An imino-Diels-Alder route to meso-2,6-disubstituted-4-piperidones

Article abstract of DOI:10.1016/j.tetlet.2004.03.195

A convenient stereoselective preparation of meso-2,6-disubstituted-4- piperidones has been developed by imino-Diels-Alder reaction of 2-amino-1,3-butadienes with imines in the presence of catalytic amount of Cu(TfO)₂.

Full text of DOI:10.1016/j.tetlet.2004.03.195

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4357–4360
An imino-Diels–Alder route to meso-2,6-disubstituted-4-piperidones
*
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Ana-Belen Garcıa, Carlos Valdes and Marıa-Paz Cabal
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ꢀ
ꢀ
ꢀ
ꢀ
Unidad asociada al CSIC, Instituto Universitario de Quımica Organometalica ‘Enrique Moles’, Universidad de Oviedo,
33071Oviedo, Spain
Received 23 January 2004; revised 15 March 2004; accepted 31 March 2004
Abstract—A convenient stereoselective preparation of meso-2,6-disubstituted-4-piperidones has been developed by imino-Diels–
Alder reaction of 2-amino-1,3-butadienes with imines in the presence of catalytic amount of Cu(TfO)2.
ꢀ 2004Elsevier Ltd. All rights reserved.
1. Introduction
have been limiting the synthetic versatility of the reac-
tion.8
meso-Compounds are attractive prochiral materials that
can be readily transformed into enantiomerically pure
compounds through various desymmetrization pro-
cesses.1 Among them, meso-2,6-disubstituted-4-piper-
idones can be regarded a interesting frameworks as
precursors of chiral biologically active and natural
alkaloids.2
In relation with an ongoing research project in our
laboratory, we were interested in synthesizing 4-piper-
idones with different substituents at R1 and R2 ¼ H. For
this reason, we set out to investigate the optimal con-
ditions for the imino-Diels–Alder reaction of 2-amino-
butadienes unsubstituted at C-3, and the application of
this methodology to the synthesis of meso-2,6-disubsti-
tuted-4-piperidones.
A research theme in our laboratory for many years has
been the study of the imino-Diels–Alder reaction of 2-
amino-1,3-butadienes with nonactivated aldimines. This
method generally furnishes 4-piperidones with high
stereoselectivity.3 It has been previously shown that this
cycloaddition can also be carried out asymmetrically to
give adducts in very high enantiomeric excess (Fig. 1).4
Moreover, this methodology has been applied to the
synthesis of alkaloids,5 structurally diverse pipecolic
acid derivatives,6 and most recently, to solid-phase
organic synthesis.7 However, the requirement of specific
substituents on the diene (R1 ¼ CH2OR, R2 ¼ alkyl)
The synthesis of 3-unsubstituted-2-aminodienes 1 and 2
were carried out from commercially available starting
reagents as propargyltriphenylphosphonium bromide,
morpholine, or N-methylaniline and aromatic aldehydes
by a modification of a previous procedure (Fig. 2).9
The synthetic sequence involves the preparation in situ
of phosphorane II by reaction of b-enaminophospho-
nium salt I with sodium hexamethyldisilazide followed
by a Wittig reaction with aromatic aldehydes affording
Figure 1. Imino-Diels–Alder reaction of 2-aminodienes.
Keywords: Imino-Diels–Alder; Piperidones; meso-Compounds;
Cu(TfO)2.
* Corresponding author. Tel.: +34-985102990; fax: +34-985193446;
e-mail: pcabal@fq.uniovi.es
Figure 2. Synthesis of 2-aminodienes.
0040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.195

