Stereoselective synthesis of meso- and cis-2,6-diarylpiperidin-4-ones catalyzed by L-proline

Article abstract of DOI:10.1055/s-2007-990814

A convenient stereoselective preparation of meso- and cis-2,6- diarylpiperidin-4-ones has been developed by aza-Diels-Alder reaction catalyzed by L-proline from simple and commercially available starting materials. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990814

PRACTICAL SYNTHETIC PROCEDURES
479
Stereoselective Synthesis of meso- and cis-2,6-Diarylpiperidin-4-ones
Catalyzed by L-Proline
S
tereoselectiv
e
e
S
ynthesis
r
of meso
n
and cis-2,6-
a
D
iarylpipe
n
ridin-4-onesdo Aznar,* Ana-Belén García, Noelia Quiñones, María-Paz Cabal
Unidad Asociada al C.S.I.C., Instituto Universitario de Química Organometálica ‘Enrique Moles’,
Universidad de Oviedo, C/ Julián Clavería 8, 33006 Oviedo, Spain
Fax +34(98)5103446; E-mail: pcabal@uniovi.es
PSP
Received 5 July 2007
No111
Abstract: A convenient stereoselective preparation of meso- and cis-2,6-diarylpiperidin-4-ones has been developed by aza-Diels–Alder
reaction catalyzed by L-proline from simple and commercially available starting materials.
Key words: 2,6-diarylpiperidin-4-ones, organocatalysis, L-proline, aza-Diels–Alder, nitrogen heterocycles
Ar1
O
Ar1
Ar1
L-proline
L-proline
R
R
Ar2
H
N
(20 mol%)
(20 mol%)
N
MeOH, r.t., 24 h
MeOH, r.t., 24 h
Ar2
O
Ar2
O
RNH2
O
1
2
3 Ar1 = Ar2
4 Ar1 = Ar2
1
Procedure 2
Procedure 1
R = allyl Grubbs' cat. (5 mol%)
Ar1 = Ar2
refluxing toluene
12 h
Ar1
NH
Ar1
O
5
Scheme 1
drawbacks such as restrictions in the choice of substitu-
ents, low yields, and elaborated starting materials. Over
Introduction
The piperidine ring is an important framework present in the past few years organocatalysis has become very pop-
a large variety of natural products.1 In particular, piperi- ular for a wide range of enantioselective transformations.
din-4-ones are versatile building blocks due to the easy In particular, L-proline has been reported to catalyzed
manipulation of the carbonyl group for the introduction of asymmetric aldol, Michael, Mannich, a-amination, Diels–
different substituents into the six-membered ring.2 Substi- Alder dimerization, and aza-Diels–Alder reactions with
tution at the C2 and C6 positions are very frequent and in cyclic enones.5 As part of our ongoing interests in the syn-
some cases biological activity studies have shown a rela- thesis of piperidin-4-ones with high stereoselectivity em-
tionship between the biological activity and the aromatic ploying the aza-Diels–Alder reaction of 2-aminobuta-1,3-
rings present in those positions.3 Even though synthesis of dienes with unactivated aldimines,6 we decided to com-
piperidin-4-ones is still a very important theme of re- bine our experience in this field and use organocatalysis to
search and several synthetic methods have been devel- described a new synthesis of 2,6-disubstituted piperidin-
oped,2b,c the number of references for the synthesis of 2,6- 4-ones by the aza-Diels–Alder reaction between an acy-
disubstituted piperidin-4-ones are remarkably fewer and, clic enone and an aldimine (or an aldehyde and an amine
in particular, in the case of 2,6-diarylpiperidin-4-ones as a multi-component reaction) in the presence of L-pro-
very few methodologies can be found in the literature.4 line as catalyst, without preformation of the aminodienes.7
Moreover some of these methods suffer from several We describe here the development of an efficient single-
step synthesis of a wide range of meso-or cis-N-substitut-
ed or N-unsubstituted 2,6-diarylpiperidin-4-ones 3–5 in
good yields and high diastereoselectivity (Scheme 1). An
SYNTHESIS 2008, No. 3, pp 0479–0484
Advanced online publication: 25.09.2007
DOI: 10.1055/s-2007-990814; Art ID: Z16207SS
x
x
.
