Synthesis of spiro[pyrrolidine or piperidine-3,9′-xanthenes] by anionic cycloacylation of carbamates

Article abstract of DOI:10.1016/j.tetlet.2003.10.065

Xanthene spiropyrrolidines and spiropiperidines were synthesized by a process in which the key step was intramolecular trapping of a xanthen-9-yl anion by a carbamate side-chain situated at the same position.

Full text of DOI:10.1016/j.tetlet.2003.10.065

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9291–9294
Synthesis of spiro[pyrrolidine or piperidine-3,9%-xanthenes] by
anionic cycloacylation of carbamates
Domingo Quinta´s, Alberto Garc´ıa and Domingo Dom´ınguez*
Departamento de Qu´ımica Orga´nica y Unidad Asociada al CSIC, Facultad de Qu´ımica, Universidad de Santiago de Compostela,
15782 Santiago de Compostela, Spain
Received 28 July 2003; revised 9 October 2003; accepted 13 October 2003
Abstract—Xanthene spiropyrrolidines and spiropiperidines were synthesized by a process in which the key step was intramolecular
trapping of a xanthen-9-yl anion by a carbamate side-chain situated at the same position.
© 2003 Elsevier Ltd. All rights reserved.
The title compounds (1, n=1, 2) have been reported to
have antibacterial and antifungal activities and to affect
the central nervous system.1 Spiropyrrolidinones have
also been reported to have sedative, analeptic and
hypotensive activities.2 All previously reported synthesis
of these spiro systems have been based on the inter-
molecular reaction of xanthen-9-yl anions with
aminoalkylating agents such as N-ethoxycarbonyl-
aziridine,3 1-ethyl-3-chloropyrrolidine,2 3-dimethyl-
aminoethyl chloride1 or, for piperidine derivatives, 3-
dimethylaminopropyl chloride.1 Of these syntheses, the
most direct one is the approach of Stamm et al.,3 but it
affords only spiropyrrolidinones in moderate yields.
ates 3 are easily prepared from readily available alde-
hydes (5 or 8), and the xanthenospirolactams 2 obtained
in the key step are easily reduced to the desired products
1.
Aldehyde 5 has previously been prepared from 9-
hydroxyxanthene by a multistep procedure.5 In this
work we introduced the acetaldehyde unit by means of
a direct nucleophilic substitution reaction. It is well
known that the hydroxy group at the doubly benzylic
position of xanthene can be easily replaced by nucle-
ophiles such as alcohols, amines, amides and active
methylene compounds;6 we found that secondary and
tertiary enamides can be introduced in the same way. In
the case of tertiary enamides, the acyl immonium inter-
mediate can either be trapped in situ by a second
nucleophile (e.g. ethanol) or hydrolyzed to an aldehyde
group. By means of the latter option, a 95% yield of
aldehyde 5 was obtained by reaction of 9-hydroxyxan-
thene 4 with N-methyl-N-vinyl acetamide in glacial
acetic acid at rt for 12 h (Scheme 2).
In this paper we report an alternative approach to these
pharmacologically interesting compounds in which the
five or six-membered aza-ring is assembled by a versatile
anionic
cycloacylation
process4
consisting
of
intramolecular trapping of the xanthen-9-yl anion by a
carbamate side-chain situated at the same position
(Scheme 1). The required carbamate-bearing intermedi-
Scheme 1.
Keywords: spiroxanthenes; pyrrolidines; piperidines; anionic cyclization; cycloacylation.
* Corresponding author. Fax: +34-981-595012; e-mail: qomingos@usc.es
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.065

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D. Quinta´s et al. / Tetrahedron Letters 44 (2003) 9291–9294
periodinane afforded aldehyde 8 in 85% yield (Scheme
3).
Transformation of the aldehydes 5 and 8 into the
required carbamates was performed by conventional
chemistry (Scheme 4): condensation with the appropri-
ate primary amine in methanol, followed by reduction
with NaBH4, gave the secondary amines, which were
treated with ethyl chloroformate to obtain carbamates
3a–c (from propionaldehyde 8) and 3d–f (from acetal-
dehyde 5) in the overall yields listed in Table 1.7
Scheme 2.
Aldehyde 8 was also prepared by a procedure that is
much more efficient than the previously reported five-
step synthesis from 9-hydroxyxanthene.5 Envisaging
that the corresponding alcohol might be obtained as the
result of nucleophilic opening of the oxetane ring by
xanthen-9-yl lithium, we reacted commercially available
xanthene 6 with n-BuLi for 1 h at rt and treated the
resulting solution with oxetane. This gave a 95% yield
of alcohol 7,5 which upon oxidation with Dess–Martin
We now approached the key step of the planned syn-
thesis: conversion of position 9 of compounds 3 into an
anion susceptible to intramolecular attack by the elec-
trophilic carbonyl group, resulting in the formation of
xanthenospirolactams 2 and concomitant loss of ethox-
ide (Scheme 4). When 1 equivalent of LDA was added
at −78°C to carbamate 3a, an intensely red solution
Scheme 3.
Scheme 4.
Table 1. Preparation of carbamates 3, their cyclization to xanthenospirolactams 2, and reduction to 1
Compound 3
R
% Yielda of 3
Equiv. of LDA
% Yielda of 28
% Yielda of 19
a (n=2)
a (n=2)
b (n=2)
c (n=2)
d (n=1)
d (n=1)
e (n=1)
f (n=1)
CH2CH2Ph
CH2CH2Ph
Bn
60
1
S.M.
60 (R=H)
55 (R=H)
85
2.5
2.5
2.5
1.2
2.5
1.2
2.5
70
76
96
Bu
60
50
CH2CH2Ph
CH2CH2Ph
Bn
42
52 (R=H)
75
85
47 (R=H)
98
80
93
90
Bu
a Yields refer to pure isolated products.