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A.-B. Garcıa et al. / Tetrahedron Letters 45 (2004) 4357–4360
4358
the corresponding 2-aminodienes in good yield (80–
98%).
cycloaddition was carried out with Cu(OTf)2 at )20 ꢁC
(entry 6).
We chose for our initial study 4-phenyl-2-amino-1,3-
butadienes 1a and 2, which bear an aromatic amine (N-
methylaniline) and an aliphatic amine (morpholine),
respectively. The reaction of both dienes with N-allyl-
benzaldimine 3a, was examined in the presence of a
variety of Lewis acids known to activate imines in aza-
Diels–Alder and Mannich type reactions10 and under
different reaction conditions (Scheme 1 and Table 1).
The high diastereoselectivity observed in the reaction is
in agreement with an endo approach of the phenyl ring
of the imine on a formal [4+2] cycloaddition. However,
there is no evidence for a concerted mechanism, and in
fact, Lewis–acid catalyzed imino-Diels–Alder reactions
with electron-rich dienes have been proposed to occur in
a stepwise fashion.11
This methodology, under these optimized conditions,
was then extended to the synthesis of different substi-
tuted meso-piperidones 4. These adducts could be
readily obtained from reactions in which the aryl sub-
stituent of the diene is properly matched with the aryl
imine 3. The results are summarized in Table 2 (Scheme
2).
Scheme 1. Cycloaddition reaction of dienes 1a and 2.
The reaction afforded, after aqueous workup, the
expected [4+2] cycloadduct 4a with very high diastereo-
selectivity. Yields varied, depending on the nature of the
Lewis acid and the diene. The meso-isomer was isolated
in nearly pure diastereoisomeric form in all the reac-
tions.ꢀ Diene 1a, substituted with an aromatic amine
furnished better yields than morpholine substituted
diene 2 under the conditions examined (entries 1 vs 8
and 3 vs 10). Moreover, while both Cu(OTf)2 and
Yb(OTf)3 promoted the cycloaddition, the best yields
and diastereoselectivities were achieved with Cu(OTf)2
as Lewis acid (entries 1 vs 3). In particular, excellent
yield and diastereoselectivity was obtained when the
Scheme 2. Preparation of meso-piperidones 4.
In most of the examples the 4-piperidones were obtained
with excellent yields and diastereoselectivities. The
reaction is fairly general regarding the structure of the
aryl substituent (from the electron rich p-MeO–Ph to the
electron poor p-F–Ph).
However, the outcome of the cycloaddition is greatly
affected by the N-substituent of the imine; with N-aryl
substituted imines we observed very low conversion, but
still high diastereoselectivities. The 4-piperidones 4 are
stable compounds under aqueous neutral conditions and
can be purified by flash chromatography on silica gel.
However, in a few cases (4c, R ¼ Bn) we detected
isomerization to the trans isomer (probably via a
reversible retro-Michael ring opening-Michael ring clo-
sure sequence) during the chromatography, lowering the
overall yield of the cis isomer.
Table 1. Synthesis of piperidone 4a under different reaction conditions
Entry Diene Lewis acid (% mol)
T (ꢁC) Yielda
(%)
Deb
(%)
1
1a
1a
1a
1a
1a
1a
1a
2
Cu(OTf)2 (20)
Rt
60
46
93
93
91
90
––c
94
2
CuClO4ÆCH3CN (20) Rt
3
Yb(OTf)3 (20)
Sc(OTf)3 (20)
ZnCl2 (100)
Rt
Rt
53
39
4
5
Rt
<10
90
Table 2. Preparation of meso-2,6-diaryl-4-piperidones 4
6
Cu(OTf)2 (20)
Yb(OTf)3 (20)
Cu(OTf)2 (20)
)20
)20
Rt
Compound 4 Ar
R
Dea (%) Yieldb (%)
7
7494
8
33
25
30
93
92
92
a
b
c
d
e
f
Ph
Ph
Allyl
Butyl
Bn
9490
9
2
CuClO4ÆCH3CN (20) Rt
>99
>99
96
87
55
20
15
79
73
89
85
80
73
10
11
12
2
Yb(OTf)3 (20)
Yb(OTf)3 (20)
ZnCl2 (100)
Rt
50
Rt
Ph
Ph
2
Traces ––c
<10
––c
Ph
2
Ph
p-MeO–Ph
Allyl
Butyl
Allyl
Butyl
Allyl
Butyl
96
96
a After chromatographic purification.
b Determined by 1H NMR on the reaction crude.
c Not determined.
p-MeO–Ph
p-MeO–Ph
o-Br–Ph
o-Br–Ph
p-FPh
p-F–Ph
g
h
i
>99
>99
>99
>99
>99
j
k
a Determined by 1H NMR on the crude reaction mixture.
b Isolated yield of the meso-diastereomer after chromatographic puri-
fication.
ꢀ
The cis arrangement of the substituents at positions 2 and 6 was
deduced from the analysis of the 1H NMR spectra and NOESY
experiments.