x
x
.2
0
0
7
© Georg Thieme Verlag Stuttgart · New York

480
F. Aznar et al.
PRACTICAL SYNTHETIC PROCEDURES
attractive feature of this chemistry includes the one-pot, tion workup in almost all the examples (except 3h–k, see
three-component, aza-Diels–Alder reaction.
experimental section for details). Two other secondary
amines were also tested as the catalyst, (S)-2-(methoxy-
methyl)pyrrolidine and (S)-1-(pyrrolidin-2-ylmethyl)pyr-
rolidine but in these cases the reaction did not proceed,
however, in the presence of 4-toluenesulfonic acid (20
Scope and Limitations
The optimal reaction conditions were as follows: com- mol%), 3a was obtained in lower yield (58% and 61% re-
mercially available (E)-4-phenylbut-3-en-2-one (1a, 4 spectively). Thus, of the three catalysts screened, L-pro-
mmol) and N-allylbenzaldimine (1 mmol) were mixed in line was the most efficient.
the presence of a catalytic amount of L-proline (20 mol%)
in methanol (1.5 mL). After vigorously stirring the mix-
ture for 24 hours, the reaction was subjected to extraction
and the crude product was purified by column chromatog-
raphy on silica gel to furnish (2R*,6S*)-1-allyl-2,6-diphe-
nylpiperidin-4-one (3a) in 77% yield with >93%
This methodology, under the optimized conditions, was
extended to the synthesis of a variety of meso-2,6-di-
arylpiperidin-4-ones 3a–k with excellent diastereoselec-
tivities and good yields (Table 1). The reaction is fairly
general with regards to the structure of the aryl substitu-
ent, both electron-rich (Table 1, entries 6 and 7) and elec-
diastereoselectivity. Solvent effects were studied for this
tron-poor (Table 1, entries 8–11) aryl groups can be
reaction and neither anhydrous solvents nor use of inert
utilized. However, the outcome of the cycloaddition is
greatly affected by the N-substituent of the imine; with N-
aryl (Ph, 4-MeOC6H4, Table 1, entries 4 and 5) and N-
atmosphere conditions were found to be necessary. When
the reaction was performed in dimethyl sulfoxide and ace-
tonitrile the yield decreased considerably (25% and 5%,
alkylimines (but-3-enyl, Bu, Table 1, entries 2 and 3) we
respectively) and when other solvents were used (THF,
observed low conversion, but still high diastereoselectivi-
CHCl3, DMF, EtOAc, dioxane, toluene) only starting ma-
ties.
terial was recovered from the reaction mixture under the
We also investigated the application of this methodology
using different aryl substituents on the a,b-unsaturated
ketone and imine. In all cases examined, we obtained
from the reaction mixture the cis-2,6-disubstituted piperi-
din-4-ones 4 as one diastereomer (Table 2) but, unfortu-
same reaction conditions. Another important factor was
the reaction temperature. The experiments were run from
–20 °C to 40 °C and we found that those conducted at
room temperature (23–25 °C) afforded higher yields,
while at 40 °C some decomposition products were ob-
nately, the reaction lacked promising enantioselectivity
served. The concentration of substrate also affects the
(by HPLC analysis).
yield of the reaction. Among all the different molar ratio
of a,b-unsaturated ketone/imine (1:1; 2:1; 4:1, 6:1) tested,
the best yield was found with a 4:1 ratio. The use of an ex-
cess of ketone is not an inconvenience since products 3
and 4 can be easily separated out by an acid–base extrac-
An important novelty and advantage of this methodology
is that the one-pot, three-component aza-Diels–Alder re-
action was also successful (procedure 2). Thus, 4-phenyl-
but-3-en-2-one 1 (4 mmol, 4 equiv) was added to a
Table 1 1-Substituted meso-2,6-Diarylpiperidin-4-ones 3 Prepared
Entry
Product
Ar1
Yielda (%)
Proc. 1
drb
Ar2
R
Proc. 2
1
2
Ph
Ph
CH2CH=CH2
(CH2)2CH=CH2
n-Bu
3a
3b
3c
3d
3e
3f
77
59
23
22
21
40
42
66
64
66
67
79
–
93:7
97:3
97:3
90:10
90:10
96:4
96:4
95:5
97:3
96:4
96:4
Ph
Ph
3
Ph
Ph
–
4
Ph
Ph
Ph
–
5
Ph
Ph
4-MeOC6H4
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
14
55
–
6
4-MeOC6H4
3,4-(MeO)2C6H3
4-FC6H4
4-ClC6H4
2-BrC6H4
2-IC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
4-FC6H4
4-ClC6H4
2-BrC6H4
2-IC6H4
7
3g
3h
3i
8
–
9
–
10
11
3j
61
–
3k
a Isolated yield after chromatographic purification.
b Determined by 1H NMR of the crude reaction mixture.
