Proline-catalyzed imino-Diels-Alder reactions: Synthesis of meso-2,6-diaryl-4-piperidones

Article abstract of DOI:10.1002/adsc.200600318

Amine-catalyzed imino-Diels-Alder reactions of acyclic α,β- unsaturated ketones with imines have been developed. L-Proline catalyzed the in situ generation of 2-amino-1,3-butadienes to provide a stereoselective synthesis of meso-2,6-diaryl-4-piperidones i

Full text of DOI:10.1002/adsc.200600318

FULL PAPERS
DOI: 10.1002/adsc.200600318
Proline-Catalyzed Imino-Diels–Alder Reactions: Synthesis of
meso-2,6-Diaryl-4-piperidones
Fernando Aznar,a,* Ana-BelØn García,a and María-Paz Cabala
a
Instituto Universitario de Química Organometµlica “Enrique Moles”, Universidad de Oviedo, Juliµn Clavería 8,
33006 Oviedo, Spain
Fax : (+34)-985-103-446; e-mail: pcabal@uniovi.es
Received: June 30, 2006; Accepted: September 14, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Amine-catalyzed imino-Diels–Alder reac- stereoselective synthesis of meso-2,6-diaryl-4-piperi-
tions of acyclic a,b-unsaturated ketones with imines dones in one direct step.
have been developed. l-Proline catalyzed the in situ
generation of 2-amino-1,3-butadienes to provide a Keywords: 2-amino-1,3-butadienes; meso-2,6-diaryl-
4-piperidones; hetero-Diels–Alder reaction; nitrogen
heterocycles; organic catalysis; l-proline
Introduction
4-Oxopiperidine ring systems play an important role
in heterocyclic chemistry from the chemical, biologi-
cal and medicinal points of view.[1] In particular, 2,6-
disubstituted-4-piperidones are found in the frame-
works of many biologically active natural products.[2]
The hetero-Diels–Alder reaction is well-known as a
powerful tool for the construction of functionalized
six-membered heterocyclic rings.[3]
Figure 1. Preparation of meso-2,6-disubstituted-4-piperi-
dones using a Lewis acid as catalyst.
have also been applied as catalysts of Diels–Alder di-
One of the ongoing themes of research in our labo- merization reactions of a,b-unsaturated carbonyl
ratory has been the synthesis of 4-piperidones with compounds, by the in situ formation of an electron-
high stereoselectivity employing the imino-Diels– deficient dienophile via iminium ion formation[12]
Alder reaction of 2-amino-1,3-butadienes with non- (Figure 2, I) and an electronically-activated diene
activated aldimines.[4] Moreover, this cycloaddition through enamine formation[13] (Figure 2, II).
can also be carried out asymmetrically to give adducts
Taking into consideration this latter strategy involv-
in very high enantiomeric excesses.[5] Recently, we de- ing the in situ generation of 2-amino-1,3-butadienes,
scribed an efficient method for the stereoselective we considered the possibility of using chiral amines as
synthesis of meso-2,6-disubstituted-4-piperidones by the catalyst for the imino-Diels–Alder reaction with
the imino-Diels–Alder reaction of 3-unsubstituted-2- aldimines (Figure 3). During the preparation of this
aminodienes using Cu(OTf)2 as a Lewis acid catalyst manuscript we became aware of the first enantioselec-
G
(Figure 1).[6] In this case, it was necessary to prepare tive aza-Diels–Alder reaction catalyzed by an amino
and isolate the 2-amino-1,3-diene reactant in advance acid, l-proline.[14] In this report, only cyclic a,b-unsa-
in order for this reaction to be successful.
turated ketones were used as substrates. Here we
In the past few years, small organic molecules such report an amine-catalyzed imino-Diels–Alder reaction
as chiral amines have been used as catalysts for a between acyclic a,b-unsaturated ketones and aldi-
wide range of enantioselective transformations.[7] In mines, providing an efficient single-step route to the
particular, l-proline has been reported to catalyze synthesis of meso-2,6-disubstituted-4-piperidones.
asymmetric aldol,[8] Michael,[9] Mannich,[10] a-amina-
tion[11] and related reactions. Recently, organoamines
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Fernando Aznar et al.
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Figure 2. Amine-catalyzed Diels–Alder dimerization reactions.
the desired cyclo product was obtained even after
72 h; only starting material was recovered from these
reaction mixtures.