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A.-B. Garcıa et al. / Tetrahedron Letters 45 (2004) 4357–4360
4359
In conclusion, we have described a very efficient method
for the stereoselective synthesis of meso-2,6-disubsti-
tuted-4-piperidones by imino-Diels–Alder reaction of 3-
unsubstituted 2-aminodienes. These compounds can be
interesting starting materials for the preparation of
enantiopure piperidine derivatives upon desymmetriza-
tion processes that are now being investigated and will
be reported in due course.
3. Typical experimental procedure for the synthesis of
meso-2,6-disubstituted-4-piperidones 4
The Lewis acid (0.2 mmol) was placed under N2 into a
flame-dried Schlenk tube. Freshly distilled anhydrous
THF (5 mL) was added with a syringe under N2 and the
resulting solution was stirred for 5 min at room tem-
perature. The solution was treated with imine 2
(1 mmol) and stirred for 10 min. Finally, a solution of
the diene 1 (1 mmol) in THF (10 mL) was added drop-
wise during 1 h. The reaction mixture was stirred at
)20 ꢁC for 24h, quenched with NaHCO 3 satd aqueous
solution, and extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated under reduced pres-
sure. The crude product purified by flash column chro-
matography (SiO2, EtOAc–hexane 1:10) to afford the
corresponding cycloadduct product 4. Yellow oil. Rf
(SiO2, EtOAc–hexanes 1:10): 4a, 0.31.
2. Typical experimental procedure for the preparation
of 4-aryl-2-amino-1,3-butadienes 1 and 2
The secondary amine (17 mmol) was added to a solution
of propargyltriphenylphosphonium bromide (15 mmol)
in Cl2CH2 (75 mL) and the solution was stirred at room
temperature for 1.5 h. After the partial evaporation of
the solvent, the resulting solution was added dropwise to
ethyl acetate forming the crystalline b-enaminophos-
phonium salt that was filtered off and dry under vacuum
to be used on the next step. To a suspension of b-en-
aminophosphonium salt (20 mmol) in anhydrous THF
(75 mL) at )60 ꢁC and under N2, was added
NaN(SiMe3)2 (1.3 equiv, 2 M in THF). The reaction
mixture was stirred for 4h, then the cold bath was
removed, and the solution was allowed to reach room
temperature (deep orange color was observed). Anhy-
drous HMPTA (1 equiv) was added at room tempera-
ture and after 30 min the reaction mixture was cooled at
)30 ꢁC. A solution of aldehyde (1.3 equiv) in anhydrous
THF (15 mL) was added dropwise in a short time (deep
orange color disappeared) and the mixture was keep at
)30 ꢁC. After 1 h, the cold bath was removed and the
solution was allowed to reach room temperature fol-
lowed by heating at 60 ꢁC during 12 h. The solvents were
removed under N2 at reduced pressure and a gummy
solid was obtained. Anhydrous hexane (60 mL) was
added to the solid and allowed to stir for few minutes,
the solid was filtered off under N2, and washed again
with dry hexane (2 · 25 mL). The solution was concen-
trated under N2 at reduced pressure (25 mL) and
allowed to stand overnight at )20 ꢁC (solid precipitated
was observed on the bottom flask). The solution was
3.1. Selected spectroscopic data for compound 4a
1H NMR (300 MHz, CDCl3):
d 2.53 (2H, dd,
J ¼ 12:8 Hz, 2.3 Hz), 2.81 (2H, t, J ¼ 12:8 Hz), 3.00
(2H, d, J ¼ 7:1 Hz), 3.96 (2H, dd, J ¼ 12:8 Hz, 2.3 Hz),
4.64 (1H, dd, J ¼ 17:1 Hz, 2.0 Hz), 5.04(1H, dd,
J ¼ 10:2 Hz, 2.0 Hz), 5.72–5.83 (1H, m), 7.30–7.49 (10H,
m) ppm; 13C NMR (75.4MHz, CDCl 3): d 50.8 (CH2),
51.0 (CH2), 64.4 (CH), 119.5 (CH2), 127.2 (CH), 127.5
(CH), 128.6 (CH), 130.5 (CH), 142.4 (C), 207.1 (C@O)
ppm.
Acknowledgements
ꢀ
This research was supported by Consejerıa de Edu-
cacion y Cultura del Principado de Asturias (FICYT
ꢀ
PC-CIS01-22) and Asturpharma S.A.
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ꢀ
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