Synthesis 2008, No. 3, 479–484 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of meso- and cis-2,6-Diarylpiperidin-4-ones
481
Table 2 cis-1-Allyl-2,6-diarylpiperidin-4-ones 4 Prepared
Entry
Product
Ar1
Yielda (%)
drb
Ar2
R
Proc. 1
47
Proc. 2
48
1
2
3
4
Ph
Ph
Ph
Ph
4-MeOC6H4
4-FC6H4
4-ClC6H4
2-BrC6H4
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
CH2CH=CH2
4a
4b
4c
4d
95:5
95:5
98:2
98:2
59
68
61
15
–
15
a Isolated yield after chromatographic purification.
b Determined by 1H NMR of the crude reaction mixture.
ture extracted thoroughly with EtOAc (3 × 20 mL). The combined
organic phases were dried (Na2SO4), concentrated, and purified by
column chromatography (silica gel, mixtures of hexane–EtOAc) to
afford the desired pure product.
mixture of an aromatic aldehyde (1 mmol, 1 equiv), allyl-
amine (1.1 mmol, 1.1 equiv), and L-proline (20 mol%) in
methanol (2 mL). After stirring the mixture for 24 hours,
the mixture was subjected to acid–base extraction workup
and the crude product was purified by column chromatog-
raphy, furnishing the products with yields (except 4c,d)
and diastereoselectivities similar to those observed for the
corresponding reaction with preformed aldimines
(Table 1, entries 1, 5, 6, 10 and Table 2, entries 1–4).
Method B: As for Method A, but in this case, acid–base extraction
was unsuccessful and the product was isolated by extraction with
sat. NaHCO3 solution followed by column chromatography (silica
gel) to give the desired pure meso-N-substituted 2,6-diarylpiperi-
din-4-ones 3h–k.
Procedure 2
Fortunately, the best results were obtained for N-allyl-
substituted imines, which have the additional advantage
that the allyl group can be easily removed after the cy-
cloaddition providing the N-unsubstituted meso-2,6-di-
arylpiperidin-4-ones 5 in good yields8 (Table 3).
To a mixture of aromatic aldehyde (1 mmol, 1 equiv), allylamine
(1.1 mmol, 1.1 equiv), and L-proline (20 mol%) in MeOH (2 mL)
was added 4-phenylbut-3-en-2-one 1 (4 mmol, 4 equiv) and the
mixture was allowed to stir at r.t. for 24 h. The solvent was then
evaporated under reduced pressure and the mixture was subject to
an acid–base extraction workup (see procedure 1, method A) to af-
ford the desired products.
Table 3 meso-2,6-Diarylpiperidin-4-ones 5 Prepared
Entry
Product
Ar1
Yielda (%)
meso-1-Allyl-2,6-diphenylpiperidin-4-one (3a)
Yellow oil; yield: 224 mg (77%, procedure 1, method A); 230 mg
(79%, procedure 2); Rf = 0.31 (hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.49–7.30 (m, 10 H), 5.83–5.72
(m, 1 H), 5.04 (dd, J = 10.2, 2.0 Hz, 1 H), 4.64 (dd, J = 17.1, 2.0 Hz,
1 H), 3.96 (dd, J = 12.8, 2.3 Hz, 2 H), 3.00 (d, J = 7.1 Hz, 2 H), 2.81
(t, J = 12.8 Hz, 2 H), 2.53 (dd, J = 12.8, 2.3 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): 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).
1
2
3
4
Ph
5a
5b
5c
5d
67
68
70
63
4-MeOC6H4
4-FC6H4
2-IC6H4
a Isolated yield after chromatographic purification.