The concentration of substrate also affects the yield
of the reaction (Table 1).[15] We found that changing
the molar ratio of a,b-unsaturated ketone:imine from
1:1 to 4:1 increased the product yield by about 30%
Figure 3. Retrosynthetic analysis for the synthesis of meso-
2,6-diaryl-4-piperidones.
Table 1. Effect of changing the molar ratios of ketone
1:imine 2 on the formation of cycloadduct 3a in the presence
of l-proline (20 mol%) in methanol.
Results and Discussion
Entry Compound 1 (equivs.)[a] Temp. [8C] Yield [%][b]
In an initial experiment commercially available trans-
4-phenyl-3-buten-2-one (2 mmol) and N-allylbenzald-
imine (1 mmol) were mixed in the presence of a cata-
lytic amount of l-proline (20 mol%) in methanol
(1.5 mL). After vigorously stirring the mixture for
24 h, the reaction was quenched by extraction and the
crude product was purified by column chromatogra-
phy on silica gel to furnish the desired imino-Diels–
1
2
3
4
1
2
4
6
r.t.
r.t.
r.t.
r.t.
50
65
77
63
[a]
[b]
Equivalents of ketone 1 to imine 2.
Yield after column chromatographic purification.
Alder product, (2R,6S)-N-allyl-2,6-diphenyl-4-piperi- (entries 1 and 3). In this case, the use of an excess of
done (3a), in 65% yield with >93% diastereoselectiv- ketone is not an inconvenience since the imino-Diels–
ity (Scheme 1).
Alder adduct can be easily separated out by an acid-
base extraction work-up. However, lower or higher
molar ratios led to a decrease in the product yield
(entries 2 and 4).
Another important factor was the reaction temper-
ature (Table 2). When the reaction of ketone 1 with
imine 2 was carried out in methanol at À208C, no cy-
cloaddition product was isolated (entry 4) and at 08C
only a trace of the product 3a was observed (entry 3).
In both cases, starting materials were recovered even
when the reaction mixture was allowed to stir for
Scheme 1. Imino-Diels–Alder reaction catalyzed by l-pro-
line.
Table 2. Effect of the reaction temperature on the yield of
the l-proline-catalyzed imino-Diels–Alder reaction between
ketone 1 and imine 2 (4:1 molar ratio) in methanol.
Encouraged by this experiment, we investigated dif-
ferent reaction conditions to optimize this process.
First, we studied the solvent effect. Neither anhydrous
solvents nor use of inert atmosphere conditions were
found to be necessary or beneficial. We obtained the
best results using MeOH as solvent; in DMSO the
yield decreased to 27%, and with CH3CN only a
trace (5%) of compound 3a was observed. When the
reaction was performed in other solvents (THF,
CHCl3, DMF, dioxane, toluene and EtOAc), none of
Entry
Compound 1 (equivs.)
Temp. [8C]
Yield [%][a]
1
2
3
4
4
4
4
4
40
r.t.
0
À20
49
77
traces (<5)
–
[a]
Yield after column chromatography purification.
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Proline-Catalyzed Imino-Diels–Alder Reactions
FULL PAPERS
Table 4. Preparation of meso-2,6-diaryl-4-piperidones
using l-proline as catalyst.
3
96 h. At room temperature (23–258C), product 3a was
obtained in 77% yield (entry 2) but at higher temper-
ature (408C) the yield decreased to only 49% due
perhaps to product decomposition (entry 1).
Besides l-proline, A, we also tested two other sec-
ondary amines as catalysts, (S)-2-methoxymethylpyr-
rolidine, B, and (S)-1-(2-pyrrolidinylmethyl)pyrroli-
dine, C (Table 3). Of the three catalysts screened for
Entry Compound Ar
R
de
Yield
[%][a] [%][b]
Table 3. Effect of catalyst on the imino-Diels–Alder reac-
tion.
1
2
3
4
5
3a
3b
3c
3d
3e
Ph
Ph
Ph
Ph
Ph
allyl
>93 77
homoallyl >97 59
Bu
Ph
p-MeO-
C6H4
allyl
>97 23
90 22
90 21
6
7
3f
3g
p-MeO-
C6H4
3,4-di-
>96 40
>96 42
allyl
Entry Catalyst (equivs.)[a] Additive (equivs.) Yield [%]
MeO-C6H3
p-F-C6H4
p-Cl-C6H4
o-Br-C6H4
o-I-C6H4
8
9
10
11
3h
3i
3j
allyl
allyl
allyl
allyl
>95 66
>97 64
>96 66
>96 67
1
2
3
4
5
6
7
A (0.2)
A (0.4)
A (0.2)
B (0.2)
B (0.2)
C (0.2)
C (0.2)
–
–
77
76
68
–
p-TsOH (0.2)
–
p-TsOH (0.2)
–
p-TsOH (0.2)
3k
58[b]
–
[a]
[b]
1
Determined by H NMR of the crude reaction mixture.