D. Quinta´s et al. / Tetrahedron Letters 44 (2003) 9291–9294
9293
Scheme 5.
formed but only starting material was recovered after 6
h of stirring at low temperature, and the same result
was obtained when 1 equiv. of BF3·OEt2 was added to
activate the carbonyl. When the reaction was allowed
to warm to rt after LDA addition, the solution turned
from red to pale yellow, but again only starting mate-
rial was recovered. Only when LDA was added in
excess (2.5 equiv.) and the temperature was raised to rt
and stirred for 6 h did cyclization take place, and
subsequent b-elimination afforded the secondary lactam
2 (n=2, R=H).
−78°C afforded a 52% yield of N-dealkylated spiro-
pyrrolidinone 2 (n=1, R=H). Cyclization of the N-benz-
yl carbamate 3e was achieved in 75% yield by
treatment with 1.2 equiv. of LDA at −78°C for 2.5 h;7,8
in this case cyclization took place at low temperature
and 2e suffered no N-debenzylation, unlike the
homologous carbamate 3b. Similar treatment of carba-
mate 3f, but using a greater excess of LDA (2.5 equiv.),
afforded an 85% yield of the cyclized pyrrolidinone
2f.7,10
Finally, reduction of the carbonyl group of lactams 2
with BH3·SMe2 or LAH in refluxing THF9 afforded the
corresponding spiropiperidine 1c and spiropyrrolidines
1d–f (Table 1).
We interpret the above results as follows. The red
solution obtained at low temperature indicates forma-
tion of an anion by deprotonation of position 9, but no
reaction occurs (Scheme 5). When the temperature is
raised, equilibrium between the xanthen-9-yl anion and
the benzylic anion of the nitrogen substituent is shifted
very much to the latter, giving the pale yellow solution,
and since cyclization is now effectively precluded and
b-elimination is slow for the acyclic carbamate, only
starting material is recovered after quenching. How-
ever, when a second equivalent of LDA is added, both
benzylic positions are deprotonated and cyclization
occurs, followed by the easier b-elimination from the
cyclic lactam (better leaving-group ability than the car-
bamate in the open derivative).
Summing up, we have developed an efficient new syn-
thetic route from xanthene or xanthone to two pharma-
cologically interesting families, xanthene spiropyrro-
lidines and xanthene spiropiperidines.
Acknowledgements
Support of this work by grants from the Spanish Min-
istries of Education and Culture (project PB-98-0606)
and Science and Technology in collaboration with
ERDF (BQU2002-01176), and by Johnson & Johnson
Pharmaceutical Research and Development, is grate-
fully acknowledged.
Similar behavior was observed with carbamate 3b: stir-
ring with 2.5 equivalent of LDA for 12 h at rt achieved
cyclization but an unexpected N-debenzylation
occurred since the major product isolated was the
unsubstituted lactam 2 (n=2, R=H). No N-dealkyla-
tion process was observed with carbamate 3c; in this
case, treatment with 2.5 equiv. of LDA10 at −78°C,
followed by stirring at rt for 3 h, afforded the expected
spiropiperidone 2c in an excellent 85% yield (Table 1).
References
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4. We have previously described anionic cycloacylation pro-
cesses leading to benzofused lactones [(a) Lamas, C.;
Castedo, L.; Dom´ınguez, D. Tetrahedron Lett. 1990, 31,
Cyclization to five-membered rings proved to be faster,
and occurred even at −78°C. When carbamate 3d was
treated with 1.2 equiv. of LDA at −78°C for 3 h, a 42%
yield of spiropyrrolidinone 2d was obtained along with
starting material (50%) and traces of the secondary
spiropyrrolidinone 2 (n=1, R=H).11 Stirring 3d at rt
for 6 h following addition of 2.5 equiv. of LDA at