HRMS: m/z [M]+ calcd for C20H21NO: 291.1623; found: 291.1616.
meso-1-But-3-enyl-2,6-diphenylpiperidin-4-one (3b)
Yellow oil; yield: 180 mg (59%, procedure 1, method A); Rf = 0.39
(hexane–EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 7.52–7.33 (m, 10 H), 5.31–5.14
(m, 1 H), 4.73–4.62 (m, 2 H), 3.99 (dd, J = 11.9, 2.9 Hz, 2 H), 2.85
(t, J = 11.9 Hz, 2 H), 2.56 (d, J = 11.9 Hz, 2 H), 2.44 (m, 2 H), 1.99–
1.92 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 207.3 (CO), 142.3 (2 C), 135.9
(CH), 128.6 (4 CH), 127.6 (2 CH), 127.2 (4 CH), 115.4 (CH2), 64.8
(2 CH), 50.5 (2 CH2), 48.7 (CH2), 26.3 (CH2).
Herein we describe two general procedures for the different sub-
strate classes depicted in Scheme 1 and in Tables 1– 3. Compound
4d has not been previously described; for the other compounds, see
ref. 7.
1-Substituted meso-2,6-Diarylpiperidin-4-ones 3a–k and
cis-1-Allyl-2-aryl-6-phenylpiperidin-4-ones 4a–d; General
Procedure
Procedure 1
Method A: To a mixture of a,b-unsaturated ketone 19 (4 mmol, 4
equiv) and L-proline (20 mol%) in MeOH (1.5 mL or 5 mL in the
case of 1e,f) was added imine 210 (1 mmol, 1 equiv) and the mixture
was allowed to stir at r.t. for 24 h. Then, the solvent (MeOH) was
evaporated under reduce pressure and the mixture was subject to an
acid–base extraction workup to eliminated the excess of ketone 1.
EtOAc (10 mL) was added to the reaction crude and the organic lay-
er was washed with 1 M HCl (3 × 5 mL). The aqueous layers were
combined and 1 M NaOH (25 mL) was added rapidly and the mix-
HRMS: m/z [M]+ calcd for C21H23NO: 305.1780; found: 305.1781.
meso-1-Butyl-2,6-diphenylpiperidin-4-one (3c)
Yellow oil; yield: 71 mg (23%, procedure 1, method A); Rf = 0.30
(hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.48–7.26 (m, 10 H), 3.92 (dd,
J = 13.7, 2.0 Hz, 2 H), 2.81 (t, J = 13.7 Hz, 2 H), 2.51 (d, J = 13.7
Synthesis 2008, No. 3, 479–484 © Thieme Stuttgart · New York

482
F. Aznar et al.
PRACTICAL SYNTHETIC PROCEDURES
Hz, 2 H), 2.35–2.29 (m, 2 H), 1.19–1.09 (m, 2 H), 0.76–0.64 (m, 2
H), 0.52 (t, J = 7.1 Hz, 3 H).
13C NMR (75.4 MHz, CDCl3): d = 207.6 (CO), 142.6 (2 C), 128.6
(4 CH), 127.5 (2 C), 127.2 (4 CH), 64.7 (2 CH), 50.6 (2 CH2), 40.8
(CH2), 23.1 (CH2), 20.1 (CH2), 13.5 (CH3).
H), 4.63 (dd, J = 17.2, 2.4 Hz, 1 H), 3.94 (dd, J = 12.9, 2.8 Hz, 2 H),
2.95 (d, J = 7.0 Hz, 2 H), 2.75 (t, J = 12.9 Hz, 2 H), 2.50 (dd,
J = 12.9, 2.8 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 206.5 (CO), 162.0 (d, J = 244.0
Hz, 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).
HRMS: m/z [M]+ calcd for C21H25NO: 307.1936; found: 307.1932.
meso-1,2,6-Triphenylpiperidin-4-one (3d)
Yellow solid; yield: 72 mg (22%, procedure 1, method A); Rf = 0.29
(hexane–EtOAc, 6:1).
HRMS: m/z [M]+ calcd for C20H19F2NO: 327.1435; found:
327.1419.
meso-1-Allyl-2,6-bis(4-chlorophenyl)piperidin-4-one (3i)
Yellow solid; yield: 231 mg (64%, procedure 1, method B); Rf =
0.43 (hexane–EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 7.43–7.33 (m, 8 H), 5.80–5.66 (m,
1 H), 5.07 (dd, J = 13.2, 2.0 Hz, 1 H), 4.67 (dd, J = 17.0, 2.0 Hz, 1
H), 3.94 (dd, J = 12.4, 2.7 Hz, 2 H), 2.97 (d, J = 7.1 Hz, 2 H), 2.73
(t, J = 12.4 Hz, 2 H), 2.50 (dd, J = 12.4, 2.7 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 206.0 (CO), 140.7 (2 C), 133.1
(2 C), 130.0 (CH), 128.9 (4 CH), 128.5 (4 CH), 119.9 (CH2), 63.5
(2 CH), 51.2 (CH2), 50.4 (2 CH2).