Isolated yield of the meso diastereomer after chromato-
graphic purification.
61[c]
[a]
[b]
[c]
Equivalents of catalyst.
de=94%.
de=92%.
tries 8–11). When the aryl substituent is halogen, the
acid-base extraction to eliminate the excess ketone 1
was unsuccessful, but the products 3h–k can be isolat-
the reaction of ketone 1 with imine 2, l-proline was ed by extraction with saturated NaCO3H solution fol-
the most efficient (entry 1). In the case of l-proline, a lowed by flash chromatography.
higher concentration of catalyst or the presence of p-
On the other hand, the reaction is highly sensitive
toluenesulfonic acid did not improve the reaction to the N-substituent of the imine. Although the reac-
yield (entries 2 and 3). When secondary amines B and tion takes place for N-arylimines [Ph, 4-MeO-C6H4
C were employed, the reaction did not proceed to any (PMP), entries 4 and 5] and N-alkylimines (Bu, homo-
measurable extent (entries 4 and 6); but in the pres- allyl; entries 2 and 3), in some cases we observed low
ence of 20 mol% of p-TsOH, the adduct 3 was ob- conversion. The best results are obtained for N-allyl-
tained in 58% and 61% yield, respectively (entries 5 substituted imines (entries 1 and 6–11), which have
and 7). These results suggest that both the amine cat- the additional and attractive advantage that the allyl
alyst and an acid catalyst are required to promote for- group can be easily removed after the cycloaddition
mation and equilibration of the initial iminium ion to following published methods.[18] Deprotection of the
the reactive enamine.
N-allyl group of piperidones 3 using a first generation
This methodology under these optimized conditions Grubbs catalyst[19] provided the N-unsubstituted
was then extended to the synthesis of different meso- meso-2,6-diaryl-4-piperidones
2,6-diaryl-4-piperidones 3. These adducts could be (Scheme 2).
4
in good yields
readily obtained from reactions in which the aryl sub-
We next investigated the application of this meth-
stituent of the a,b-unsaturated ketone 1[16] is properly odology to the preparation of enantiomerically en-
matched with the arylimine 2.[17] The results are sum- riched 2,6-disubstituted-4-piperidones by using differ-
marized in Table 4.
ent aryl substituents (Ar1, Ar2) on the a,b-unsaturated
The reaction is general and the meso-2,6-diaryl-4- ketone and imine (Scheme 3). In all cases examined,
piperidones 3 were obtained with excellent diastereo- the cis-2,6-disubstituted-4-piperidones 5 were ob-
selectivities and fairly good yields regardless of the tained from the reactions as one diastereoisomer but,
structure of the aryl substituent, from electron-rich unfortunately, the compound was racemic (by HPLC
(MeO, entries 6 and 7) to electron poor (halogen, en- analysis).[20] Also, a small amount (<5%) of meso
Adv. Synth. Catal. 2006, 348, 2443 – 2448
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Fernando Aznar et al.
FULL PAPERS
mediates are in equilibrium (Scheme 4). First, the 2-
amino-1,3-butadiene IV is generated in situ by the re-
action of the a,b-unsaturated ketone with l-proline,
giving the iminium zwitterion III. Equilibration of III
to 2-amino-1,3-butadiene IV, followed by cycloaddi-
tion with the imine, provides tethahydropyridine
adduct V which hydrolyzes to the unsymetrical 4-pi-
peridone 5. Alternatively, intermediate V could un-
dergo equilibration under the reaction conditions to
its regioisomer Vꢀ prior to hydrolysis, and then under-
go retro-imino-Diels–Alder cycloaddition to obtain
the 2-amino-1,3-butadiene and the imine in which the
Ar1 and Ar2 groups have been interchanged relative
to the initial starting materials. Cycloaddition be-
tween the two sets of dienes and imines present in the
Scheme 2. Deprotection of N-allyl-4-piperidones using
Grubbs catalyst.
compounds 3a, f, h, i could be obtained from the media could thereby give rise to the meso-4-piperi-
crude reaction mixtures.
dones 3 byproducts observed in these reactions.
