H, m, HPh); 13C NMR
(100 MHz, CDCl3, d): 20.4 (+), 20.6 (+), 26.7 (+), 34.9
(ꢀ), 39.0 (ꢀ), 42.9 (ꢀ), 48.8, 49.4 (ꢀ), 49.5 (ꢀ), 63.4 (ꢀ),
114.5 (+), 125.8, 126.1, 127.0 (+), 127.3 (+), 127.4 (+),
128.2 (+, 2C), 129.1 (+, 2C), 138.4, 140.6; GC–MS: tR
41.18 min; mass spectrum (EI): m/z (%) 320 (M+, 51), 277
(4), 229 (7), 201 (13), 186 (75), 173 (47), 158 (36), 146 (46),
134 (24), 118 (7), 91 (100), 65 (9), 56 (7). Found: C, 82.51;
H, 8.96; N, 8.75. Calcd for C22H28N2: C, 82.45; H, 8.81;
N, 8.74.
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glia, W.; Gianella, M.; Piergentili, A.; Pigini, M.; Brasili,
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2000, 3765–3774; (c) Brieger, G.; Nestrick, T. J. Chem.
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R.; Burkamp, F.; Blurton, P.; Cheng, S. K. F.; Clarkson,
R.; O’Connor, D.; Spinks, D.; Tudge, M.; van Niel, M. B.;
Patel, S.; Chapman, K.; Marwood, R.; Shepheard, S.;
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Hutson, P. H.; MacLeod, A. M. J. Med. Chem. 2002, 45,
492–503.
14. General procedure for the synthesis of 30,40-dihydro-
spiro[piperidine-4,20-(10H)quinolines] 6. The spiro com-
pound 5b (1.00 g, 3.12 mmol) and HCOONH4 (0.98 g,
15.6 mmol) were heated to reflux in MeOH (25 mL) for
10 min in the presence of 10% Pd/C (0.16 g). The reaction
was monitored via TLC. The solid residue after methanol
separation was purified by alumina column chromatogra-
phy with methanol and ethyl acetate (1:10) to afford 0.64 g
(89%) of 6b as white crystals; mp >300 ꢁC. IR (KBr): mNH
3445, 3311 cmꢀ1; 1H NMR (400 MHz, D2O, d): 1.13 (3H,
d, J = 6.7 Hz, 40-CH3), 1.19 (1H, t, J = 12.8 Hz, 30-Ha),
1.54 (1H, ddd, J = 12.7, 7.9, 4.0 Hz, 3-Ha), 1.66–1.69 (2H,
m, 5-H), 1.76 (1H, br t, J = 4.0 Hz, 3-He), 2.01 (1H, dd,
J = 13.7, 6.2 Hz, 30-He), 2.12 (3H, s, 60-CH3), 2.73 (1H,
sept, J = 6.4 Hz, 40-H), 2.98–3.07 (2H, m, 2-H), 3.09–3.23
(2H, m, 6-H), 6.51 (1H, d, J = 8.1 Hz, 80-H), 6.77 (1H, d,
J = 8.0 Hz, 70-H), 6.98 (1H, s, 50-H); 13C NMR (100 MHz,
D2O + acetone-d6, d): 19.5 (+, 60-CH3), 20.1 (+, 40-CH3),
26.3 (+, 40-C), 30.3 (ꢀ, 3-C), 34.6 (ꢀ, 5-C), 39.3 (ꢀ, 30-C),
40.1 (ꢀ, 6-C), 40.4 (ꢀ, 2-C), 48.2 (4-C), 116.5 (+, 80-C),
127.6 (+, 70-C), 127.8 (4a0-C), 127.9 (+, 50-C), 129.3 (60-
C), 139.4 (8a0-C); COSY correlations [dH/dH (H/H)]: 1.13/
2.73 [40-CH3/40-H], 1.19/2.01/2.73 [30-Ha/30-He/40-H],
1.54/1.76/2.98–3.07 [3-Ha/3-He/2-H], 1.66–1.69/3.09–
3.23 [5-H/6-H], 1.76/1.54/2.98–3.07 [3-He/3-Ha/2-H],
2.01/1.19/2.73 [30-He/30-Ha/40-H], 2.73/1.13/2.01 [40-H/
40-CH3/30-He], 2.98–3.07/1.54/1.76 [2-H/3-Ha/3-He],
3.09–3.23/1.66–1.69 [6-H/5-H], 6.51/6.77 [80-H/70-H],
6.77/6.51/6.98 [70-H/80-H/50-H], 6.98/6.77 [50-H/70-H];
HMQC correlations [dH/dC (C/H)]: 19.5/2.12 [60-CH3/60-
CH3], 20.1/1.13 [40-CH3/40-CH3], 26.3/2.73 [40-C/40-H],
30.3/1.54/1.76 [3-C/3-Ha/3-He], 34.6/1.66–1.69 [5-C/5-H],
39.3/1.19/2.01 [30-C/30-Ha/30-He], 40.1/3.09–3.23 [6-C/6-
H], 40.4/2.98–3.07 [2-C/2-H], 116.5/6.51 [80-C/80-H],
127.6/6.77 [70-C/70-H], 127.9/6.98 [50-C/50-H]; HMBC
8. Spiro[4-oxobenzo[1]pyran-2,40-piperidines], type D: Hars-
´
anyi, K.; Szabadkai, I.; Borza, I.; Karpati, E.; Kiss, B.;
Pellionisz, M.; Farkas, S.; Horvath, C.; Csomov, K.;
Lapis, E.; Laszlovszky, I.; Szabo, S.; Kis-Varga, A.; Laszy,
J.; Gere, A. PTC Int. Appl. WO 9737,630, 1997; Chem.