1H NMR (300 MHz, CDCl3): d = 7.51–7.30 (m, 13 H), 7.12 (t,
J = 8.3 Hz, 2 H), 4.62 (dd, J = 12.8, 2.7 Hz, 2 H), 3.05 (t, J = 12.8
Hz, 2 H), 2.57 (dd, J = 12.8, 2.7 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 207.7 (CO), 143.1 (2 C), 136.0
(C), 129.9 (CH), 129.3 (4 CH), 128.7 (4 CH), 128.6 (5 CH), 128.1
(CH), 64.7 (2 CH), 50.2 (2 CH2).
HRMS: m/z [M]+ calcd for C23H21NO: 327.1623; found: 327.1619.
meso-1-(4-Methoxyphenyl)-2,6-diphenylpiperidin-4-one (3e)
Yellow solid; yield: 75 mg (21%, procedure 1, method A); 50 mg
(14%, procedure 2); Rf = 0.26 (hexane–EtOAc, 8:1).
HRMS: m/z [M]+ calcd for C20H19Cl2NO: 359.0844; found:
359.0833.
1H NMR (300 MHz, CDCl3): d = 7.38–7.16 (m, 10 H), 6.82 (d,
J = 10.5 Hz, 2 H), 6.45 (d, J = 10.5 Hz, 2 H), 4.52 (dd, J = 10.8, 3.3
Hz, 2 H), 3.56 (s, 3 H), 3.12–2.91 (m, 2 H), 2.75 (dd, J = 10.8, 3.3
Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 207.4 (CO), 158.9 (C), 142.5 (2
C), 134.8 (C), 128.9 (4 CH), 128.5 (4 CH), 127.5 (2 CH), 127.1 (2
CH), 114.0 (2 CH), 64 (2 CH), 55.9 (CH3), 50.9 (2 CH2).
meso-1-Allyl-2,6-bis(2-bromophenyl)piperidin-4-one (3j)
Yellow oil; yield: 296 mg (66%, procedure 1, method B); 274 mg
(61%, procedure 2); Rf = 0.28 (hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.85 (d, J = 7.3 Hz, 2 H), 7.55 (d,
J = 7.3 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 2 H), 7.15 (t, J = 7.3 Hz, 2 H),
5.83–5.75 (m, 1 H), 5.10 (d, J = 10.0 Hz, 1 H), 4.64 (d, J = 17.1 Hz,
1 H), 4.52 (dd, J = 12.0, 2.0 Hz, 2 H), 2.98 (d, J = 6.9 Hz, 2 H),
2.63–2.54 (m, 4 H).
HRMS: m/z [M]+ calcd for C24H23NO2: 357.1729; found: 357.1735.
meso-1-Allyl-2,6-bis(4-methoxyphenyl)piperidin-4-one (3f)
White solid, yield: 141 mg (40%, procedure 1, method A); 194 mg
(55%, procedure 2); mp 142–146 °C; Rf = 0.34 (hexane–EtOAc,
5:1).
1H NMR (300 MHz, CDCl3): d = 7.37 (d, J = 8.6 Hz, 4 H), 6.91 (d,
J = 8.6 Hz, 4 H), 5.85–5.65 (m, 1 H), 5.03 (dd, J = 10.2, 2.0 Hz, 1
H), 4.65 (dd, J = 17.1, 2.0 Hz, 1 H), 3.85 (dd, J = 12.5, 2.8 Hz, 2 H),
3.83 (s, 6 H), 2.97 (d, J = 7.0 Hz, 2 H), 2.77 (t, J = 12.5 Hz, 2 H),
2.48 (dd, J = 12.5, J = 2.8 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 205.7 (CO), 141.2 (2 C), 133.1
(2 CH), 130.6 (CH), 129.1 (2 CH), 128.8 (2 CH), 128.1 (2 CH),
122.8 (2 C), 120.4 (CH2), 62.0 (2 CH), 51.9 (CH2), 48.5 (2 CH2).