To explain the formation of these minor (meso) by-
products we propose a mechanism where all the inter-
Scheme 3. Preparation of unsymmetrical 2,6-disubstituted-4-piperidones 5.
Scheme 4. A putative pathway for the proline-catalyzed imino-Diels–Alder reaction leading to unsymmetrical 2,6-disubstitut-
ed-4-piperidones 5.
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Proline-Catalyzed Imino-Diels–Alder Reactions
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meso-N-Allyl-2,6-bis(4-fluorophenyl)-4-piperidone (3h):
Conclusions
Employing Method B; yield: 216 mg (66%); yellow solid,
1
mp 107–1098C; Rf = 0.26 (hexane/EtOAc, 10:1); H NMR
In summary, we have described, to the best of our
knowledge, the first synthesis of meso-2,6-diaryl-4-pi-
peridones by an l-proline-catalyzed imino-Diels–
Alder reaction between acyclic a,b-unsaturated ke-
tones and aldimines. The simplicity and mildness of
the reaction protocol make this a very efficient and
stereoselective method to obtain meso or cis-N-substi-
tuted or N-unsubstituted-2,6-diaryl-4-piperidones in
good yields. Compared to previously reported meth-
ods, this l-proline-catalyzed cycloaddition methodolo-
gy has the advantages that neither the use of a metal
catalyst [Cu(II)] nor the restriction of having to iso-
late the diene intermediate prior to the cycloaddition
is required, and the reaction can easily be run on a
multigram scale. Further studies aimed at exploring
the applications of this strategy are underway in our
laboratory.
(CDCl3, 300 MHz): d=7.48–7.38 (m, 4H), 7.08 (t, J=8.8
Hz, 4H), 5.83–5.63 (m, 1H), 5.05 (dd, J=10.0, 2.4 Hz, 1H),
4.63 (dd, J=17.2, 2.4 Hz, 1H), 3.94 (dd, J=12.9, 2.8 Hz,
2H), 2.95 (d, J=7.0 Hz, 2H), 2.75 (t, J=12.9 Hz, 2H), 2.50
(dd, J=12.9, 2.8 Hz, 2H); 13C NMR (CDCl3, 75.4 MHz): d=
206.5 (CO), 162.0 (d, J=244.0; 2”C), 138.0 (2”C), 130.3
(CH), 128.7 (d, J=7.9 Hz, 4”CH), 119.6 (CH2), 115.6 (d,
J=21 Hz, 4”CH), 63.6 (2”CH), 51.2 (CH2), 50.7 (2”CH2);
HR-MS: m/z=327.1419, calcd. for C20H19F2NO: 327.1435.
General Experimental Procedure for the
Deprotection of meso-N-Allyl-2,6-diaryl-4-
piperidones. Synthesis of meso-2,6-Diaryl-4-
piperidones 4a, f, h, k
Bis(tricyclohexylphosphine)benzylidine ruthenium(IV) chlo-
ride (5 mol%, Grubbsꢁ catalyst) was added in portions
under nitrogen to a solution of the corresponding meso-N-
allyl-2,6-diaryl-4-piperidones 3a, f, h, k (100 mg) in anhy-
drous toluene (5 mL) and the mixture was heated at reflux
for 12 h. Then, the mixture was concentrated under reduced
pressure and was purified by flash column chromatography
(silica gel, mixtures of hexane/EtOAc) to afford the desired
N-unprotected meso-2,6-diaryl-4-piperidones 4a, f, h, k.
meso-2,6-Diphenyl-4-piperidone (4a): yield: 168 mg
(67%); white solid, mp 102–1058C; Rf = 0.43 (hexane/
Experimental Section
Typical Experimental Procedure for the Preparation
of meso-N-Substituted-2,6-diaryl-4-piperidones 3a–k
Method A: To a mixture of a,b-unsaturated ketone 1[16]
(4 mmol, 4 equivs.) and l-proline (20 mol%) in MeOH
(1.5 mL or 5 mL in the case of 1e, f) was added imine 2[17]
(1 mmol, 1 equiv.) and the reaction mixture was allowed to
stir at room temperature for 24 h. Then, the solvent
(MeOH) was evaporated under reduced pressure and the
reaction mixture was subject to an acid-base extraction
work-up to eliminate the excess of ketone 1. Ethyl acetate
(10 mL) was added to the reaction crude and the organic
layer was washed with HCl (1 N) (3”5 mL). The aqueous
layers were combined and added quickly to a solution of 1
N NaOH (25 mL) and extracted thoroughly with EtOAc
(3”20 mL). The combined organic phases were dried
(Na2SO4), concentrated, and purified by flash column chro-
matography (silca gel, mixtures of hexane/EtOAc) to afford
the desired pure meso-N-substituted-2,6-diaryl-4-piperidones
3a–g.