Abstr. 1997, 127, 346379e.
9. Spiro[4-oxoquinazoline-2,40-piperidines], type E: Bartane,
S., Schoen, I.; Pellioniszne, P. M.; Kiss, B.; Karpati, E.;
Kis-Varga, A.; Lapis, E.; Gere, A.; Laszlovszky, I.;
Farkas, S.; Csomov, K.; Horvath, C.; Szabo, S.; Horvath,
P.; Laszy, J.; Szantay, C. Hung. Teljes HU 76,345, 1997;
Chem. Abstr. 1998, 128, 154093f.
10. (a) Cossy, J.; Poitevin, C.; Gomez Pardo, D.; Peglion,
J.-L.; Dessinges, A. Tetrahedron Lett. 1998, 38, 2965–
2968; (b) Cossy, J.; Poitevin, C.; Gomez Pardo, D.;
Peglion, J.-L.; Dessinges, A. J. Org. Chem. 1998, 63,
4554–4557; (c) Brown, D. W.; Mahon, M. F.; Ninan,
A.; Sainsbury, M. J. Chem. Soc., Perkin Trans. 1 1997,
2329–2336; (d) Dorey, G.; Lockhart, B.; Lestage, P.;
Casara, P. Bioorg. Med. Chem. Lett. 2000, 10, 935–
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1368; (b) Nasipuri, D.; Das, G. J. Chem. Soc., Perkin
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Rozo, W.; Stashenko, E.; Bahsas, A.; Amaro-Luis, J.
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V.; Palma, A.; Rozo, W.; Stashenko, E.; Bahsas, A.;
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12. General procedure for the synthesis of 1-benzyl-30,40-dihy-
drospiro[piperidine-4,20-(10H)quinolines] 5. Sulfuric acid

2512
L. Y. Vargas Me´ndez, V. V. Kouznetsov / Tetrahedron Letters 48 (2007) 2509–2512
correlations [dH/dC (C/H)]: 19.5/6.77/6.98[60-CH3/70-
Ha/3-Ha/5-H/3-He/30-He/2-H/6-H], 116.5/6.77 [80-C/70-
H], 127.6/2.12/6.98 [70-C/60-CH3/50-H], 127.8/1.13/6.51
[4a0-C/40-CH3/40-H/80-H], 127.9/2.73/6.77 [50-C/40-H/70-
H], 129.3/6.51 [60-C/80-H], 139.4/6.77/6.98 [8a0-C/70-H/50-
H]; GC–MS: tR 19.05 min; mass spectrum (EI): m/z (%)
230 (M+, 52), 185 (100), 173 (54), 158 (84), 143 (29), 115
(18), 96 (16), 56 (45). Calcd for C15H22N2: C, 78.21; H,
9.63; N, 12.16. Found: C, 78.44; H, 9.86; N, 11.72.
H/50-H], 20.1/1.19/2.73 [40-CH3/40-H/30-Ha], 26.3/1.13/
1.19/2.01/6.98 [40-C/40-CH3/30-Ha/30-He/50-H], 30.3/1.19/
1.66–1.69/2.98–3.07 [3-C/30-Ha/5-H/2-H], 34.6/1.19/1.54/
1.76/2.01/3.09–3.23 [5-C/30-Ha/3-Ha/3-He/30-He/6-H], 39.3/
1.13/1.66–1.69
[30-C/40-CH3/5-H],
40.1/2.98–3.07
[6-C/2-H], 40.4/1.66–1.69/3.09–3.23 [2-C/5-H/6-H], 48.2/
1.19/1.54/1.66–1.69/1.76/2.01/2.98–3.07/3.09–3.23 [4-C/30-