HRMS: m/z [M]+ calcd for C20H19Br2NO: 446.9833; found:
446.9839.
meso-1-Allyl-2,6-bis(2-iodophenyl)piperidin-4-one (3k)
Yellow solid; yield: 364 mg (67%, procedure 1, method B); mp 98–
100 °C; Rf = 0.36 (hexane–EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 7.82 (d, J = 7.8 Hz, 4 H), 7.44 (t,
J = 7.8 Hz, 2 H), 6.99 (td, J = 7.4, 1.6 Hz, 2 H), 5.93–5.72 (m, 1 H),
5.15 (dd, J = 10.2, 1.6 Hz, 1 H), 4.66 (dd, J = 17.2, 1.6 Hz, 1 H),
4.33 (dd, J = 10.2, 4.0 Hz, 2 H), 2.98 (d, J = 7.1 Hz, 2 H), 2.59 (td,
J = 13.3, 3.9 Hz, 4 H).
13C NMR (75.4 MHz, CDCl3): d = 205.2 (CO), 143.8 (2 C), 139.7
(CH), 130.4 (CH), 129.11 (4 CH), 128.8 (4 CH), 98.6 (2 C), 66.8 (2
CH), 51.6 (CH2), 48.43 (2 CH2).
HRMS: m/z [M]+ calcd for C20H19I2NO: 542.9556; found:
542.9560.
13C NMR (75.4 MHz, CDCl3): d = 207.7 (CO), 158.9 (2 C), 134.7
(2 C), 130.9 (1 CH), 128.4 (4 CH), 119.3 (1 CH2), 114.0 (4 CH),
63.9 (2 CH), 55.2 (2 CH3), 51.1 (3 CH2).
HRMS: m/z [M]+ calcd for C22H25NO3: 351.1834; found: 351.1829.
meso-1-Allyl-2,6-bis(3,4-dimethoxyphenyl)piperidin-4-one (3g)
Yellow solid; yield: 173 mg (42%, procedure 1, method A); mp
109–112 °C; Rf = 0.27 (hexane–EtOAc, 6:1).
1H NMR (300 MHz, CDCl3): d = 7.02–6.81 (m, 6 H), 5.83–5.69 (m,
1 H), 5.03 (d, J = 10.2 Hz, 1 H), 4.67 (d, J = 17.2 Hz, 1 H), 3.92 (s,
6 H), 3.88 (s, 6 H), 3.85 (d, J = 12.9 Hz, 2 H), 3.01 (d, J = 6.9 Hz, 2
H), 2.79 (t, J = 12.9 Hz, 2 H), 2.50 (d, J = 12.9 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 207.2 (CO), 149.1 (2 C), 148.2
(2 C), 134.9 (2 C), 131.1 (CH), 119.5 (2 CH), 119.1 (CH2), 110.9 (2
CH), 110.1 (2 CH), 64.2 (2 CH), 55.8 (2 CH3), 55.7 (2 CH3), 51.2
(CH2), 50.7 (2 CH2).
cis-1-Allyl-2-(4-methoxyphenyl)-6-phenylpiperidin-4-one (4a)
Yellow oil; yield: 151 mg (47%, procedure 1, method A); 154 mg
(48%, procedure 2); Rf = 0.26 (hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.49–7.28 (m, 7 H), 6.93 (d,
J = 8.3 Hz, 2 H), 5.84–5.70 (m, 1 H), 5.04 (dd, J = 10.3, 1.0 Hz, 1
H), 4.65 (dd, J = 17.1, 1.0 Hz, 1 H), 3.96–3.84 (m, 2 H), 3.84 (s, 3
H), 2.98 (d, J = 7.1 Hz, 2 H), 2.79 (t, J = 12.7 Hz, 2 H), 2.54–2.48
(m, 2 H).
HRMS: m/z [M]+ calcd for C24H29NO5: 411.2046; found: 411.2040.
meso-1-Allyl-2,6-bis(4-fluorophenyl)piperidin-4-one (3h)
Yellow solid; yield: 216 mg (66%, procedure 1, method B); mp
107–109 °C; Rf = 0.26 (hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.48–7.38 (m, 4 H), 7.08 (t,
J = 8.8 Hz, 4 H), 5.83–5.63 (m, 1 H), 5.05 (dd, J = 10.0, 2.4 Hz, 1
13C NMR (75.4 MHz, CDCl3): 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
Synthesis 2008, No. 3, 479–484 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of meso- and cis-2,6-Diarylpiperidin-4-ones
483
(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).