Method B: It is the same procedure as Method A but in
this case the acid-base extraction was unsuccessful and the
product could be isolated by extraction with saturated
NaHCO3 solution followed by flash chromatograghy column
on silica gel to furnish the desired pure meso-N-substituted-
2,6-diaryl-4-piperidones 3h–k.
meso-N-Allyl-2,6-diphenyl-4-piperidone (3a): Employing
Method A, yield: 224 mg (77%); yellow oil; Rf = 0.31
(hexane/EtOAc, 10:1); 1H NMR (CDCl3, 300 MHz): d=
7.49–7.30 (m, 10H), 5.83–5.72 (m, 1H), 5.04 (dd, J=10.2, 2.0
Hz, 1H), 4.64 (dd, J=17.1, 2.0 Hz, 1H), 3.96 (dd, J=12.8,
2.3 Hz, 2H), 3.00 (d, J=7.1 Hz, 2H), 2.81 (t, J=12.8 Hz,
2H), 2.53 (dd, J=12.8, 2.3 Hz, 2H); 13C NMR (CDCl3,
75.4 MHz): d=207.1 (CO), 142.4 (2”C), 130.5 (CH), 128.6
(4”CH), 127.5 (2”CH), 127.2 (4”CH), 119.5 (CH2), 64.4
(2”CH), 51.0 (CH2), 50.8 (2”CH2); HR-MS: m/z=
291.1616, calcd. for C20H21NO: 291.1623.
1
EtOAc, 5:1); H NMR (CDCl3, 300 MHz): d=7.53–7.28 (m,
10H), 4.11 (dd, J=10.1, 4.2 Hz, 2H), 2.71–2.58 (m, 4H),
2.18 (bs, 1H); 13C NMR (CDCl3, 75.4 MHz): d=208.0 (CO),
142.6 (2”C), 128.6 (4”CH), 127.8 (2”CH), 126.5 (4”CH),
61.0 (2”CH), 50.3 (2”CH2); HR-MS: m/z=251.1301, calcd.
for C17H17NO: 251.1310.
Typical Experimental Procedure for the Preparation
of cis-N-Allyl-2,6-disubstituted-4-piperidones 5f, h, i
The same procedure described for the preparation of meso-
N-substituted-2,6-diaryl-4-piperidones 3a–k (Method A) has
been used for the synthesis of 5f, h, i.
cis-N-Allyl-2-(4-methoxyphenyl)-6-phenyl-4-piperidone
(5f): yield: 151 mg (47%); yellow oil; Rf =0.26 (hexane/
EtOAc, 10:1); 1H NMR (CDCl3, 300 MHz): d=7.49–7.28
(m, 7H), 6.93 (d, J=8.3 Hz, 2H), 5.84–5.70 (m, 1H), 5.04
(dd, J=10.3, 1.0 Hz, 1H), 4.65 (dd, J=17.1, 1.0 Hz, 1H),
3.96–3.84 (m, 2H), 3.84 (s, 3H), 2.98 (d, J=7.1 Hz, 2H),
2.79 (t, J=12.7 Hz, 2H), 2.54–2.48 (m, 2H); 13C NMR
(CDCl3, 75.4 MHz): d=207.5 (CO), 158.9 (C), 142.5 (C),
134.5 (C), 130.7 (CH), 128.7 (2”CH), 128.3 (2”CH), 127.5
(CH), 127.3 (2”CH), 119.4 (CH2), 114.0 (2”CH), 64.5
(CH), 63.8 (CH), 55.2 (CH3), 51.1 (CH2), 51.0 (CH2), 50.9
(CH2); HR-MS: m/z=321.1715, calcd. for C21H23NO2:
321.1729.
Supporting Information
Experimental datas for compounds 3b–g, 3i–k, 4f, 4h, 4k, 5h
1
and 5i. H and 13C NMR spectra for all compounds.
Adv. Synth. Catal. 2006, 348, 2443 – 2448
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
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Fernando Aznar et al.
FULL PAPERS
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Acknowledgements
Financial support by Asturpharma S.A. and the projects PC-
CIS01–22 (FICYT) and PR-01-GE-9 (Grupo de Excelencia
FICYT) from the Consejería de Educación y Cultura del
Principado de Asturias are gratefully acknowledged.
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