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D. Quinta´s et al. / Tetrahedron Letters 44 (2003) 9291–9294
6247–6248; (b) Paleo, M. R.; Lamas, C.; Castedo, L.;
lidinone 2e (250 mg, 0.73 mmol) in 20 mL of dry THF
was added BH3·SMe2 complex (0.44 mL, 4.4 mmol). The
reaction mixture was refluxed under argon for 6 h and
then cooled to 0°C, 10 mL of aqueous KOH were added
and the resulting mixture was refluxed for 10 min and
cooled. The solvents were removed under vacuum, the
residue was taken up in ethyl acetate, and the organic
layer was washed with water and brine, dried over
Na2SO4 and evaporated to dryness. Chromatography of
this residue on a SiO2 column using an 85:15 mixture of
hexane and ethyl acetate afforded the spiropyrrolidine 1e
Dom´ınguez, D. J. Org. Chem. 1992, 57, 2029–2033] and
2-aminoindanones [(c) Paleo, M. R.; Castedo, L.;
Dom´ınguez, D. J. Org. Chem. 1993, 58, 2763–2767].
5. Pelliciari, R.; Constantino, G.; Marinozzi, M.;
Machiarulo, A.; Amori, L.; Flor, P. J.; Gasparini, F.;
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6. (a) Phillis, R. F.; Burnett, M. P. J. Am. Chem. Soc. 1943,
65, 1355–1357; (b) Oliverio, V. T.; Sawicki, E. J. Org.
Chem. 1956, 21, 183–189.
7. All new compounds were fully characterized spectroscop-
ically and had satisfactory elemental analyses or HRMS
data.
8. The following cycloacylation procedure was typical. To a
solution of carbamate 3e (1.02 g, 2.63 mmol) in 30 mL of
dry THF at −78°C was added 3.16 mmol LDA (1.2
equiv.). The red solution so obtained was kept at that
temperature for 2.5 h and then quenched with aq.
NH4Cl. The solvents were evaporated and the residue
was dissolved in EtOAc and washed with water. Chro-
matography of this crude on a SiO2 column using a 4:1
mixture of hexane and ethyl acetate as eluent afforded
0.67 g of 2e (75% yield) as a white solid. Mp 165–166°C.
1H NMR (250 MHz, CDCl3) l 7.43–7.36 (m, 5H), 7.28–
7.21 (m, 2H), 7.11 (d, J=8.6, 2H), 7.12–7.01 (m, 4H),
4.72 (s, 2H), 3.43 (t, J=7.0, 2H), 2.38 (t, J=7.0, 2H).
13C-DEPT NMR (250 MHz, CDCl3) l 174.8 (C), 150.9
(2×C), 136.2 (C), 128.9 (2×C), 128.6 (2×CH), 128.4 (2×
CH), 127.9 (CH), 126.5 (2×CH), 124.4 (2×C), 123.6 (2×
CH), 116.7 (2×CH), 48.9 (C), 47.6 (CH2), 43.6 (CH2),
40.1 (CH2). IR wmax 3060–2860, 1684, 1480. EI-MS m/z
(%) 341 (17), 250 (94), 208 (53), 207 (53), 194 (100).
HRMS for C23H19NO2 calcd 341.1415, found 341.1419.
9. (a) The following procedure was typical for reduction of
lactams with BH3·SMe2: To a solution of the spiropyrro-
1
(235 mg, 98%) as a white solid. Mp 239–241°C (dec.). H
NMR (250 MHz, CDCl3) l 7.74 (dd, J=7.8 and 1.4,
2H), 7.41 (d, J=7.0, 2H), 7.33 (t, J=7.0, 2H), 7.25 (t,
J=7.1, 1H), 7.21 (td, J=7.8 and 1.5, 2H), 7.11 (td,
J=7.5 and 1.4, 2H), 7.01 (dd, J=8.0 and 1.4, 2H), 3.75
(s, 2H), 3.04 (s, 2H), 3.02 (t, J=7.1, 2H), 2.51 (t, J=7.1,
2H). 13C-DEPT NMR (250 MHz, CDCl3) l 150.0 (2×C),
139.6 (C), 130.0 (2×C), 128.9 (2×CH), 128.7 (2×CH),
128.5 (2×CH), 127.8 (2×CH), 127.3 (CH), 123.5 (2×CH),
116.2 (2×CH), 74.9 (CH2), 60.2 (CH2), 55.9 (CH2), 48.7
(CH2), 43.6 (C). IR wmax 3100–2940, 1572, 1484. EI-MS
m/z (%) 327 (100), 236 (13), 208 (49), 207 (58), 133 (88).
HRMS for C23H21NO calcd 327.1623, found 327.1638.
(b) Lactams 2 (n=1, R=H) and 2c were reduced by
treatment with LAH for 24 h in refluxing THF, which
gave 1 (n=1, R=H)1 and 1c in moderate yields (Table
1).
10. We choose to use an excess of LDA since it is not
deleterious and gives higher yields.
11. Compound 2 (n=1, R=H) was previously prepared by
reaction of the xanthen-9-yl anion with N-ethoxycar-
bonylaziridine, which involves a cyclization of intermedi-
ate isocyanates that is related to the processes described
in the present paper; see Ref. 3a.