13C NMR (75.4 MHz, CDCl3): 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).
HRMS: m/z [M]+ calcd for C21H23NO2: 321.1729; found: 321.1715.
HRMS: m/z [M]+ calcd for C17H17NO: 251.1310; found: 251.1301.
cis-1-Allyl-2-(4-fluorophenyl)-6-phenylpiperidin-4-one (4b)
Yellow solid; yield: 183 mg (59%, procedure 1, method A); 211 mg
(68%, procedure 2); mp 136–139 °C; Rf = 0.28 (hexane–EtOAc,
10:1).
1H NMR (300 MHz, CDCl3): d = 7.40–7.31 (m, 7 H), 7.10 (t,
J = 8.6 Hz, 2 H), 5.85–5.71 (m, 1 H), 5.00 (dd, J = 10.1, 1.8 Hz, 1
H), 4.66 (dd, J = 17.1, 1.8 Hz, 1 H), 3.97 (dd, J = 9.2, 2.4 Hz, 2 H),
3.03–2.91 (m, 2 H), 2.82–2.71 (m, 2 H), 2.54–2.47 (m, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 206.8 (CO), 161.9 (d, J = 244.4
Hz, C), 142.2 (C), 138.1 (C), 130.4 (CH), 128.8 (CH), 128.7 (3 CH),
127.6 (CH), 127.2 (2 CH), 119.5 (CH2), 115.5 (d, J = 21.2 Hz, 2
CH), 64.3 (CH), 63.6 (CH), 51.1 (CH2), 50.8 (CH2), 50.7 (CH2).
meso-2,6-Bis(4-methoxyphenyl)piperidin-4-one (5b)
White solid; yield: 60.2 mg (68%); Rf = 0.20 (hexane–EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 7.38 (d, J = 8.5 Hz, 4 H), 6.89 (d,
J = 8.5 Hz, 4 H), 4.01 (dd, J = 10.8, 3.1 Hz, 2 H), 3.80 (s, 6 H),
2.64–2.51 (m, 4 H), 2.03 (br s, 1 H, NH).
13C NMR (75.4 MHz, CDCl3): d = 208.5 (CO), 159.0 (2 C), 134.8
(2 C), 127.6 (4 CH), 113.9 (4 CH), 60.5 (2 CH), 55.2 (2 CH3), 50.4
(2 CH2).
HRMS: m/z [M]+ calcd for C19H21NO3: 311.1521; found: 311.1535.
meso-2,6-Bis(4-fluorophenyl)piperidin-4-one (5c)
Yellow oil; yield: 61.4 mg (70%); Rf = 0.16 (hexane–EtOAc, 10:1).
HRMS: m/z [M]+ calcd for C20H20FNO: 309.1529; found: 309.1522.
1H NMR (300 MHz, CDCl3): d = 7.44 (dd, J = 8.1, 5.2 Hz, 4 H),
7.04 (t, J = 8.1 Hz, 4 H), 4.05 (dd, J = 9.4, 5.0 Hz, 2 H), 2.53 (m, 4
H), 2.36 (br s, 1 H).
13C NMR (75.4 MHz, CDCl3): d = 207.3 (CO), 162.1 (d, J = 244.2
Hz, 2 C), 138.2 (2 C), 128.0 (4 C), 115.4 (d, J = 20.8 Hz, 4 C), 60.2
(2 CH), 50.1 (2 CH2).
cis-1-Allyl-2-(4-chlorophenyl)-6-phenylpiperidin-4-one (4c)
White solid; yield: 199 mg (61%, procedure 1, method A); 49 mg
(15%, procedure 2); Rf = 0.27 (hexane–EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.46–7.28 (m, 9 H), 5.79–5.68 (m,
1 H), 5.04 (dt, J = 10.3, 0.9 Hz, 1 H), 4.63 (dd, J = 16.9, 0.9 Hz, 1
H), 3.93 (dt, J = 11.8, 3.7 Hz, 2 H), 3.03–2.90 (m, 2 H), 2.81–2.70
(m, 2 H), 2.53–2.46 (m, 2 H).
HRMS: m/z [M]+ calcd for C17H15F2NO: 287.1122; found:
287.1127.
13C NMR (75.4 MHz, CDCl3): d = 206.8 (CO), 142.3 (C), 141.1
(C), 133.2 (C), 130.4 (CH), 128.9 (2 CH), 128.7 (2 CH), 128.6 (2
CH), 127.6 (CH), 127.3 (2 CH), 119.8 (CH2), 64.5 (CH), 63.8 (CH),
51.3 (CH2), 50.8 (CH2), 50.7 (CH2).
HRMS: m/z [M]+ calcd for C20H20ClNO: 325.1233; found:
325.1230.
meso-2,6-Bis(2-iodophenyl)piperidin-4-one (5d)
White solid; yield: 58.3 mg (63%); Rf = 0.27 (hexane–EtOAc, 6:1).
1H NMR (300 MHz, CDCl3): d = 7.86 (dd, J = 7.8, 1.2 Hz, 2 H),
7.78 (d, J = 7.8 Hz, 2 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.03 (td, J = 7.8,
2.0 Hz, 2 H), 4.41 (dd, J = 12.1, 2.4 Hz, 2 H), 2.78 (dd, J = 12.1, 2.4
Hz, 2 H), 2.46 (t, J = 12.1 Hz, 2 H).
13C NMR (75.4 MHz, CDCl3): d = 206.5 (CO), 144.0 (2 C), 139.6
(2 CH), 129.6 (2 CH), 128.8 (2 CH), 127.5 (2 CH), 98.9 (2 C), 63.7
(2 CH2), 47.8 (2 CH).
HRMS: m/z [M]+ calcd for C17H15I2NO: 502.9243; found:
502.9256.
cis-1-Allyl-2-(2-bromophenyl)-6-phenylpiperidin-4-one (4d)
Yellow oil; yield: 55 mg (15%, procedure 2); Rf = 0.53 (hexane–
EtOAc, 10:1).
1H NMR (300 MHz, CDCl3): d = 7.86 (dd, J = 7.8, 1.7 Hz, 1 H),
7.46–7 (m, 9 H), 5.79–5.56 (m, 1 H), 5.06 (dd, J = 10.2, 2.1 Hz, 1
H), 4.65 (dd, J = 17.1, 2.1 Hz, 1 H), 4.48 (dd, J = 10, 5.1 Hz, 1 H),
4.01 (dd, J = 11.7, 3.3 Hz, 1 H), 2.90 (d, J = 7.2 Hz, 2 H), 2.78 (dd,
J = 13.5, 11.8 Hz, 1 H), 2.57 (m, 2 H).
Acknowledgment
13C NMR (75.4 MHz, CDCl3): d = 206.65 (CO), 142.55 (C), 141.37
(C), 133.12 (CH), 130.78 (CH), 129.30 (CH), 128.86 (2 CH),
128.82 (CH), 128.18 (CH), 127.73 (CH), 127.38 (2 CH), 122.87
(C), 120.03 (CH2), 64.12 (CH), 62.40 (CH), 51.64 (CH2), 50.71
(CH2), 48.77 (CH2).
This research was supported by MCT-04-CTQ-2004-08077-C02-
01. FICYT doctoral fellowship to N.Q. is gratefully acknowledged.
References
MS EI (70 eV): m/z (%) = 369 [M+ Br79] (10), 371 [M+ Br81] (10),
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meso-2,6-Diarylpiperidin-4-ones 5a–d; General Procedure
Bis(tricyclohexylphosphine)benzylideneruthenium(IV) chloride (5
mol%, Grubbs’catalyst) was added in portions under argon to a so-
lution of the corresponding meso-1-allyl-2,6-diarylpiperidin-4-ones
3a,f,h,k (100 mg) in anhydrous toluene (5 mL) and the mixture was
heated at reflux for 12 h. Then, the mixture was concentrated under
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meso-2,6-Diphenylpiperidin-4-one (5a)
White solid; yield: 58 (67%); mp 102–105 °C; Rf = 0.43 (hexane–
EtOAc, 5:1).
1H NMR (300 MHz, CDCl3): d = 7.53–7.28 (m, 10 H), 4.11 (dd,
J = 10.1, 4.2 Hz, 2 H), 2.71–2.58 (m, 4 H), 2.18 (br s, 1 H).
Synthesis 2008, No. 3, 479–484 © Thieme Stuttgart · New York

484
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Synthesis 2008, No. 3, 479–484 © Thieme Stuttgart · New York